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Influence of High Altitude Exposure on the Immune System: A Review
Abstract
High altitude may be defined as elevations as low as 1500 meters to those as high as 8800 meters. Very few studies have been conducted so far at high altitude for the specific purpose of monitoring different immune parameters in humans. Military personnel and mountaineers may be required to perform in environmental extremes such as high altitude. The stressors they experience are numerous and varied, e.g., high altitude, humidity and the availability of food and water, prolonged moderate to heavy physical activities, limited or inadequate sleep, increased susceptibility to infection and injury, etc. In this article we review the immunological consequences of high altitude exposure.
... There are conflicting reports regarding how hypoxia regulates B cell populations and their function at high altitude. Several studies report that high altitude does not alter B cell population or function (Facco et al., 2005;Meehan, 1987), while others report increases in both of these parameters (Chohan et al., 1975;Feuerecker et al., 2019;Mishra & Ganju, 2010). Our findings support the conclusion that acute high-altitude exposure does increase B cell populations (Figure 1e). ...
... T lymphocyte balance has also been found to be affected by acute high-altitude hypoxia exposure (Facco et al., 2005;Feuerecker et al., 2019;Klokker et al., 1993;Meehan et al., 1988;Mishra & Ganju, 2010). Likewise, our data show that total CD3 + T cells were significantly reduced throughout high-altitude exposure, including both CD4 + T cells and CD8 + T cells (Figure 1f-h). ...
... While our study does not distinguish between specific CD4 + helper subsets (Thelper cells 1 (Th1) vs T-helper cells 2 (Th2)), previous research demonstrates that the Th1/Th2 immune balance was dysregulated at high altitude (Caldwell et al., 2001;Facco et al., 2005). Furthermore, studies have also found that T cells cultured in hypoxic conditions or collected at high altitude had significantly reduced function and proliferative response when stimulated with mitogen (PHA) (Facco et al., 2005;Klokker et al., 1993;Mishra & Ganju, 2010;Tingate et al., 1997). However, this is controversial, as conflicting studies have found no change or even increased function and cytokine production following stimulation (Caldwell et al., 2001;Feuerecker et al., 2019). ...
The immune response to acute hypoxemia may play a critical role in high‐altitude acclimatization and adaptation. However, if not properly controlled, hypoxemia‐induced inflammation may exacerbate high‐altitude pathologies, such as acute mountain sickness (AMS), or other hypoxia‐related clinical conditions. Several studies report changes in immune cell subsets at high altitude. However, the mechanisms underlying these changes, and if these alterations are beneficial or maladaptive, remains unknown. To address this, we performed multiparameter flow cytometry on peripheral blood mononuclear cells (PBMCs) collected throughout 3 days of high‐altitude acclimatization in healthy sea‐level residents (n = 20). Additionally, we conducted in vitro stimulation assays to test if high‐altitude hypoxia exposure influences responses of immune cells to subsequent inflammatory stimuli. We found several immune populations were altered at high altitude, including monocytes, T cells, and B cells. Some changes in immune cell populations are potentially correlated with AMS incidence and severity. In vitro high‐altitude PBMC cultures stimulated with lipopolysaccharide (LPS) showed no changes in pro‐inflammatory cytokine production after 1 day at high‐altitude. However, by day three pro‐inflammatory cytokine production in response to LPS decreased significantly. These results indicate that high‐altitude exposure may initiate an inflammatory response that encompasses innate immune sensitization, with adaptive immune suppression following acclimatization.
... This was consistent with our observations. Exposure to hypoxia on the other hand is less studied under normobaric conditions but more under longer-lasting high-altitude (hypobaric) hypoxia [27,41,42]. Up to date, no other study focused on the effects of LPS-induced immune activation regarding the HIF pathway nor the potential influence of hypoxic priming on immune cell regulation. ...
... Evidence suggests that high altitude-hypoxia affects blood leukocytes, for example, the redistribution of circulating T cells, but not B lymphocytes [14,41,42]. Additionally, reduced cytokine levels following prolonged exposure to high-altitude hypoxia over the course of days to weeks, particularly under unstimulated baseline conditions, have been reported [14,41]. ...
... Evidence suggests that high altitude-hypoxia affects blood leukocytes, for example, the redistribution of circulating T cells, but not B lymphocytes [14,41,42]. Additionally, reduced cytokine levels following prolonged exposure to high-altitude hypoxia over the course of days to weeks, particularly under unstimulated baseline conditions, have been reported [14,41]. Controversially, in other studies, increased IL-6 levels were measured upon hypoxia in human blood, which was interpreted as facilitating angiogenesis through the induction of VEGF and EPO [27,34,39]. ...
Cells of the immune defence, especially leukocytes, often have to perform their function in tissue areas that are characterized by oxygen deficiency, so-called hypoxia. Physiological hypoxia significantly affects leukocyte function and controls the innate and adaptive immune response mainly through transcriptional gene regulation via the hypoxia-inducible factors (HIFs). Multiple pathogens including components of bacteria, such as lipopolysaccharides (LPS) trigger the activation of leukocytes. HIF pathway activation enables immune cells to adapt to both hypoxic environments in physiological and inflammatory settings and modulates immune cell responses through metabolism changes and crosstalk with other immune-relevant signalling pathways. To study the mutual influence of both processes in vivo, we used a human endotoxemia model, challenging participants with an intravenous LPS injection post or prior to a 4-h stay in a hypoxic chamber with normobaric hypoxia of 10.5% oxygen. We analysed changes in gene expression in whole blood cells and determined inflammatory markers to unveil the crosstalk between both processes. Our investigations showed differentially altered gene expression patterns of HIF and target genes upon in vivo treatment with LPS and hypoxia. Further, we found evidence for effects of hypoxic priming upon inflammation in combination with immunomodulatory effects in whole blood cells in vivo. Our work elucidates the complex interplay of hypoxic and inflammatory HIF regulation in human immune cells and offers new perspectives for further clinical research.
... Typical and well-studied symptoms with an onset two hours after the in vivo LPS injection can include u-like symptoms with fever, myalgia, and headache [1,38,40,41]. Exposure to hypoxia on the other hand is less studied under normobaric conditions but more under longer-lasting high-altitude (hypobaric) hypoxia [29,44,45]. Up to date, no other study focused on the effects of LPS-induced immune activation regarding the HIF pathway nor the potential in uence of hypoxic priming on immune cell regulation. ...
... Evidence suggests that high altitude-hypoxia affects blood leukocytes, for examples, the redistribution of circulating T cells, but not B lymphocytes [15,44,45]. Additionally, reduced cytokine levels following prolonged exposure to high-altitude hypoxia over the course of days to weeks, particularly under unstimulated baseline conditions have been reported [15,44]. ...
... Evidence suggests that high altitude-hypoxia affects blood leukocytes, for examples, the redistribution of circulating T cells, but not B lymphocytes [15,44,45]. Additionally, reduced cytokine levels following prolonged exposure to high-altitude hypoxia over the course of days to weeks, particularly under unstimulated baseline conditions have been reported [15,44]. Controversially, in other studies increased IL-6 levels were measured upon hypoxia in human blood, which was interpreted as facilitating angiogenesis through the induction of VEGF and EPO [29,36,42]. ...
Cells of the immune defence, especially leukocytes, often have to perform their function in tissue areas that are characterized by oxygen deficiency, so called hypoxia. Physiological hypoxia significantly affects leukocyte function and controls the innate and adaptive immune response mainly through transcriptional gene regulation via the hypoxia-inducible factors (HIFs). Multiple pathogens including components of bacteria, such as lipopolysaccharides (LPS) trigger the activation of leukocytes. HIF pathway activation enables immune cells to adapt to both, hypoxic environments in physiological and inflammatory settings and modulates immune cell responses through metabolism changes and crosstalk with other immune-relevant signaling pathways. To study the mutual influence of both processes in vivo , we used a human endotoxemia model, challenging participants with an intravenous LPS injection post or prior to a 4-hour stay in a hypoxic chamber with normobaric hypoxia of 10.5 % oxygen. We analyzed changes in gene expression in whole blood cells and determined inflammatory markers to unveil the crosstalk between both processes. Our investigations showed differentially altered gene expression patterns of HIF and target genes upon in vivo treatment with LPS and hypoxia. Further, we found evidence for effects of hypoxic priming upon inflammation in combination with immunomodulatory effects in leukocytes in vivo . Our work elucidates the complex interplay of hypoxic and inflammatory HIF regulation in human immune cells and offers new perspectives for further clinical research.
... Animals in higher elevations may have smaller body extremities, such as bird beaks, for reducing heat loss (Symonds & Tattersall, 2010). Temperature, together with other environmental factors such as the oxygen level and high ultraviolet (UV) light that changes along elevation, could have also caused physiological adaptations in respiratory, cardiovascular, immune and metabolic systems (Mishra & Ganju, 2010;Scott et al., 2008;Siebenmann et al., 2017). Although these phenotypic changes imply natural selection for beneficial alleles in the corresponding genes, it is difficult to tell how the evolutionary processes actually unfolded in wild populations. ...
... Altitudinal adaptation may also involve physiological changes such as those in respiratory and cardiovascular systems to survive in the hypoxia condition of high elevation. In addition, UV light intensity and low temperature in montane areas could induce changes in immune and metabolic systems (Mishra & Ganju, 2010;Scott et al., 2008;Siebenmann et al., 2017). Because of these features, the rufous-capped babbler is thus a valuable system for examining the molecular mechanism and structural genomic variations underlying the altitudinal adaptation of animals during their initial stages of ecological divergence. ...
... We also found regulatory target genes functioning to modulate the IgG2a level and the pre-B cell number. In fact, the amounts of immunoglobulins (e.g., IgA, IgM, and IgG) and B cells alter in humans when they experience elevational change (Mishra & Ganju, 2010). Our findings echo previous studies which found selection signals in or varying copy numbers of immune genes across elevations in songbirds and chickens (Qu et al., 2013;Zhang et al., 2016). ...
Organisms often acquire physiological and morphological modifications to conquer ecological challenges when colonizing new environments which lead to their adaptive evolution. However, deciphering the genomic mechanism of ecological adaptation is difficult because ecological environments are often too complex for straightforward interpretation. Thus, we examined the adaptation of a widespread songbird-the rufous-capped babbler (Cyanoderma ruficeps)-to a relatively simple system: distinct environments across elevational gradients on the mountainous Taiwan island. We focused on the genomic sequences of 43 birds from five populations to show that the Taiwan group split from its sister group in mainland China around 1-2 Ma and colonized the montane habitats of Taiwan at least twice around 0.03-0.22 Ma. The montane and lowland Taiwan populations diverged with gene flow between them, suggesting strong selection associated with different elevations. We showed that the montane babblers had smaller beaks than the lowland ones, consistent with Allen's rule, and identified candidate genes-COL9A1 and SOX11-underlying the beak size changes. We also found that altitudinally divergent mutations were mostly located in non-coding regions and tended to accumulate in chromosomal inversions and autosomes. The altitudinally divergent mutations might regulate genes related to hematopoietic, metabolic, immune, auditory and vision functions as well as cerebrum morphology and plumage development. The results decode the genomic bases of morphological and physiological adaptation in this species to the low temperature, hypoxia and high UV light environment in high elevation. These findings improve our understanding of how ecological adaptation drives population divergence from the perspective of genomic architecture.
... High-altitude (defined as >2,500 m above mean sea level) hypoxia (HAH) readily results in a pathological state compared with the normal state in mammals, affecting the entire body, including lung (Hotta et al., 2004), brain (Kapoor, 2013), mesentery (Kotwal et al., 2015), peripheral vessels (Kotwal et al., 2007), and retina (Bhende et al., 2013). Usually, HAH affects the function of the immune system, decreasing the release of cytokines and increasing the vulnerability of the human body to infection and disease (Mishra and Ganju, 2010). Similarly, a significant effect of HAH for cows that are not native to HAH is the elevation of pulmonary arterial pressure (Yuan and Xie, 2005), particularly for those rapidly transported from plain to plateau. ...
... A previous study showed that HAH influences the function of the immune system, increasing the vulnerability to infection and disease (Mishra and Ganju, 2010). High-altitude hypoxia can decrease the release of cytokines and variably affect immunoglobulin secretion at different altitudes and durations (Mishra and Ganju, 2010). ...
... A previous study showed that HAH influences the function of the immune system, increasing the vulnerability to infection and disease (Mishra and Ganju, 2010). High-altitude hypoxia can decrease the release of cytokines and variably affect immunoglobulin secretion at different altitudes and durations (Mishra and Ganju, 2010). In the present study, the level of serum IgM decreased significantly, whereas levels of IgG and IgA were not significantly changed. ...
Blood has been widely collected and analyzed for diagnosing and monitoring diseases in humans and animals; a range of plasma proteins and peptide can be used as biomarkers to describe pathological or physiological status. Changes in the environment such as high-altitude hypoxia (HAH) can lead to adaptive changes in the blood system of mammals. However, the adaptation mechanism induced by HAH remains unclear. In this study, we used 12 multiparous Jersey cattle (400 ± 35 kg, average 3 yr old, dry period). We applied an iTRAQ (isobaric tags for relative and absolute quantitation) proteomics approach and microRNA (miRNA) microarray to explore differences in the plasma proteomic and miRNA profiles of Jersey cattle exposed to HAH conditions in Nyingchi, Tibet (altitude 3,000 m) and HAH-free conditions in Shenyang, China (altitude 50 m). Such quantitative proteomic strategies are suitable for accurate and comprehensive prediction of miRNA targets. In total, 264 differentially expressed proteins (127 upregulated, fold-change >1.2; 137 downregulated, fold-change <0.8) and 47 differential miRNAs (25 upregulated, fold-change >2; 22 downregulated, fold-change <0.5) were observed in the HAH-stressed group compared with the HAH-free group. Integrative analysis of proteomic and miRNA profiles demonstrated that the biological processes associated with differentially expressed proteins were immune response, complement system, and conjugation system. Integrative analysis of canonical pathways showed that most were associated with acute phase response signaling (z-score = −0.125), liver X receptor/retinoid X receptor (LXR/RXR) activation pathway (z-score = 1.134), coagulation system (z-score = −0.943), and complement system (z-score = −0.632). The current results indicated that Jersey cattle exposed to HAH could adapt to that condition through regulation of inflammatory homeostasis by inhibiting the acute phase response, coagulation system, and complement system and promoting LXR/RXR activation.
... High altitudes negatively impact the normal bodily functions of individuals, whether they are accustomed or unaccustomed to such environments. Mishra and Ganju (2010) reviewed environmental factors at high altitudes, such as cold and hypobaric hypoxia, which affect the immune system, making it more susceptible to conditions like cancer, infections, and autoimmune diseases (Mishra and Ganju, 2010). Inadequate hypoxia management affects reproduction and fertility traits, including reduced intrauterine growth in sheep (Parraguez et al., 2005) and impaired development and function of the corpus luteum (Parraguez et al., 2013). ...
... High altitudes negatively impact the normal bodily functions of individuals, whether they are accustomed or unaccustomed to such environments. Mishra and Ganju (2010) reviewed environmental factors at high altitudes, such as cold and hypobaric hypoxia, which affect the immune system, making it more susceptible to conditions like cancer, infections, and autoimmune diseases (Mishra and Ganju, 2010). Inadequate hypoxia management affects reproduction and fertility traits, including reduced intrauterine growth in sheep (Parraguez et al., 2005) and impaired development and function of the corpus luteum (Parraguez et al., 2013). ...
Yaks, native to high-altitude regions, exhibit remarkable adaptations to the challenging environments they inhabit. Over generations, these robust animals have evolved various physiological, morphological, biochemical, and genetic traits through natural selection. These adaptations allow them to thrive in conditions characterized by low temperatures and oxygen pressure. Notable features include their thick, insulating coats, efficient respiratory systems, and specialized metabolism suited for high-altitude forage. Such unique evolutionary adjustments enable yaks to navigate the harsh terrains and limited resources of their high-altitude habitats, showcasing their exceptional resilience and suitability to these challenging ecosystems. Through extensive selective pressures over time, yaks have developed stable and distinctive genetic traits that facilitate their physiological, biochemical, and morphological adaptations to high-altitude environments. Consequently, yaks serve as a representative model for investigating mammalian adaptability to plateaus. The comprehension of these adaptive mechanisms offers unparalleled insights into evolutionary adaptations, with direct implications for the selective breeding of domesticated yaks. This review provides a comprehensive overview of the genetic adaptations in yak to the rigors of high-altitude environmental stress. Advances in genomics and theoretical frameworks have collectively illuminated the genetic underpinnings of high-altitude adaptations.
... By adding obesity and COVID-19, a summative effect with an extremely exaggerated immune response can be supposed. Chronic high-altitude exposure can inhibit the immune system, changing the quantity and functionality of immune cells [68][69][70]. The sympatho-adrenal axis may play a role in the immune adaptations at high altitude [71]. ...
... The sympatho-adrenal axis may play a role in the immune adaptations at high altitude [71]. Prolonged exposure to high altitudes may stimulate the innate immune system while suppressing cell-mediated immunity (Th1) [70,72,73]. Studies carried out at 2850 m above sea level examined the expression pattern of microRNAs and mRNAs associated with inflammation in T2D monocytes and found that the inflammatory state was reduced even if the patients' lipid profiles were aberrant, and their BMI were higher [74] with less inflammation in obese T2D patients when compared with Dutch T2D patients who live at sea level [75]. ...
Background:
Obesity is a common chronic comorbidity of patients with COVID-19, that has been associated with disease severity and mortality. COVID-19 at high altitude seems to be associated with increased rate of ICU discharge and hospital survival than at sea-level, despite higher immune levels and inflammation. The primary aim of this study was to investigate the survival rate of critically ill obese patients with COVID-19 at altitude in comparison with overweight and normal patients. Secondary aims were to assess the predictive factors for mortality, characteristics of mechanical ventilation setting, extubation rates, and analytical parameters.
Methods:
This is a retrospective cohort study in critically ill patients with COVID-19 admitted to a hospital in Quito-Ecuador (2,850 m) from Apr 1, 2020, to Nov 1, 2021. Patients were cathegorized as normal weight, overweight, and obese, according to body mass index [BMI]).
Results:
In the final analysis 340 patients were included, of whom 154 (45%) were obese, of these 35 (22.7%) were hypertensive and 25 (16.2%) were diabetic. Mortality in obese patients (31%) was lower than in the normal weight (48%) and overweight (40%) groups, but not statistically significant (p = 0.076). At multivariable analysis, in the overall population, older age (> 50 years) was independent risk factor for mortality (B = 0.93, Wald = 14.94, OR = 2.54 95%CI = 1.58-4.07, p < 0.001). Ferritin and the neutrophil/lymphocyte ratio were independent predictors of mortality in obese patients. Overweight and obese patients required more positive and-expiratory pressure compared to normal-weight patients. In obese patients, plateau pressure and mechanical power were significantly higher, whereas extubation failure was lower as compared to overweight and normal weight.
Conclusions:
This preliminary study suggests that BMI was not associated with mortality in critically ill patients at high altitude. Age was associated with an increase in mortality independent of the BMI. Biomarkers such as ferritin and neutrophils/lymphocytes ratio were independent predictors of mortality in obese patients with COVID-19 at high altitude.
... The effect of high altitude on the immune system was not thoroughly investigated in humans (Mishra and Ganju, 2010), and the studies conducted thus far raise a complex and not always coherent picture. While some studies indicate immune suppression at high altitude, others point toward increase in the pro-inflammatory response (Pham et al., 2021;Wang et al., 2021). ...
... Sustained hypoxia, a major factor in the pathophysiology of mountain sickness, was shown to modulate the immune response in animal models, including exacerbation of inflammatory responses. The crosstalk between hypoxia and inflammation is implicated in various morbidities such as chronic obstructive pulmonary disease and obstructive sleep apnea, as well as cardiovascular diseases (Kammerer et al., 2020;Liu et al., 2017;Mishra and Ganju, 2010). Our digital cytometry analysis shows an altitude-and time-dependent increase in M2 macrophages and monocytes but an altitude-dependent decrease in NK and regulatory T cells. ...
High altitude exposes humans to hypobaric hypoxia, which induces various physiological and molecular changes. Recent studies point toward interaction between circadian rhythms and the hypoxic response, yet their human relevance is lacking. Here, we examine the effect of different high altitudes in conjunction with time of day on human whole-blood transcriptome upon an expedition to the highest city in the world, La Rinconada, Peru, which is 5,100 m above sea level. We find that high altitude vastly affects the blood transcriptome and, unexpectedly, does not necessarily follow a monotonic response to altitude elevation. Importantly, we observe daily variance in gene expression, especially immune-related genes, which is largely altitude dependent. Moreover, using a digital cytometry approach, we estimate relative changes in abundance of different cell types and find that the response of several immune cell types is time- and altitude dependent. Taken together, our data provide evidence for interaction between the transcriptional response to hypoxia and the time of day in humans.
... A large variety of interventions are known to boost the immune system 17 , e.g., exercise 21 , influenza vaccination 22 , cholera vaccination 23 , exposure to low-level radiation 24 , radon spa therapy 25 , fruitvegetable diet 26 , reducing red meat in diet 27 , aspirin 28 , statins 29 , smoking cessation 30 , rhythmic breathing 31 , Vitamin D supplementation 32 , hyperthermia 33 , and living at a high elevation 34 . In the cited studies, different interventions have been observed to enhance different aspects of the immune system, and some aspects of the immune system were not enhanced by some of the interventions. ...
... For example, as reported in a compilation of the effects of exercise on the aging immune system 35 , whereas some of the studies showed enhancement of NK-cell cytotoxicity, T-cell proliferation, IFN-γ, CD4+ T-cell counts, or CD8+ T-cell counts following the interventions, other studies did not show increase in these aspects. Another example is that the interventions of rhythmic breathing 31 and living at a high elevation 34 increased the NK-cell numbers but exercise in breast cancer survivors 21 and radon spa therapy 25 did not. In addition to such reported variability in the average responses to the different immune boosting interventions, the nature of the immune system response in any particular individual may also depend on the individual's gender, age, the intensity and frequency of the interventions, genetic factors, etc. ...
Cancer risk is known to increase tremendously when the immune system is suppressed, e.g., as observed in young organ-transplant recipients and AIDS patients. Based on such data, it may be hypothesized that the main reason for the development of clinical cancer is the weakening or suppression of the immune system, and that uncontrolled multiplication of cancer cells occurs when some aspects of the immune system fall below certain critical levels. Therefore, cancer may be prevented and treated by boosting these critical aspects of the immune system so that they are maintained above the critical levels. If multiple immune system boosting interventions are utilized, more aspects of the immune system would be boosted, increasing the likelihood of enhancing the critical aspects of the immune system and generating a cancer preventive and/or therapeutic effect. Clinical trials are needed to validate this approach for cancer prevention and treatment. If validated, the proposed approach could result in a major reduction of the death and suffering caused by cancer in the world.
... High-altitude (defined as 8000 ft above sea level) hypoxia (HAH) continuously affect physical and mental performances of people and animals [1]. HAH affects the immune system, makes the human body more susceptible to various infectious and autoimmune diseases [2], and decreases the production of cytokines [3]. Additionally, hypoxia is associated with the homeostasis and metabolic rate of adult tissues [4]. ...
... IL, interleukin; TNF-α, tumor necrosis factor-α.2 SL, Holstein dairy cows fed for 30 d in Shenyang, Liaoning (50 m above sea level; SL group); HA, Holstein dairy cows fed for 30 d in Nyingchi, Tibet (3000 m above sea level; HA group). ...
Simple Summary
Blood has been widely collected and analyzed for diagnosing and monitoring diseases in human beings and animals. A range of plasma proteins and peptides were set as biomarkers for pathological and physiological status. Previous researchers have explored how humans, pigs, dogs, and horses adapt to hypoxia at high altitudes. Additionally, the mechanism of hypoxia adaptation in human, mice, and shrimp was studied by proteomics. However, information on the adaptation mechanism of Holstein cows introduced to high altitudes is limited. The present study was conducted to the adaptation mechanism of Holstein dairy cows to high-altitude hypoxia by miRNA microarray analysis and the isobaric tags for relative and absolute quantitation (iTRAQ) iTRAQ technology. Based on the obtained results, Holstein dairy cows transported to Nyingchi may adapt to the high-altitude hypoxia through regulation of inflammatory homeostasis by up-regulating the acute phase response (APR) APR and activation of the liver X receptor/retinoid X receptor (LXR/RXR)LXR/RXR and farnesoid X receptor/ retinoid X receptor (FXR/RXR) FXR/RXR pathways.
Abstract
Changes in the environment such as high-altitude hypoxia (HAH) high-altitude hypoxia can lead to adaptive changes in the blood system of mammals. However, there is limited information about the adaptation of Holstein dairy cows introduced to high-altitude areas. This study used 12 multiparous Holstein dairy cows (600 ± 55 kg, average three years old) exposed to HAH conditions in Nyingchi of Tibet (altitude 3000 m) and HAH-free conditions in Shenyang (altitude 50 m). The miRNA microarray analysis and iTRAQ proteomics approach (accepted as more suitable for accurate and comprehensive prediction of miRNA targets) were applied to explore the differences in the plasma proteomic and miRNA profiles in Holstein dairy cows. A total of 70 differential miRNAs (54 up-regulated, Fold change (FC) FC > 2, and 16 down-regulated, FC < 0.5) and 226 differential proteins (132 up-regulated, FC > 1.2, and 94 down-regulated, FC < 0.8) were found in the HAH-stressed group compared with the HAH-free group. Integrative analysis of proteomic and miRNA profiles demonstrated the biological processes associated with differential proteins were the immune response, complement activation, protein activation, and lipid transport. The integrative analysis of canonical pathways were most prominently associated with the APR signaling (z = 1.604), and LXR/RXR activation (z = 0.365), and FXR/RXR activation (z = 0.446) pathways. The current results indicated that Holstein dairy cows exposed to HAH could adapt to high-altitude hypoxia by up-regulating the APR, activating the LXR/RXR and FXE/RXR pathways.
... High-altitude environmental factors (such as UV exposure, cold and hypobaric hypoxia) can affect the immune system and increase susceptibility to cancer, various infections, and even autoimmune disease [83]. BPI and LBP were identified in the selection signatures of GJ. ...
Background
To solve the problem of an insufficient supply of dairy products in Tibet, work has been carried out to improve native dairy cattle and introduce purebred dairy cattle from low-altitude areas. The harsh environment of the plateau not only severely limits the production performance of high-yielding dairy cattle, such as Holstein and Jersey cattle, but also challenges their survival. The population structure and plateau adaptation mechanism of plateau dairy cattle are rarely reported. In this study, key genes and pathways affecting plateau purebred and crossbred dairy cattle were explored using genetic chip information.
Results
The results showed that the genetic diversity of the Tibet dairy cattle population was higher than that of the native cattle and plains dairy cattle. Purebred Holstein and Jersey cattle in Tibet were genetically closer to dairy cattle in the plains, and crossbred dairy cattle were admixed with more Tibet cattle and Apaijiza cattle. Based on the fixation index (FST), integrated haplotype score (iHS), and cross-population extend haplotype homozygosity (XP-EHH) approaches, 60 and 40 genes were identified in plateau Holstein and Jersey cattle, respectively. A total of 78 and 70 genes were identified in crossbred cattle compared to Holstein and Tibet cattle respectively. These genes are related to cardiac health and development, neuronal development and function, angiogenesis and hematopoietic, pigmentation, growth and development, and immune response.
Conclusions
Our results provide a glimpse into diverse selection signatures in plateau dairy cattle, which can be used to enhance our understanding of the genomic basis of plateau adaptation in dairy cattle. These results support further research on breeding strategies such as marker-assisted selection and gene editing in plateau dairy cattle populations.
... High-altitude environments pose unique challenges, including hypobaric hypoxia, cold stress, and oxidative stress, which weaken the immune system and increase disease susceptibility (Mishra, 2010). These conditions also impair normal physiological functions, including reproduction and fecundity (Parraguez, 2005). ...
Yaks are indispensable to high-altitude communities, providing essential resources such as milk, meat, and transportation. However, their reproductive efficiency is influenced by a multitude of factors, including climate change, nutrition, genetics, and physiology. This review synthesizes current knowledge on the aspects and factors affecting yak reproduction, with a focus on high-altitude ecosystems. An in-depth literature analysis reveals that climate change, nutritional deficiencies, and genetic factors impact yak fertility. The review also depicts the importance of mineral supplements, particularly calcium and phosphorus, in maintaining reproductive health. These findings have pivotal implications for developing strategies to enhance yak reproductive performance, ensuring the sustainability of yak herding in high-altitude regions. Certainly, this review contributes to a deeper understanding of the complex interplay between environmental, nutritional, and genetic factors influencing yak reproductive biology.
... Acute hypoxia will lead to a cascade of physiological changes that affect multiple systems in the body. In severe cases, it can result in high-altitude pulmonary edema (HAPE), high-altitude cerebral edema (HACE) and high-altitude pulmonary hypertension [1,2]. Acute exposure to hypoxia conditions can have a less-favorable physiological effect on the human immune system. ...
A high-altitude, low-pressure hypoxic environment has severe effects on the health and work efficiency of its residents, and inadequate preventive measures and adaptive training may lead to the occurrence of AMS. Acute exposure to hypoxia conditions can have a less-favorable physiological effect on the human immune system. However, the regulation of the immune system in high-altitude environments is extremely complex and remains elusive. This study integrated system bioinformatics methods to screen for changes in immune cell subtypes and their associated targets. It also sought potential therapeutically effective natural compound candidates. The present study observed that monocytes, M1 macrophages and NK cells play a crucial role in the inflammatory response in AMS. IL15RA, CD5, TNFSF13B, IL21R, JAK2 and CXCR3 were identified as hub genes, and JAK2 was positively correlated with monocytes; TNFSF13B was positively correlated with NK cells. The natural compound monomers of jasminoidin and isoliquiritigenin exhibited good binding affinity with JAK2, while dicumarol and artemotil exhibited good binding affinity with TNFSF13B, and all are expected to become a potential therapeutic agents.
... High-altitude environmental factors, such as hypobaric hypoxia, UVR, and low temperatures, can affect an animal's immune system [68]. Moreover, high-altitude adaptation correlated neatly with activation of the immune system, for example, up-regulated genes in high altitudedwelling species were significantly enriched in the immunity pathway compared to their low-altitude counterparts [69]. ...
Background
Organisms have evolved a range of phenotypic and genetic adaptations to live in different environments along an altitudinal gradient. Herein, we studied the widely distributed Chinese toad, Bufo gargarizans, as a model and used an integrated phenotype-genotype approach to assess adaptations to different altitudinal environments.
Results
Comparison of populations from four altitudes (50 m, 1200 m, 2300 m, and 3400 m) showed more effective defenses among high-altitude toads. These included thickened epidermis, more epidermal capillaries and granular glands, greater gland size in skin, and higher antioxidant enzyme activities in plasma. High-altitude toads also showed increased erythrocytes and hematocrit and elevated hemoglobin concentration, potentially improving oxygen delivery. Elevated altitude led to a metabolic shift from aerobic to anaerobic metabolism, and high-altitude populations favored carbohydrates over fatty acids to fuel for energy metabolism. Differentially expressed genes were associated with adaptive phenotypic changes. For instance, expression of genes associated with fatty acid metabolism showed greater suppression at high altitude (3400 m), consistent with decreased flux of β-hydroxybutyric acid and lower free fatty acids levels. Moreover, down-regulation of genes involved in carbon metabolism processes at high altitude (3400 m) were coincident with reduced TCA cycle flux. These results suggest that high-altitude toads adopt a metabolic suppression strategy for survival under harsh environmental conditions. Moreover, the hypoxia-inducible factor signaling cascade was activated at high altitude.
Conclusions
Collectively, these results advance our comprehension of adaptation to high-altitude environments by revealing physiological and genetic mechanisms at work in Chinese toads living along altitudinal gradients.
... To systematically study the effects of exercise with different intensity on the physiological acclimatization of HA lowlanders, the present study implemented exercise interventions with low-, 2 -SU ET AL. medium-, and high-intensity performed by young lowlanders who had lived at HA for more than 2 years. This was followed by measuring the cardiovascular function, O 2 transport of red blood cells, renal function (Palubiski et al., 2020), and immune function (Mishra & Ganju, 2010;Pham et al., 2021), given the reports of their association with HA acclimatization. Based on accumulated evidence, hypotheses are made as follows: (H1) LI aerobic exercise does not cause changes in physiological performance; (H2) MI aerobic exercise can improve O 2 transport capacity but not alter the blood viscosity; (H3) HI aerobic exercise can also improve O 2 transport capacity, but increase the blood viscosity, renal, and immune response. ...
This study investigates whether exercise as a strategy for improving physical fitness at sea level also offers comparable benefits in the unique context of high altitudes (HA), considering the physiological challenges of hypoxic conditions. Overall, 121 lowlanders who had lived on the Tibetan Plateau for >2 years and were still living at HA during the measurements were randomly classified into four groups. Each individual of the low‐intensity (LI), moderate‐intensity (MI), and high‐intensity (HI) groups performed 20 sessions of aerobic exercise at HA (3680 m) over 4 weeks, while the control group (CG) did not undergo any intervention. Physiological responses before and after the intervention were observed. The LI and MI groups experienced significant improvement in cardiopulmonary fitness (0.27 and 0.35 L/min increases in peak oxygen uptake [V˙ O2peak], both p < 0.05) after exercise intervention, while the hematocrit (HCT) remained unchanged (p > 0.05). However, HI exercise was less efficient for cardiopulmonary fitness of lowlanders (0.02 L/min decrease in V˙ O2peak, p > 0.05), whereas both the HCT (1.74 %, p < 0.001) and glomerular filtration rate (18.41 mL/min, p < 0.001) increased with HI intervention. Therefore, LI and MI aerobic exercise, rather than HI, can help lowlanders in Tibet become more acclimated to the HA by increasing cardiopulmonary function and counteracting erythrocytosis.
... Cytokines play a central role in the immune response by promoting the activation of antigen-specific and nonspecific effector mechanisms and tissue repair. Cytokines are important immune response modulators that may be affected by exposure to high altitude [28]. For example, hypobaric hypoxia causes an inflammatory response through the release of cytokines [29]. ...
Rumen metabolism is closely related to feed utilization and the environmental adaptability of cows. However, information on the influence of altitude on ruminal metabolism is limited. Our study aimed to investigate differences in rumen metabolism and blood biochemical indicators among Sanhe heifers residing at various altitudes. A total of 20 serum and ruminal fluid samples were collected from Sanhe heifers in China, including those from Hulunbeier City (approximately 700 m altitude; 119°57′ E, 47°17′ N; named LA) and Lhasa City (approximately 3650 m altitude; 91°06′ E, 29°36′ N; named HA). Compared with LA heifers, HA heifers had higher levels of serum cortisol, glucose, and blood urea nitrogen (p < 0.05) and lower Ca2+ concentrations (p < 0.05). Using liquid chromatography–mass spectrometry (LC–MS)-based untargeted metabolomic technology, we identified a significant difference in 312 metabolites between the LA and HA groups. Metabolic pathway analysis, based on significantly different rumen metabolites, identified 20 enriched metabolic pathways within hierarchy III, which are encompassed within 6 broader metabolic pathways in hierarchy I. This study constitutes the first elucidation of the altitudinal adaptation mechanism of ruminants from the perspective of rumen metabolism, thereby offering a novel angle for investigating high-altitude adaptation in both humans and animals.
... Thus, a significant number of regulatory T cells and immunosuppressive myeloid subpopulations, including M2 macrophages and type 2 dendritic cells with low HLA-DR expression, were found in tumor regions with high hypoxia [34]. The proliferation of T-cells is suppressed during a long stay in high-altitude conditions [35]. We investigated the distribution of CD45-negative and CD45-positive erythroid cells within each stage of differentiation under normal and hypoxic conditions. ...
Hypoxia leads to metabolic changes at the cellular, tissue, and organismal levels. The molecular mechanisms for controlling physiological changes during hypoxia have not yet been fully studied. Erythroid cells are essential for adjusting the rate of erythropoiesis and can influence the development and differentiation of immune cells under normal and pathological conditions. We simulated high-altitude hypoxia conditions for mice and assessed the content of erythroid nucleated cells in the spleen and bone marrow under the existing microenvironment. For a pure population of CD71+ erythroid cells, we assessed the production of cytokines and the expression of genes that regulate the immune response. Our findings show changes in the cellular composition of the bone marrow and spleen during hypoxia, as well as changes in the composition of the erythroid cell subpopulations during acute hypoxic exposure in the form of a decrease in orthochromatophilic erythroid cells that are ready for rapid enucleation and the accumulation of their precursors. Cytokine production normally differs only between organs; this effect persists during hypoxia. In the bone marrow, during hypoxia, genes of the C-lectin pathway are activated. Thus, hypoxia triggers the activation of various adaptive and compensatory mechanisms in order to limit inflammatory processes and modify metabolism.
... Apparently, this finding is due to the physiological changes that occur in the respiratory system depending on the altitude, such as the alteration of the nasal mucociliary transport, nasal congestion, and alteration of the epithelium, that favor colonization by (26) microorganisms and the development of the disease . The previous anatomical and physio pathological changes related to higher altitude could potentially lead to hypoxemia, associated with functional alteration of phagocytic cells, natural killer lymphocytes and T-lymphocytes and reduce production of IL-6, tumor necrosis (27) factor α and IL-10 . ...
Objetivo. Estimar la proporción de muertes en los casos confirmados según las categorías de altitud (baja, media y alta) y evaluar una posible asociación entre el grado de altitud y la mortalidad por COVID-19 en Colombia, durante las dos primeras olas de la epidemia. Métodos. Estudio de corte transversal, analítico. La población de estudio fueron adultos residentes en Colombia durante 2020, con confirmación microbiológica de infección por SARS-CoV-2. Se calculó la tasa de letalidad utilizando un intervalo de confianza binomial, dividiendo la altitud en tres categorías. También se realizó un modelo de regresión logística para evaluar la asociación entre la altitud y la mortalidad por COVID-19. Resultados. Se analizaron los datos de casos confirmados de COVID-19 durante el periodo comprendido entre el 06 de marzo de 2020 y el 15 de diciembre de 2020, reportados en 1.112 municipios de Colombia. Se notificaron un total de 994.738 casos confirmados, incluidas 32.034 muertes (0,03%). La edad media de los casos fue de 39,8 años y 504.476 (50,4%) eran varones. El rango de altitud varió entre 0 m y 3.350 m. La tasa de letalidad estimada fue de 0,042 (IC 95% 0,042 - 0,043; valor de p <0,001); 0,027 (IC 95% 0,027 - 0,028; valor de p <0,001) y 0,026 (IC 95% 0,025 - 0,026; valor de p <0,001) para altitud baja, media y alta, respectivamente. Encontramos que, por cada km de aumento de altitud, la probabilidad de morir por COVID-19 disminuye un 20% (OR 0,8; IC 95% 0,785 - 0,815; valor de p <0,001), controlando por variables como sexo biológico, edad y número de habitantes por municipio. Conclusiones. Nuestros resultados demuestran que la altitud es un potencial factor protector frente a la mortalidad por COVID-19 de acuerdo con datos de población colombiana, durante las primeras dos olas de la pandemia.
... The liver is not only a major metabolic organ, but also an important mediator of immune function, playing an important role in the defense of Tibetan pigs against viral and bacterial infections in the highland environment. It has been found that the extreme environment of high altitude affects the function of the immune system and makes it more susceptible to viral infections and organismal damage [39,40]. SNT and LZT live at a higher altitude, which greatly increases their degree of liver damage. ...
In this study, the differences in protein profiles between the livers of Shannan Tibetan pigs (SNT), Linzhi Tibetan pigs (LZT) and Jiuzhaigou Tibetan pigs (JZT) were comparatively analyzed by tandem mass spectrometry-labeling quantitative proteomics. A total of 6804 proteins were identified: 6471 were quantified and 1095 were screened as differentially expressed proteins (DEPs). Bioinformatics analysis results show that, compared with JZT livers, up-regulated DEPs in SNT and LZT livers mainly promoted hepatic detoxification through steroid hormone biosynthesis and participated in lipid metabolism to maintain body energy homeostasis, immune response and immune regulation, while down-regulated DEPs were mainly involved in lipid metabolism and immune regulation. Three proteases closely related to hepatic fatty acid oxidation were down-regulated in enzymatic activity, indicating higher levels of lipid oxidation in SNT and LZT livers than in JZT livers. Down-regulation of the expression of ten immunoglobulins suggests that JZT are more susceptible to autoimmune diseases. It is highly likely that these differences in lipid metabolism and immune-related proteins are in response to the ecological environment at different altitudes, and the findings contribute to the understanding of the potential molecular link between Tibetan pig livers and the environment.
... A large population visit to high-altitude areas above 9000 ft for various purposes such as pilgrimage, trekking, mountaineering, and safeguarding the country. Upon rapid ascent, many of them may suffer with high-altitude illnesses like acute mountain sickness (AMS) or life-threatening high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE) due to low oxygen availability and low barometric pressure (Mishra and Ganju 2010;Mishra et al. 2016;Khanna et al. 2017;Basnayat 2014). The symptoms of mountain sickness may include headache, nausea or vomiting, fatigue, and dizziness or light-headedness. ...
When sojourners visit to high altitude, various symptoms may appear in the body including gastrointestinal symptoms such as poor appetite or nausea, vomiting, and incapacitating. The gastrointestinal tract is a key organ involved in the development of acute mountain sickness (AMS). The intestinal epithelial lining is covered by mucus layer. Mucosal barrier is considered as first line of protection of the gut wall which not only helps in lubricating and facilitating progression of bolus but also protects intestinal epithelial lining. Gut microbes play a major role in alterations of mucus barrier and may have important role in curtailing gastrointestinal symptoms at high altitude. In our previous study, we have reported ~ 17% decrease in Akkermansia muciniphila bacteria under hypobaric hypoxia exposure in Sprague–Dawley rats. A. muciniphila is a mucin-degrading bacterium. Its presence in the human intestine is inversely associated to a number of diseases. A. muciniphila is found in the mucus layer, where it helps to maintain intestinal integrity and protects from various inflammatory diseases. Hypoxia decreases A. muciniphila bacterium in gut leading to gastrointestinal barrier injury. It could be an important probiotic that may have physiological benefits in high-altitude hypoxia induced clinical scenarios. A large-scale clinical experiments, production feasibility, and regulatory clearances need to be resolved to develop it as next generation probiotic. In this review, we have searched various databases including PubMed and Google Scholar with keywords Akkermansia muciniphila, A. muciniphila, human physiology, etc. to comprehensively highlight the importance of this gut bacterium.
Key points
• High-altitude hypoxia leads to gastrointestinal barrier injury.
• Hypoxia decreases Akkermansia muciniphila bacterium in gut.
• A. muciniphila as probiotic may help to maintain intestinal integrity.
... In the present study, lower CD19 + B cells existing in altitude population might impair their immune system. NK-cell is an important mediator in immunity, and is enhanced in humans exposed to high altitude [43]. Mishra et al. [44] revealed that the percentage of NK cells (CD16/56) was upregulated in hypoxia exposure, consistent with our finding, suggesting NK cells can adapt to the hypoxic environment. ...
Background:
Tibetans have lived at very high altitudes for thousands of years, and have a distinctive suite of physiological traits that enable them to tolerate environmental hypoxia. Expanding awareness and knowledge of the differences in hematology, hypoxia-associated genes, immune system of people living at different altitudes and from different ethnic groups may provide evidence for the prevention of mountain sickness.
Method:
Ninety-five Han people at mid-altitude, ninety-five Tibetan people at high-altitude and ninety-eight Han people at high-altitude were recruited. Red blood cell parameters, immune cells, the contents of cytokines, hypoxia-associated gene single nucleotide polymorphisms (SNPs) were measured.
Results:
The values of Hematocrit (HCT), Mean cell volume (MCV) and Mean cell hemoglobin (MCH) in red blood cell, immune cell CD19+ B cell number, the levels of cytokines Erb-B2 receptor tyrosine kinase 3 (ErbB3) and Tumor necrosis factor receptor II (TNF-RII) and the levels of hypoxia-associated factors Hypoxia inducible factor-1α (HIF-1α), Hypoxia inducible factor-2α (HIF-2α) and HIF prolyl 4-hydroxylase 2 (PHD2) were decreased, while the frequencies of SNPs in twenty-six Endothelial PAS domain protein 1 (EPAS1) and Egl-9 family hypoxia inducible factor 1 (EGLN1) were increased in Tibetan people at high-altitude compared with that of Han peoples at high-altitude. Furthermore, compared with mid-altitude individuals, high-altitude individuals showed lower blood cell parameters including Hemoglobin concentration (HGB), HCT, MCV and MCH, higher Mean cell hemoglobin concentration (MCHC), lower immune cells including CD19+ B cells, CD4+ T cells and CD4/CD8 ratio, higher immune cells containing CD8+ T cells and CD16/56NK cells, decreased Growth regulated oncogene alpha (GROa), Macrophage inflammatory protein 1 beta (MIP-1b), Interleukin-8 (IL-8), and increased Thrombomodulin, downregulated hypoxia-associated factors including HIF1α, HIF2α and PHD2, and higher frequency of EGLN1 rs2275279.
Conclusions:
These results indicated that biological adaption to hypoxia at high altitude might have been mediated by changes in immune cells, cytokines, and hypoxia-associated genes during the evolutionary history of Tibetan populations. Furthermore, different responses to high altitude were observed in different ethnic groups, which may provide a useful knowledge to improve the protection of high-altitude populations from mountain sickness.
... People with high alcohol intake have higher LYMPH# (49) . However, this physiological indicator has not been adequately studied in high-altitude environments, and the underlying mechanisms remain uncertain (50) . According to one empirical study, LYMPH# was elevated when participants reached high altitudes, but no consistent conclusion was obtained. ...
Background: Although dietary patterns of highlander have been widely investigated, no study has explored the relationship between dietary patterns and physical examination indicators in high-altitude migrants. This cross-sectional study aimed to investigate the relationship between dietary and physiological indexes and explore the suitable dietary patterns of Tibetan migrants.
Methods: 116 participants who had migrated to Tibet for > 2 years were recruited. Dietary patterns and physical examination indicators were assessed using a self-adjusted food frequency questionnaire and blood gas analysis, and six principal dietary patterns were obtained using principal component analysis.
Results: The following results were obtained: adherence to a coarse grain dietary pattern was positively associated with mean corpuscular hemoglobin concentration (odds ratio (OR) = 1.077, p = 0.054) and negatively associated with urea level (OR = 0.601, p = 0.013). High meat dietary pattern is positively associated with creatinine level (OR = 1.050, p = 0.023) but negatively associated with glomerular filtration rate (OR = 0.960, p = 0.020). Adherence to the beverage dietary pattern was positively associated with uric acid levels (OR = 1.005, p = 0.044). High fruit intake is positively correlated with aspartate transaminase/alanine transaminase level (OR = 5.271, p = 0.005) and red blood cell count (OR = 4.805, p = 0.033). An unhealthy dietary pattern was positively correlated with lymphocyte counts (OR = 2.904, p = 0.011).
Conclusions: In summary, a coarse grain-rich diet is suitable for Tibetan migrants. However, meat and fruit should not be consumed in excessive amounts, and sweetened drinks and alcohol should be avoided.
... With advancing understanding of the risk factors for hypertension, environmental factors have attracted increasing attention in recent research [3], one of them being residential altitude. On the one hand, experts found that the prevalence of hypertension was higher in populations that re-sided in high altitudes than in those residing in low and moderate altitudes, where high altitudes were defined as elevations as low as 1,500 m to those as high as 8,800 m [4][5][6][7]. On the other hand, several observational and clinical studies have reported a significant correlation between hypertension risk and residential altitude [8][9][10]. ...
Background:
Research on the relationship between residential altitude and hypertension incidence has been inconclusive. Evidence at low altitudes (i.e., <1,500 m) is scarce, let alone in older adults, a population segment with the highest hypertension prevalence. Thus, the objective of this study is to determine whether hypertension risk may be affected by altitude in older adults living at low altitudes.
Methods:
This prospective cohort study collected data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). We selected 6,548 older adults (≥65 years) without hypertension at baseline (2008) and assessed events by the follow-up surveys done in 2011, 2014, and 2018 waves. The mean altitude of 613 residential units (county or district) in which the participants resided was extracted from the Digital Elevation Model (DEM) of the National Aeronautics and Space Administration (NASA) and was accurate to within 30 m. The Cox regression model with penalized splines examined the linear or nonlinear link between altitude and hypertension. A random-effects Cox regression model was used to explore the linear association between altitude and hypertension.
Results:
The overall rate of incident hypertension was 8.6 per 100-person years. The median altitude was 130.0 m (interquartile range [IQR] = 315.5 m). We observed that the exposure-response association between altitude and hypertension incidence was not linear. The shape of the exposure-response curve showed that three change points existed. Hypertension risk increased from the lowest to the first change point (247.1 m) and slightly fluctuated until the last change point (633.9 m). The risk decreased above the last change point. According to the categories stratified by the change points, altitude was only significantly associated with hypertension risk (hazard ratio [HR] = 1.003; 95% confidence interval [CI] = 1.002-1.005) under the first change point (247.1 m) after adjusting for related covariates.
Conclusion:
Our study found that the association between altitude and hypertension risk might not be linear. We hope the further study can be conducted to confirm the generality of our findings.
... Increasing evidence shows that the harsh environment of hypoxia may regulate the immune system (Mishra and Ganju, 2010;Gaur et al., 2020). In the present study, we found that the immune system of the spleen in gayal and yak was highly regulated. ...
Gayal and yak are well adapted to their local high-altitude environments, yet the transcriptional regulation difference of the plateau environment among them remains obscure. Herein, cross-tissue and cross-species comparative transcriptome analyses were performed for the six hypoxia-sensitive tissues from gayal, yak, and cattle. Gene expression profiles for all single-copy orthologous genes showed tissue-specific expression patterns. By differential expression analysis, we identified 3,020 and 1,995 differentially expressed genes (DEGs) in at least one tissue of gayal vs. cattle and yak vs. cattle, respectively. Notably, we found that the adaptability of the gayal to the alpine canyon environment is highly similar to the yak living in the Qinghai-Tibet Plateau, such as promoting red blood cell development, angiogenesis, reducing blood coagulation, immune system activation, and energy metabolism shifts from fatty acid β-oxidation to glycolysis. By further analyzing the common and unique DEGs in the six tissues, we also found that numerous expressed regulatory genes related to these functions are unique in the gayal and yak, which may play important roles in adapting to the corresponding high-altitude environment. Combined with WGCNA analysis, we found that UQCRC1 and COX5A are the shared differentially expressed hub genes related to the energy supply of myocardial contraction in the heart-related modules of gayal and yak, and CAPS is a shared differential hub gene among the hub genes of the lung-related module, which is related to pulmonary artery smooth muscle contraction. Additionally, EDN3 is the unique differentially expressed hub gene related to the tracheal epithelium and pulmonary vasoconstriction in the lung of gayal. CHRM2 is a unique differentially expressed hub gene that was identified in the heart of yak, which has an important role in the autonomous regulation of the heart. These results provide a basis for further understanding the complex transcriptome expression pattern and the regulatory mechanism of high-altitude domestication of gayal and yak.
... Both physiological and pathological hypoxia have been described to function in regulating peripheral immunity and inflammation partially through their effect on physiological (bone marrow, lymphoid tissue, placenta, intestinal mucosa, etc.) and pathological (tumors and chronically inflamed, infected or ischemic tissues, etc.) immunological niches (Taylor and Colgan, 2017). A series of studies on peripheral immunity of temporary and native residents in Tien Shan and Pamir mountains showed that hypobaric hypoxia differentially affected the number, activity, or proliferation of T, B, NK, and phagocytic cells as well as peripheral cytokine profile (Mishra and Ganju, 2010). In a study on the alterations of immune system induced by acute and chronic exposure to high altitude, T lymphocytes were found significantly decreased during both acute and chronic hypoxia, which was totally attributed to CD4 + T cells reduction. ...
Given combined efforts of neuroscience and immunology, increasing evidence has revealed the critical roles of the immune system in regulating homeostasis and disorders of the central nervous system (CNS). Microglia have long been considered as the only immune cell type in parenchyma, while at the interface between CNS and the peripheral (meninges, choroid plexus, and perivascular space), embryonically originated border-associated macrophages (BAMs) and multiple surveilling leukocytes capable of migrating into and out of the brain have been identified to function in the healthy brain. Hypoxia-induced neuroinflammation is the key pathological procedure that can be detected in healthy people at high altitude or in various neurodegenerative diseases, during which a very thin line between a beneficial response of the peripheral immune system in maintaining brain homeostasis and a pathological role in exacerbating neuroinflammation has been revealed. Here, we are going to focus on the role of the peripheral immune system and its crosstalk with CNS in the healthy brain and especially in hypobaric or ischemic hypoxia-associated neuroinflammation.
... Hypoxia stimulates the expression of pro-and anti-inflammatory cytokines in different cell types and tissues of high-altitude residents [14]. For example, after spending three consecutive nights above 3400 m, healthy volunteers demonstrate elevated levels of circulating IL-6, IL-6 receptor, and C-reactive protein [15]. ...
Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.
... However, the actual mechanism involved in the change of immune function under chronic hypoxia remains unclear, especially with regards to changes in the complement system under hypoxic stress. As a significant response of the immune system, the coagulation complement system can induce various mechanisms of immune regulation 31 and play an important role in fighting infection. Previous studies have found that complement components C1, C4, C5, C6, C7, C8, C9, and complement factor H, are downregulated under hypoxic conditions at high altitude 30 . ...
Abstract To use isobaric tags for relative and absolute quantification (iTRAQ) technology to study the pathogenesis of chronic mountain sickness (CMS), identify biomarkers for CMS, and investigate the effect of total flavones of Dracocephalum moldavica L. (TFDM) on a rat model of CMS. We simulated high altitude hypobaric hypoxia conditions and generated a rat model of CMS. Following the administration of TFDM, we measured the pulmonary artery pressure and serum levels of hemoglobin (Hb), the hematocrit (Hct), and observed the structure of the pulmonary artery in experimental rats. Furthermore, we applied iTRAQ-labeled quantitative proteomics technology to identify differentially expressed proteins (DEPs) in the serum, performed bioinformatics analysis, and verified the DEPs by immunohistochemistry. Analysis showed that the pulmonary artery pressure, serum levels of Hb, and the Hct, were significantly increased in a rat model of CMS (P
... High altitudes negatively impact the normal bodily functions of individuals, whether they are accustomed or unaccustomed to such environments. Mishra and Ganju reviewed high-altitude environmental factors, such as cold and hypobaric hypoxia, which affect the immune system, making it more susceptible to cancer, infection, and autoimmune disease [23]. Inadequate hypoxia treatment affects reproduction and fertility traits, including reduced intrauterine growth in sheep [24] and impaired development and function of corpus luteum [25]. ...
Simple Summary
The yak is a multipurpose domesticated animal that serves as a protein source for local herders and a sacred carrier of culture and religion. Besides their economic significance, yaks harbor special morphological, physiological, biochemical, and genetic adaptations for tolerance to high-altitude stress. Morphologically, yaks have large hearts and lungs, compact bodies, thick outer hair covering, and nonfunctional sweat glands, which help to withstand hypoxia and cold stress. A reduced heat production, decreased respiration and sweating, reduced metabolism, and efficient nitrogen utilization are the major physiological and biochemical mechanisms for yak survival at high altitudes. Furthermore, the yak has undergone long-term natural selection and developed a unique genetic architecture that favors survival in hostile environments. The yak expresses the HIF-1α pathway-related genes (ADAM17, ARG2, and MMP3) putatively involved in hypoxia response and nutrition pathways genes (CAMK2B, GENT3, HSD17B12, WHSC1, and GLUL) for nutritional assimilation at high altitudes.
Abstract
Living at a high altitude involves many environmental challenges. The combined effects of hypoxia and cold stress impose severe physiological challenges on endothermic animals. The yak is integral to the livelihood of the people occupying the vast, inhospitable Qinghai–Tibetan plateau and the surrounding mountainous region. Due to long-term selection, the yak exhibits stable and unique genetic characteristics which enable physiological, biochemical, and morphological adaptations to a high altitude. Thus, the yak is a representative model for mammalian plateau-adaptability studies. Understanding coping mechanisms provides unique insights into adaptive evolution, thus informing the breeding of domestic yaks. This review provides an overview of genetic adaptations in Bos grunniens to high-altitude environmental stress. Combined genomics and theoretical advances have informed the genetic basis of high-altitude adaptations.
... Overall, high altitude exposure induced consistent postural disturbances at an elevation increase as little as ~ 1600 m (Stadelmann et al. 2015). These balance impairments could-in part-be owing to reductions in P I O 2 or other environmental factors related to increased altitude such as lowered temperature, and/or humidity (Mishra and Ganju 2010). Similarly, studies involving a hypobaric hypoxia chamber observed consistent quiet standing decrements ranging from 6 to 240% (Table 2; Degache et al. 2012Degache et al. , 2020Fraser et al. 1987;Hoshikawa et al. 2010;Nordahl et al. 2002;Šarabon et al. 2018). ...
PurposeStanding balance control is important for everyday function and often goes unnoticed until impairments appear. Presently, more than 200 million people live at altitudes > 2500 m above sea level, and many others work at or travel to these elevations. Thus, it is important to understand how hypoxia alters balance owing to implications for occupations and travelers. Herein, the influence of normobaric and hypobaric hypoxia on standing balance control is reviewed and summarized. As postural control relies on the integration of sensorimotor signals, the potential hypoxic-sensitive neurophysiological factors that contribute to balance impairments are also reviewed. Specifically, we examine how hypoxia impairs visual, vestibular, and proprioceptive cues, and their integration within subcortical or cortical areas.Methods
This systematic review included a literature search conducted via multiple databases with keywords related to postural balance, hypoxia, and altitude. Articles (n = 13) were included if they met distinct criteria.ResultsCompared to normoxia, normobaric hypoxia worsened parameters of standing balance by 2–10% and up to 83 and 240% in hypobaric hypoxia (high-altitude and lab-based, respectively). Although balance was only disrupted during normobaric hypoxia at FIO2 < ~ 0.15, impairments consistently occurred during hypobaric hypoxia at altitudes > 1524 m (~ FIO2 < 0.18).Conclusion
Hypoxia, especially hypobaric, impairs standing balance. The mechanisms underpinning postural decrements likely involve alterations to processing and integration of sensorimotor signals within subcortical or cortical structures involving visual, vestibular, and proprioceptive pathways and subsequent motor commands that direct postural adjustments. Future studies are required to determine the sensorimotor factors that may influence balance control in hypoxia.
... The concentration of O 2 required for the human organism to function adequately is 21%, which equals sea level. At high altitude, the decrease in oxygen available for cellular metabolism compromises the permanence and performance of the human being and presents several repercussions in the homeostasis of different biological systems [17]. Several acute physiological responses tend to minimize the deleterious effects of the low O 2 available in different tissues, including changes in different physiological systems, such as respiratory, cardiovascular, immunological and hormonal and hematological components [18]. ...
Hypoxia induced by low O 2 pressure is responsible for several physiological and behavioral alterations. Changes in physiological systems are frequent, including inflammation and psychobiological declines such as mood and cognition worsening, resulting in increased reaction time, difficulty solving problems, reduced memory and concentration. The paper discusses the possible relationship between glutamine supplementation and worsening cognition mediated by inflammation induced by high altitude hypoxia. The paper is a narrative literature review conducted to verify the effects of glutamine supplementation on psychobiological aspects. We searched MEDLINE/PubMed and Web of Science databases and gray literature by Google Scholar for English articles. Mechanistic pathways mediated by glutamine suggest potential positive effects of its supplementation on mood and cognition, mainly its potential effect on inflammation. However, clinical studies are scarce, making any conclusions impossible. Although glutamine plays an important role and seems to mitigate inflammation, clinical studies should test this hypothesis, which will contribute to a better mood and cognition state for several people who suffer from problems mediated by hypoxia.
... While the effect of altitude training on the immune system presents a complex picture (Mishra & Ganju, 2010), there is at least some evidence indicating an immediate and ongoing increase in immunological function following acute hypoxic exposure (Mazzeo, 2005). The effect of hypoxic exposure on the athlete may therefore be reflected in the resting levels of 7,8dihydroneopterin (measured using total neopterin) and provide insight into the athlete's overall recovery and readiness for performance. ...
Objectives: Neopterin has been used as a stress marker in team sport athletes, but its use
in monitoring stress in hypoxic training requires further investigation. The objective of this
study was to determine whether neopterin measures could detect differences between
hypoxic and normoxic training stress and whether such levels could predict subsequent
performance. Methods: Nineteen amateur club rugby players completed two repeated
sprint (cycling) sessions per week for 3 weeks in either hypoxic (RSH, n = 9, FIO2 = 0.145)
or normoxic (RSN, n = 10, FIO2 = 0.209) conditions. Repeated sprint ability (RSA,
running), and the Yo-Yo Intermittent Recovery Level 1 test (YYIR1) were assessed pre- and
post- intervention. Resting neopterin, total neopterin, and the difference between resting
and post-exercise neopterin and total neopterin levels (acute change) were monitored
during training. Results: Neopterin and total neopterin measurements demonstrated high
individual variability in all participants. Neopterin and total neopterin were likely and very
likely elevated respectively in RSH vs RSN between weeks 1 and 3 (neopterin, 56.4 %, ±
55.6, p = 0.10; percent change, ± 90% confidence interval, p value; total neopterin, 42.2 %,
± 23.5, p = 0.02). Aside from a moderate correlation between the acute change in total
neopterin with YYIR1 (r = -0.38) there were no substantial correlations between neopterin
and total neopterin measures and post-intervention performance. Conclusions: Neopterin
or total neopterin can distinguish between hypoxic and normoxic training. However, high
individual variability and limited predictive ability of subsequent performance may restrict
the practical application of this stress marker.
... With this in mind, further research is clearly required before NAC can be recommended as a useful supplement for use prior to and/or throughout altitude exposure in athletes, with factors such as dose, duration of consumption and the resultant potential for mechanistic promise to convert to enhanced adaptation all needing further clarification. Any indirect benefits of a supplement that might support an athlete's immune function are of key interest, since it is well-documented that unaccustomed altitude exposure places an additional burden on the immune system [158]. Maintaining an athlete's immune function and/or reducing the impact of any altitude-induced illness while under such environmental stress may lead to enhanced overall adaptations. ...
Training at low to moderate altitudes (~ 1600-2400 m) is a common approach used by endurance athletes to provide a distinctive environmental stressor to augment training stimulus in the anticipation of increasing subsequent altitude- and sea-level-based performance. Despite some scientific progress being made on the impact of various nutrition-related changes in physiology and associated interventions at mountaineering altitudes (> 3000 m), the impact of nutrition and/or supplements on further optimization of these hypoxic adaptations at low-moderate altitudes is only an emerging topic. Within this narrative review we have highlighted six major themes involving nutrition: altered energy availability, iron, carbohydrate, hydration, antioxidant requirements and various performance supplements. Of these issues, emerging data suggest that particular attention be given to the potential risk for poor energy availability and increased iron requirements at the altitudes typical of elite athlete training (~ 1600-2400 m) to interfere with optimal adaptations. Furthermore, the safest way to address the possible increase in oxidative stress associated with altitude exposure is via the consumption of antioxidant-rich foods rather than high-dose antioxidant supplements. Meanwhile, many other important questions regarding nutrition and altitude training remain to be answered. At the elite level of sport where the differences between winning and losing are incredibly small, the strategic use of nutritional interventions to enhance the adaptations to altitude training provides an important consideration in the search for optimal performance.
... First, high-altitude environments experience strong UV radiation, low oxygen, and low temperatures. These factors can negatively affect the immune system and make animals more susceptible to infections 41 . As reported previously, the dermis thickness is lower in juvenile yak than adults 10 . ...
The yak, Bos grunniens, is the only large mammal in the Qinghai-Tibet Plateau and has been bred to provide meat, milk, and transportation. Previous studies indicate that the immune system contributes to the yak’s adaptation to high-altitude environments. In order to further investigate changes in immune function during yak development, we compared the transcriptome profiles of gluteus and lung tissues among yaks at 6, 30, 60, and 90 months of age. Analyses of significantly differentially expressed genes (DEGs) in lung tissues revealed that immune function was more activated at 6-months and less activated at 90-months than in the 30 and 60-month-old animals. DEG exploration in gluteal tissues revealed that immune functions were more highly activated at both 6 and 90-months, compared with 30 and 60-months. Immune system activation in the muscle and lung tissues of 30-month-old yaks may increase their resistance to infections, while decreased may be due to aging. Furthermore, the higher immune activation status in the gluteal tissues in 90-month-old yaks could be due to muscle injury and subsequent regeneration, which is supported by the fact that 5 unigenes related with muscle injury and 3 related to muscle regeneration displayed greater expression levels at 90-months than at 30 and 60-months. Overall, the present study highlights the important role of the immune system in yak development, which will facilitate future investigations.
... About 2% sojourners travelling to South Pole suffers with altitude sickness. In our studies, we found that apart from altitude sickness, hypoxia also affects human immunity [3][4][5][6]. We have reported that not only hypoxia but extreme conditions of Antarctica at coastal station Maitri affects human immunity during summer as well as winter overstay [7][8][9][10][11][12]. ...
Objective: The aim of the study was to determine the effect a mountain expedition (>3000 m) would have on the physical performance and nutritional indices of alpinists’ health status. Methods: The study included 17 men aged 30.29 ± 5.8 years participating in mountain expeditions to peaks of 5000–8000 m, lasting an average of 34 ± 6 days. The following were assessed: aerobic and anaerobic capacity, body composition and the values of selected biochemical and hematological indices of blood and urine before and after returning from the expeditions and a quantitative analysis of the alpinists’ diet. Results: There was a statistically significant decrease (p ≤ 0.05) in aerobic capacity, anaerobic capacity, subjects’ body mass, muscle mass and the lean body mass of the upper and lower extremities. There was a significant increase (p ≤ 0.05) in erythrocytes, hemoglobin, hematocrit, leukocytes, platelets, neutrophils, monocytes and a significant decrease (p ≤ 0.05) in total and high-density lipoprotein cholesterol, total bilirubin, albumin and total protein. A small percentage of the subjects met the requirements for iron (29.41%), folate (35.29%) and vitamin D (17.65%) supply with diet, as reflected in the blood test results. Conclusions: Despite the observed positive effect of three-week hypoxic exposure on the climbers’ health, the deterioration of aerobic and anaerobic capacity was shown, which, in addition to environmental conditions and systemic inflammation, may have been influenced by adverse changes in body composition. To improve the nutritional status of the body during the expedition and upon return, alpinists should consider including the necessary supplementation of deficient components.
Doğa sporlarında ortaya çıkan kazalar, genellikle sporcuların dikkatsizliği, tecrübesizliği, yanlış ekipman kullanımı veya doğal unsurlardan kaynaklanmaktadır. Bu kazalar sonucunda ise, yaralanma, hastalık veya ölüm gibi durumlara neden olmaktadır. Bu nedenle, doğa sporları aktivitelerinde eğitim almak, güvenlik kurallarına uymak ve uygun ekipman kullanmak oldukça önemlidir. Ayrıca, doğada bulunan risklerin farkında olması ve doğru önlemleri alması, kazaların önlenmesine yardımcı olabilmektedir. Bu araştırma, doğa sporlarında ortaya çıkan kaza türlerini sistematik bir biçimde ortaya koymak amacıyla gerçekleştirilmiştir. Bu bağlamda, doğa sporları aktivitelerinde ortaya çıkan; boğulma, dehidrasyon, zehirlenme, yanık yaralanmaları, yangınlar, hipotermi ve donma, doğal afetler, güneş çarpması ve güneş yanığı, vahşi hayvan saldırıları ve yüksek irtifa hastalığı gibi en sık kazaya neden olan türlerin nedenlerini, sonuçlarını ve katılımcıların bu durumlara karşı alması gereken tedbirlerin ortaya konmasını amaçlanmıştır. Doğa sporları, heyecan verici ve keyifli olmasının yanı sıra çeşitli riskleri de beraberinde getirir. Bu riskler arasında boğulma, dehidrasyon, zehirlenme, yanık yaralanmaları, yangınlar, hipotermi ve donma, doğal afetler, güneş çarpması, vahşi hayvan saldırıları ve yüksek irtifa hastalığı gibi durumlar yer alır. Sonuç olarak, doğa sporları aktivitelerinin katılımcıları çeşitli risklere maruz bırakabileceği söylenebilir. Bu riskler arasında boğulma, dehidrasyon, zehirlenme, yanık yaralanmaları, yangınlar, hipotermi ve donma, doğal afetler, güneş çarpması, vahşi hayvan saldırıları ve yüksek irtifa hastalığı gibi durumlar bulunmaktadır. Bu nedenle, doğa sporlarıyla ilgilenenlerin bu riskleri göz önünde bulundurarak doğru önlemleri alması ve güvenliğe önem vermesi gerekmektedir. Katılımcıların deneyim seviyelerine uygun eğitim alması, güvenlik ekipmanlarını doğru kullanması ve güvenlik kurallarına sıkı bir şekilde uyması, potansiyel riskleri azaltmada önemli bir rol oynamaktadır.
The dramatic changes in physiology at high altitude (HA) as a result of the characteristic hypobaric hypoxia condition can modify innate and adaptive defense mechanisms of the body. As a consequence, few sojourners visiting HA with mild or asymptomatic infection may have an enhanced susceptibility to high-altitude pulmonary edema (HAPE), an acute but severe altitude sickness. It develops upon rapid ascent to altitudes above 2500 m, in otherwise healthy individuals. Though HAPE has been studied extensively, an elaborate exploration of the HA disease burden and the potential risk factors associated with its manifestation are poorly described. The present review discusses respiratory tract infection (RTI) as an unfamiliar but important risk factor in enhancing HAPE susceptibility in sojourners for two primary reasons. First, the symptoms of RTI s resemble those of HAPE. Secondly, the imbalanced pathways contributing to vascular dysfunction in HAPE also participate in the pathogenesis of the infectious processes. These pathways have a crucial role in shaping host response against viral and bacterial infections and may further worsen the clinical outcomes at HA. Respiratory tract pathogenic agents, if screened in HAPE patients, can help in ascertaining their role in disease risk and also point toward their association with the disease severity. The microbial screenings and identifications of pathogens with diseases are the foundation for describing potential molecular mechanisms underlying host response to the microbial challenge. The prior knowledge of such infections may predict the manifestation of disease etiology and provide better therapeutic options.
Given the meteorological conditions on the Tibetan plateau such as low temperatures and large diurnal range, people moving in and out of buildings are inevitably exposed to the transient, step change thermal environments. Significant temperature changes are closely related to humans' thermoregulatory processes, and the hypoxic environment may affect the thermoregulation process of sojourners in Tibet, which makes it difficult for people to adapt to temperature changes in time and increases the risk of disease. Nevertheless, most experimental studies on temperature step change were carried out in plain. Only a few experimental studies focused on the effect of temperature step change on human thermal comfort under low temperature and hypoxic environment. In order to understand the impact of this condition, the same temperature step change experiment was conducted in Xi'an and Lhasa, respectively. The results showed that the hypoxic environment of the plateau could cause decreasing of sojourners’ thermal sensation and skin temperature in Tibet under low temperature environment, and prolong the time needed for skin to rewarm. The results of this study can help provide a better thermal environment in buildings to ensure the health and thermal comfort of Tibetan sojourners.
Species are facing strong selection pressures to adapt to inhospitable
high-altitude environments. Yaks are a valuable species and an iconic symbol of
the Qinghai-Tibet Plateau. Extensive studies of high-altitude adaptation have
been conducted, but few have focused on metabolism. In the present study, we
determined the differences in the serum metabolomics between yaks and the
closely related species of low-altitude yellow cattle and dairy cows. We
generated high-quality metabolite profiling data for 36 samples derived from the
three species, and a clear separation trend was obtained between yaks and the
other animals from principal component analysis. In addition, we identified a
total of 63 differentially expressed metabolites among the three species.
Functional analysis revealed that differentially expressed metabolites were
related to the innate immune activation, oxidative stress-related metabolism,
and energy metabolism in yaks, which indicates the important roles of
metabolites in high-altitude adaptation in yaks. The results provide new
insights into the mechanism of adaptation or acclimatization to high-altitude
environments in yaks and hypoxia-related diseases in humans.
Military personnel are often exposed to high altitude (HA, ca. 4500–5000 m) for combat operations associated with neurological dysfunctions. HA is a severe stressful situation and people frequently use methamphetamine (METH) or other psychostimulants to cope stress. Since military personnel are prone to different kinds of traumatic brain injury (TBI), in this review we discuss possible effects of METH on concussive head injury (CHI) at HA based on our own observations. METH exposure at HA exacerbates pathophysiology of CHI as compared to normobaric laboratory environment comparable to sea level. Increased blood-brain barrier (BBB) breakdown, edema formation and reductions in the cerebral blood flow (CBF) following CHI were exacerbated by METH intoxication at HA. Damage to cerebral microvasculature and expression of beta catenin was also exacerbated following CHI in METH treated group at HA. TiO2-nanowired delivery of H-290/51 (150 mg/kg, i.p.), a potent chain-breaking antioxidant significantly enhanced CBF and reduced BBB breakdown, edema formation, beta catenin expression and brain pathology in METH exposed rats after CHI at HA. These observations are the first to point out that METH exposure in CHI exacerbated brain pathology at HA and this appears to be related with greater production of oxidative stress induced brain pathology, not reported earlier.
Yaks display unique properties of the lung and heart, enabling their adaptation to high‐altitude environments, but the underlying molecular mechanisms are still largely unknown. In the present study, the proteome differences in lung and heart tissues were compared between yak (Bos grunniens) and three cattle strains (Bos taurus, Holstein, Sanjiang and Tibetan cattle) using the sequential window acquisition of all theoretical mass spectra/data‐independent acquisition (SWATH/DIA) proteomic method. In total, 51,755 peptides and 7215 proteins were identified. In the lung tissue, there were 162, 310 and 118 differential abundance proteins (DAPs) in Tibetan, Holstein and Sanjiang cattle compared to yak respectively. In the heart tissue, there were 71, 57 and 78 DAPs in Tibetan, Holstein and Sanjiang cattle compared to yak respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the DAPs were enriched for the retinol metabolism and toll‐like receptor categories in lung tissue. The changes in these two pathways may regulate hypoxia‐induced factor and immune function in yaks. Moreover, DAPs in heart tissues were enriched for cardiac muscle contraction, Huntington's disease, chemical carcinogenesis and drug metabolism‐cytochrome P450. Further exploration indicated that yaks may alter cardiac function through regulation of type 2 ryanodine receptor (RyR2) and Ca2+‐release channels. The present results are useful to further develop an understanding of the mechanisms underlying adaptation of animals to high‐altitude conditions.
OBJECTIVE
To review the different causes of secondary immunodeficiencies and provide clinicians with an updated overview of potential factors that contribute to immunodeficiency. DATA SOURCES Recent published literature obtained through PubMed database searches, including research articles, review articles, and case reports.
STUDY SELECTIONs
PubMed database searches were conducted using the keywords: immunodeficiency, antibody deficiency, immunosuppressive drugs, genetic syndrome, malignancy, HIV infection, viral infection, secondary immunodeficiency, nutrition, prematurity, aging, protein-losing enteropathy, nephropathy, trauma, space travel, high altitude and ultraviolet light. Studies published in the last decade and relevant to the pathogenesis, epidemiology, and clinical characteristics of secondary immunodeficiencies were selected and reviewed.
RESULTS
Researchers continue to investigate and report abnormal immune parameters in the different entities collectively known as secondary immunodeficiencies. Immunodeficiency might occur as a consequence of malnutrition, metabolic disorders, use of immunosuppressive medications, chronic infections, malignancies, severe injuries and exposure to adverse environmental conditions. The neonate and the elderly may show decreased immune responses relative to healthy adults. Each of these conditions may present with different immune defects of variable severity. The acquired immunodeficiency syndrome results from infections by the human immunodeficiency virus, which targets CD4 T cells leading to defective immune responses. Rituximab is a monoclonal antibody that targets CD20 B cells and its use might result in persistent hypogammaglobulinemia.
CONCLUSION
Clinician should consider secondary immunodeficiencies in the differential diagnosis of a patient with recurrent infections and abnormal immunological evaluation. The use of biological agents for the treatment of inflammatory conditions and malignancies is an increasingly important cause of secondary immunodeficiency.
To study the immune reactivity in people of different ages living at different heights of the mountainous area. The following task was solved to achieve the aim of the research: to study of the age-related features of immune reactivity in healthy individuals living in low- and high-mountainous regions. Modern and classical methods of immunological analysis were used to determine the immune status and natural resistance in humans. The article presents the results of the study of immune reactivity in 116 people of both sexes aged from 16 to 63 years old that were divided into 3 age groups living at different altitude zones — in the low mountains (930 m above sea level) and in the highlands (2800 m above sea level). Results. Comparative evaluation of immune reactivity in low-mountain areas in two age groups (II–III) revealed significant changes, compared with the first age group. In the third age group, there is a distinctly pronounced decrease in all the basic indices of phagocytosis, as well as the level of lysozyme and complement. For all age groups in the highlands compared with the low-mountain range, there is a decrease in the number of all T-lymphocytes, their subpopulations and functional activity of all types of cells participating in phagocytosis. An increased concentration of circulating immune complexes (CIC) was detected. The revealed quantitative changes in the immunity indices in all age groups examined indicate a reduction in the reserve capacity of the body’s immune defenses with age, but more significantly in high-altitude inhabitants.
The Qing-Tibet Plateau is characterized by low oxygen pressure, which is an important biomedical and ecological stressor. However, the variation in gene expression during periods of stay on the plateau has not been well studied. We recruited eight volunteers to stay on the plateau for 3, 7, and 30 days. Human Clariom D arrays were used to measure transcriptome changes in the mRNA expression profiles in these volunteers' blood. Analysis of variance (ANOVA) indicated that 699 genes were significantly differentially expressed in response to entering the plateau during hypoxic exposure. The genes with changes in transcript abundance were involved in the terms phosphoprotein, acetylation, protein binding, and protein transport. Furthermore, numerous genes involved in hematopoietic functions, including erythropoiesis and immunoregulation, were differentially expressed in response to hypoxia. This phenomenon may be one of reasons why the majority of people entering the plateau do not have excessive erythrocyte proliferation and are susceptible to infection.
The yak is a valuable species in the Qinghai-Tibet Plateau of China. Nevertheless, the molecular mechanisms underlying its adaptation to high-altitude environments remain largely unknown. In the present study, comparative transcriptome sequencing was performed for lung and gluteus tissues from two species of low-altitude cattle (Sanjiang and Holstein cattle), Tibetan cattle (living at a moderate altitude), and yak (living at a high altitude) and the differentially expressed genes were validated using real-time quantitative PCR. The results showed that CD36 antigen was up-regulated and CD59 antigen was down-regulated in yak in comparison to the other animals, which might promote the development of red blood cells and inhibit the development of lymphocytes in yak. In addition, thrombospondin type 1, coagulation factor 5/8, and fibronectin were all down-regulated, but serpin and alpha 2-macroglobulin (A2M) were up-regulated. These differences would inhibit blood coagulation, thus reducing the risk of pulmonary edema. The expression levels of the calcium-release, potassium, and transient receptor potential channels decreased in yak, minimizing membrane depolarization and the harmful effects of pulmonary edema. Eleven KEGG pathways associated with innate immunity were more activated in yak and Tibetan cattle than in other cattle strains, which should reduce their risk of infection and disease. These changes together might facilitate the adaptation of yak and Tibetan cattle to live in high-altitude habitats.
Background: The aim of the study was to find the effect of hypobaric hypoxia (HH)
on IgA and complement system activation in time-dependent manner.
Methods: Serum levels of IgA, C3, C3a, C5, C5a, SERPING1 and Complement
Factor Properdin (CFP) were detected by Enzyme-linked immunosorbent assay in
male Sprague Dawley rats under HH at 25,000 ft (7620m). SD rats were exposed for
1, 3, 7 and 14 days in animal decompression chamber and relation between control
versus HH exposed rats was analyzed.
Results: Serum levels of immunoglobulin IgA were upregulated with HH exposure and
complement proteins like C3, C5 (p<0.01) were found to be maximum on 14th day of
exposure. Anaphylatoxin, C3a also upregulated significantly on14th day. C5a, another
anaphylatoxin increased upto 7th day though not significantly. CFP was significantly
down regulated with hypoxia exposure of 1 and 3 days and levels increased on further
exposure. SERPING1 levels increased significantly on 14th day of exposure.
Discussion: Our study on rats revealed that hypobaric hypoxia alters the secretary
IgA level and complement proteins in a time-dependent manner. Thus concluding that
extreme environmental condition may alter the humoral immune response.
After immunization, normal H-2 heterozygous mice (for example H-2(b) × H-2(d)) generate two populations of cytotoxic effector
T cells, one specific for target cells expressing H-2(b)-plus-antigen and the other specific for H- 2(d)-plus-antigen. With
a multideterminant antigen, these two populations have about the same activity. We show here that the H-2 type of resident
cells in the thymus determines the H-2 preference of cytotoxic T lymphocytes. F(1)(B 10 × B 10.D2) (H-2(b) × H-2 (d)) mice
were thymectomized, lethally irradiated, and reconstituted with T-cell-depleted syngeneic hematopoietic cells. Groups of such
ATXBM mice were grafted subcutaneously with neonatal thymus lobes from parental mice, either B10 (H-2 (b)) or B10.D2 (H-2(d)).
2-3 mo later, the mice were immunized against the minor histocompatibility antigens on F(1)(BALB/c × BALB.B) cells and assayed
for cytotoxic T-cell activity. H-2(b) × H-2(d) ATXBM mice with H-2(b) thymus grafts responded to antigen-plus-H-2(b) much
better than to antigen-plus-H-2(d), and vice versa for the mice with H-2(d) thymus grafts. As judged by antiserum treatment,
the effector cells were of F(1) origin.
To explore the possibility that the "thymus preference" may have been due to suppression of T-cell activity, nonimmune spleen
and lymph node cells from normal H-2(b) × H-2(d) mice and cells from H-2(b) × H-2(d) mice bearing a homozygous thymus were
mixed 1:1 and immunized in adoptive transfer. The mixture responded to antigen-plus-H-2(b) and antigen-plus-H-2(d) equally
well, demonstrating that the cells that showed a "thymus preference" could not suppress a response to antigen in association
with the nonthymic H-2 type. We conclude from these and other experiments that H-2 antigens present on resident cells of the
thymus determine the spectrum of specificity of T cells which mature in that thymus and eventually make up the peripheral
T- cell pool.
Acute mountain sickness (A.M.S.) and its severe complications, high-altitude pulmonary oedema (H.A.P.O.) and cerebral oedema (C.O.), were studied in 278 unacclimatised hikers at 4243 m altitude at Pheriche in the Himalayas of Nepal. The overall incidence of A.M.S. was 53%, the incidence being increased in the young and in those who flew to 2800 m, climbed fast, and spent fewer nights acclimatising en route. It was unrelated to sex, to previous altitude experience, to the load carried, and to recent respiratory infections. The severity of A.M.S. was inversely related to age (independent of rate of ascent) and the highest altitude attained, and was highly ocrrelated with speed of ascent. There were 7 cases of H.A.P.O. and 5 with the more intractable C.O. and, of these 12, 11 had flown in, 9 had spent only one night at Pheriche, and none were on acetazolamide. 11 required evacuation. Acetazolamide, compared in a double-blind study with a placebo and also compared with no tablets at all, reduced both the incidence and the severity of A.M.S. in those who flew to 2800 m but not in those who hiked up to that altitude. Prevention consists in slow ascent, rapid recognition of warning signs, and prompt descent to avoid progression.
The chronic exposure at high altitude (HA) represents an ideal model for evaluating the in vivo effects of hypobaric hypoxia. Taking advantage of the EV-K2-CNR Pyramid, this study was designed to evaluate whether acute and chronic hypoxia differently modulates the in vivo immune responses.
The study includes 13 healthy female moderately active volunteers participating to the Italian HA project EV-K2-CNR. Peripheral blood lymphocytes, collected at sea level and at HA in the Pyramid Laboratory of CNR, Nepal (5050 m), were immunologically characterized by flow cytometry and a series of molecular and functional analyses.
Flow cytometric analyses showed that: a) CD3+ T lymphocytes significantly decreased during both acute and chronic exposure to HA, b) T-cell fall was totally due to CD4+ T-cell reduction, c) B lymphocytes were not influenced by the exposure to HA, and d) natural killer (NK) cells significantly increased during acute and chronic exposure. The evaluation of the Th1/Th2 pattern demonstrated a significant decrease of the expression of the Th1 cytokine interferon-gamma (IFN-gamma) by circulating T cells during acute and chronic exposure to HA. The expression by T cells of CXCR3, a chemokine receptor typically expressed by Th1/Tc1 cells, paralleled the decrease of IFN-gamma. On the contrary, the expression of IL-4 was not conditioned by the exposure to HA. Finally, functional studies showed a significant reduction of the proliferative activity in response to mitogen (PHA) both in acute and chronic HA exposure. Despite the increased number of NK cells, NK cytotoxic activity was not influenced by the HA exposure.
Our results indicate that the in vivo exposure to HA leads to an impairment of the homeostatic regulation of Th1/Th2 immune balance that potentially could favor long-term immunological alterations and increase the risk of infections.
Recent studies have demonstrated that brief daily IAE (intermittent altitude exposure) was equally as effective as continuous altitude residence in inducing physiological adaptations consistent with altitude acclimatization. Although the positive benefits of IAE have been clearly defined, the potential negative consequences of IAE on health, specifically the immune system, remain undefined. The present study determined the effects of IAE on WBC (white blood cell) and hormonal responses during rest and exercise at 4300 m altitude. Six lowlanders (age, 23+/-2 years; body weight, 77+/-6 kg; values are means+/-S.E.M.) completed a VO(2)max (maximal O(2) uptake) and submaximal cycle ergometer test during a 30-h SL (sea level) exposure and during a 30 h exposure to 4300 m altitude-equivalent once before (PreIAE) and once after (PostIAE) a 3-week period of IAE (4 hxday(-1), 5 daysxweek(-1), 4300 m). The submaximal cycle ergometer test consisted of two consecutive 15-min work bouts at 40% and 70% of altitude-specific VO(2)max. Blood samples were obtained at rest and during both exercise work bouts for measurements of WBC count, leucocyte subset counts, cortisol, adrenaline (epinephrine) and noradrenaline (norepinephrine). WBC, neutrophil and lymphocyte counts increased significantly (P<0.05) during rest and exercise from SL to PreIAE and decreased (P<0.05) during rest and exercise from PreIAE to PostIAE. Monocyte counts decreased (P<0.05) during rest and exercise from PreIAE to PostIAE, but eosinophil and basophil counts did not change. Cortisol, adrenaline and noradrenaline did not change during rest or exercise from SL to PreIAE or PostIAE, but all increased significantly (P<0.05) from rest during the two work bouts. In conclusion, this type of IAE stimulus did not induce a hormonal stress response and did no harm in terms of activation of the immune system at altitude, as measured by WBC and leucocyte subset counts. This method of pre-acclimatization can therefore be highly recommended for inducing altitude acclimatization without the 'altitude residency' requirement.
It remains unclear whether gammadelta T cell antigen receptors (TCRs) detect antigens in a way similar to antibodies or alphabeta TCRs. Here we show that reactivity between the G8 and KN6 gammadelta TCRs and the major histocompatibility complex class Ib molecule T22 could be recapitulated, with retention of wild-type ligand affinity, in an alphabeta TCR after grafting of a G8 or KN6 complementarity-determining region 3-delta (CDR3delta) loop in place of the CDR3alpha loop of an alphabeta TCR. We also found that a shared sequence motif in CDR3delta loops of all T22-reactive gammadelta TCRs bound T22 in energetically distinct ways, and that T10(d), which bound G8 with weak affinity, was converted into a high-affinity ligand by a single point mutation. Our results demonstrate unprecedented autonomy of a single CDR3 loop in antigen recognition.
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Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.
B lymphocytes, the cellular source of antibody, are critical components of the immune response. They develop from multipotential stem cells, progressively acquiring the traits that allow them to function as mature B lymphocytes. This developmental program is dependent on appropriate interactions with the surrounding environment. These interactions, mediated by cell-cell and cell-matrix interactions, provide the growth and differentiation signals that promote progression along the developmental pathway. This chapter addresses the properties of developing B lineage cells and the nature of the environmental signals that support B lineage progression.
A constitutional susceptibility has been suggested in the development of high-altitude pulmonary edema (HAPE) because HAPE generally affects healthy young people, some of whom suffer recurrent episodes. We examined whether immunogenetic susceptibility is present in HAPE-susceptible subjects.
The frequencies of human leukocyte antigen (HLA) alleles in 28 male and 2 female subjects with a history of HAPE were compared with those in 100 healthy volunteers. We assayed the HLA-A, -B, -C, -DR, and -DQ antigens serologically. The pulmonary hemodynamics on admission to the hospital and the ventilatory response to hypoxia and hypercapnia were retrospectively examined in 10 of the HAPE-susceptible subjects. HLA-DR6 was positive in 14 (46.7%) of the subjects with HAPE but only 16.0% of the control subjects (P=.0005), and HLA-DQ4 was positive in 12 (40.0%) of the subjects with HAPE but only 10.0% of the control subjects (P=.0001). HLA-DR6 or HLA-DQ4 was positive in 8 (100%) of the subjects with recurrent HAPE. The pulmonary arterial pressure on admission of the HLA-DR6-positive subjects with HAPE was significantly higher than that of the HLA-DR6-negative subjects with HAPE.
There were significant associations of HAPE with HLA-DR6 and HLA-DQ4 and of pulmonary hypertension with HLA-DR6. An immunogenetic susceptibility, which is associated with HLA class II alleles located within the major histocompatibility complex, may underlie the development of HAPE, at least in some of its forms.
We previously confirmed that high altitude (HA) exposure can modify the number and function of immune cells, leading to a disruption in the homeostatic regulation of T helper1 (Th1)/T helper2 (Th2) immune responses. Our aim was to evaluate possible relationships between the stress response and immunological parameters during HA exposure. Thirteen healthy women spent 21 days at 5050 m. Before (SL1), the first and the 21st day at HA (HA1 and HA2, respectively), and the day after returning at sea level (SL2), we collected blood samples for immunologic parameters, and 24-h urine samples for norepinephrine, epinephrine, and cortisol. Norepinephrine and cortisol significantly increased (p<0.01) at HA1 and HA2 compared to SL1, while epinephrine did not change. At HA1, CD3+ T-cell fell significantly (p<0.001) with respect to SL1, owing to a significant (p<0.001) CD4+ T-cell reduction, while CD16+ and CD56+ increased (p<0.001) at HA2 compared to SL1. The expression of interferon-gamma (IFN-gamma) decreased (p<0.0005) at HA1 and HA2 with respect to SL1. At HA1 different lymphocyte subset (CD3+, CD4+, CD19+) were well correlated with epinephrine (p<0.05), whereas in analyzing the combined data (SL1-HA1-HA2-SL2), CD3+ (r=-0.310), CD4+ (r=-0.332), CD16+ (r=0.404), and CD56+ (r=0.373) demonstrated moderate but significant correlations (p<0.05) with norepinephrine. Moreover, norepinephrine levels were inversely correlated (r=-0.591; p<0.001) with IFN-gamma expression, a typical Th1 cytokine. We suggest that the sympatho-adrenal axis may have a role on the immunologic adaptations observed during HA exposure, and specifically on the observed impairment of the Th1/Th2 immune balance.
The effect of hypoxic hypoxia on the specific factors of immunity of 16 test subjects was studied during their 30-day exposure to an altitude of 2100-4200 m above the sea level in the area of the Elbrus mountain. In order to differentiate the effect of hypoxia per se from that of other factors typical of highlands, five runs of altitude chamber experiments were carried out. In each run the test subjects were 10 times lifted to altitudes of 3200 m, 4200 m and 5200 m. The chamber experiments were performed on 28 test subjects, aged 26-46. During an exposure to an altitude the test subjects did two or three times exercises of 450-900 kgm/min on a bicycle ergometer. The experimental findings show that hypoxic hypoxia brings about consistent changes in the immunobiological status of man that are directly correlated with the level of hypoxia. These changes include a decline in the acquired antiviral and antitoxic immunity activation of the autoimmune process and an increase in the phagocytic activity of neutrophils. Our results suggest optimal profiles of the hypoxic effect to which test subjects should be exposed during mountain training for a specific occupational activity.
After immunization, normal H-2 heterozygous mice (for example H-2(b) x H-2(d)) generate two populations of cytotoxic effector T cells, one specific for target cells expressing H-2(b)-plus-antigen and the other specific for H- 2(d)-plus-antigen. With a multideterminant antigen, these two populations have about the same activity. We show here that the H-2 type of resident cells in the thymus determines the H-2 preference of cytotoxic T lymphocytes. F(1)(B 10 x B 10.D2) (H-2(b) x H-2 (d)) mice were thymectomized, lethally irradiated, and reconstituted with T-cell-depleted syngeneic hematopoietic cells. Groups of such ATXBM mice were grafted subcutaneously with neonatal thymus lobes from parental mice, either B10 (H-2 (b)) or B10.D2 (H-2(d)). 2-3 mo later, the mice were immunized against the minor histocompatibility antigens on F(1)(BALB/c x BALB.B) cells and assayed for cytotoxic T-cell activity. H-2(b) x H-2(d) ATXBM mice with H-2(b) thymus grafts responded to antigen-plus-H-2(b) much better than to antigen-plus-H-2(d), and vice versa for the mice with H-2(d) thymus grafts. As judged by antiserum treatment, the effector cells were of F(1) origin. To explore the possibility that the "thymus preference" may have been due to suppression of T-cell activity, nonimmune spleen and lymph node cells from normal H-2(b) x H-2(d) mice and cells from H-2(b) x H-2(d) mice bearing a homozygous thymus were mixed 1:1 and immunized in adoptive transfer. The mixture responded to antigen-plus-H-2(b) and antigen-plus-H-2(d) equally well, demonstrating that the cells that showed a "thymus preference" could not suppress a response to antigen in association with the nonthymic H-2 type. We conclude from these and other experiments that H-2 antigens present on resident cells of the thymus determine the spectrum of specificity of T cells which mature in that thymus and eventually make up the peripheral T- cell pool.
Prolonged stay at high altitude significantly lowers the incidence of some of the diseases commonly encountered at sea level. This conclusion is based on a study involving 130,700 men stationed on plains between 760 m and sea level and 20,000 men stationed at altitudes between 3692 and 5538 m during the period 1965 to 1972. When yearwise differences in morbidity rates were determined for this period it was found that apart from amoebic hepatitis, goitre and lobar pneumonia, which show a higher incidence, the incidence of infections of bacterial, viral and protozoal origin, diabetes mellitus, hypertension and ischaemic heart disease, asthma and rheumatoid arthritis, gastric disorders, skin diseases, psychiatric ailments and anaemia was significantly lower at high altitude than at sea level. When the trend in morbidity rates was compared over the two subperiods of 1965 to 1968 and 1969 to 1972 it was found that generally increasing or decreasing trends on plains were reflected at high altitude. The overall incidence at high altitude however remained low. Part I of our communication deals with epidemiological data and these findings. Part II surveys the available literature and attempts to explain how improved hormonal state, enhanced fibrinolytic activity, accelerated humoral and cellular immune responses, favourable haemodynamics, better cardiac and cerebral functions, improved metabolic functions, and a relatively stable, dry and cold climate favourably influence the incidence of diseases at high altitude.
The recognition of the existence of natural cell-mediated immunity, particularly natural cell-mediated cytotoxicity, has significantly altered the concepts concerning the potential mechanisms for in vivo resistance against tumor growth and for in vitro cell-mediated immune reactions. When cytotoxic reactions are measured, the evaluation of the role of natural killer (NK) cells and other more well-known mechanisms of cytotoxicity must be done carefully. This chapter focuses on natural cell-mediated cytotoxicity. It summarizes the known information on the expression of natural cytotoxicity in rodents and in man, its specificity, the nature of the effector cells and their relationship to other immune mechanisms, and the possible in vivo relevance of natural cytotoxicity, particularly in regard to resistance against tumor growth. The basic observation that initiated the studies of natural cell mediated cytotoxicity includes that lymphoid cells from some normal mice, rats, and human donors, which are not inoculated with tumor cells or other sources of antigen, exhibit significant levels of cytotoxic reactivity against certain syngeneic or allogeneic tumor cells.
Cell mediated immunity (CMI) was assessed by determining total and differential leucocyte and absolute lymphocyte counts, T and B-rosettes, PHA-blast transformation of lymphocytes, lymphocyte migration index (LMI), and DNCB response in 66 sea-level residents, 45 temporary residents, and 24 natives at high altitude (3,692 m). An accentuated CMI, indicated by increase in PHA-blasts, increased lymphocyte migration index, and intense DNCB response, was present, despite a mild decrease in total leucocytes in temporary residents and in lymphocytes in natives at high altitude. While T-rosettes did not show any change in numbers, B-rosettes were increased in temporary residents, and natives at high altitude. A qualitative change had, therefore, occurred in lymphocytes at high altitude. CMI is equally augmented in temporary residents and natives at high altitude and prevails at a higher plane than at sea-level. Augmentation of CMI at high altitude, therefore, could be used as a therapeutic measure.
Levels of immunoglobulins were determined in persons exposed to high altitude. The individuals studied included high altitude natives, sea level residents at high altitude for 2 years, and recent arrivals at high altitude. Increased IgG and IgA levels were found in high altitude natives and sea level residents at high altitude for 2 years when compared with sea level residents. In recent arrivals marked increase of IgG and IgG levels and slight rise in IgM was seen. Recent arrivals who suffered from high altitude pulmonary oedema showed marked elevation of IgG, IgM, and IgA. Immunoglobulin responses to both primary and secondary TAB inoculation were of a higher magnitude and more sustained at high altitude than at sea level.
DNA-labeling studies in alpha beta T cell receptor (TCR) transgenic mice show that the lifespan of immature CD4+8+ thymocytes is 3.5 days irrespective of whether they are selected for maturation or not. While nonselected cells die, the binding of the TCR to thymic major histocompatibility complex molecules rescues CD4+8+ cells from programmed cell death and induces first upregulation of the TCR level and then differentiation into CD4+8- or CD4-8+ cells in the absence of any cell division. When most CD4+8+ thymocytes express a selectable transgenic TCR the formation of mature cells with high TCR levels is 10-20 times as efficient as observed in normal mice, yet still only 20% of the CD4+8+ cells become mature. This is due to the limited availability of selecting 'niches': most CD4+8+ thymocytes with a selectable transgenic TCR will undergo maturation when they represent only 5% or less of all CD4+8+ cells.
Intrathymic T-cell differentiation requires a symbiotic interaction between thymic microenvironments and developing T cells. This paper attempts to provide insight into lympho-stromal interaction and reviews the architecture of thymic microenvironments, the phenotype of thymic microenvironments, the in vitro culture of thymic microenvironments, and the supportive role of thymic microenvironments in T-cell differentiation. Moreover, we discuss experimental manipulation of thymic microenvironments in vivo and in vitro, using monoclonal antibodies directed to cell surface determinants on stromal cells or their ligands on lymphoid cells. Finally, new types of experimental mouse models are considered with special reference to the role of thymic microenvironments in positive and negative selection of the T-cell repertoire, and the potential influence of T cells on the development of thymic microenvironments.
In order to get some insight on the physiology of the immune system during prolonged exposure to hypobaric hypoxia we evaluated the effects of high altitude on the in vivo immune response to a T-independent antigen. A group of 18 men who participated in a scientific project EV-K2-CNR to Mount Poumori, Nepal for 20 d at 4,930 m (16,174 ft) were immunized with a single subcutaneous dose of antimeningococcal vaccine Menpovax A + C (Sclavo) containing 50 micrograms of polysaccharide A (PsA) and 50 micrograms of polysaccharide C (PsC) of N. meningitidis. A group of 18 men of comparable age were vaccinated at sea level. Antibody titers against both polysaccharides were determined by enzyme-linked immunosorbent assay (ELISA) before and 18 d after vaccination. All subjects examined developed a good antibody response and no statistically significant differences were observed between the two groups. Spectrotypic analysis of antibody response to PsC was also performed by isoelectric focusing. No qualitative differences in the antibody response to PsC were found in the hypoxia-exposed group with respect to the control group. A group of 10 BALB/c inbred mice were kept in a hypobaric chamber at 5,500 m (18,000 ft) for 30 d. After 10 d, the mice were vaccinated with 1 micrograms of Menpovax A + C. Anti-PsA and anti-PsC antibodies were quantified by ELISA in sera collected at day 0 and 30. A control group of 10 mice of the same strain underwent the same study protocol but at sea level. Both groups developed a good antibody response to both polysaccharides and no significant differences were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Immunological aspects of the adaptation process were investigated in 57 male test subjects that stayed for 30 days at an altitude of 3600 m above sea level (Eastern Pamir Mountain Range). The uneventful development of adaptation was accompanied by a short-term decrease in the number and activity of T-lymphocytes. An acute mountain disease led to a distinct deficiency of T-cell immunity which still persisted on test day 30. Besides, the content of zero cells in circulating blood was increased and the blast-transformation reaction of lymphocytes to concanavalin A was inhibited. Prior to the ascent the test subjects who were susceptible to the acute mountain disease showed a lower content of T-lymphocytes and a higher content of zero cells in circulating blood.
In the NMRI mouse embryo, the thymus develops from the third endodermal pouch and the third ectodermal cleft. The cervical vesicle, formed not by the closure of the sinus cervicalis but by an invagination of the dorsal segment of the ectoderm between the third and fourth branchial clefts, contributes to the formation of the thymus. The intense proliferation of the ectoderm of the third cleft on the eleventh day covers the endodermal part.
The thymus is thus composed of a central endodermal region and a peripheral ectodermal region. The normal adult thymus, then, has a mixed origin, the cortical cells being ectodermal, and the medullary cells endodermal in origin.
The fourth endodermal pouch gives rise to the ultimo-branchial body, which becomes entirely incorporated within the thyroid on the fourteenth day. There is no formation of a thymus IV nor of a second pair of parathyroids from the fourth endodermal pouch.
In the Nude mouse embryo, the third branchial pouch and cleft, as well as the cervical vesicle, develop normally for the first 11½ days. From this point on, the ectoderm of the third cleft ceases to develop further. The endoderm is, now, no longer covered by ectoderm and, deprived of its normal inducing agent, ceases to develop further. Thymic dysgenesis is thus ectodermal in origin. The fourth endodermal pouch develops normally. No development of an accessory “thymus-like” structure from the fourth pouch was observed. The dysgenetic thymus originates entirely from the third branchial pouches and clefts.
In both Nude and NMRI embryos, the parathyroids develop at about 11½ days from a very limited area in the dorsal region of the cranial wall of the third endodermal pouch between the pharyngo-branchial and ecto-branchial ducts. Morphometric analysis shows that the volume of the parathyroids is the same in both strains of mice at each stage of development; nor does their microscopic appearance differ. Thus, mutation in the Nude mouse does not affect the development of the parathyroids from the third pouch, even though the first anomalies in the development of the thymus are observed at the precise moment at which the parathyroid primordium appears.
Recent advances in cell isolation techniques have greatly enhanced our understanding of the phenotype and function of hematopoietic stem cells in mice and humans. Many clinical studies have established the efficacy of using peripheral blood stem cells to supplement or replace bone marrow transplantation as a therapeutic modality for several types of malignancies. This new approach to malignant disease management, perhaps in combination with posttransplantation cytokine therapy, promises to completely alter the clinical course of bone marrow transplantation.
The polymerase chain reaction allows the characterization of RNA and DNA sequences in samples as small as a single cell. The recent development of amplification systems designed to isolate rearranged immunoglobulin genes from single B lineage cells has provided a powerful tool to investigate various aspects of B-cell development.
Differential expression of c-kit, CD25 (TAC), surrogate L chain and cytoplasmic μH chain, and surface expression of IgM and
IgD allows the separation of B220 (CD45+)B cell subpopulations. PCR analyses with DNA of single cells developed by others and by us have been used to monitor the
conformation of the Ig H and L chain gene loci in these different B lineage subpopulations. The results of these analyses
indicate that B220+/c-kit+/CD25− cells are the precursors of large B220+/CD25+/slgM− which, in turn, are the precursors of small B220+/CD25+/slgM− cells. The majority of B220+/c-kit+/CD25− cells are DHJH-rearranged, with L chain loci in germline configuration and are thus pre-B I cells. More than 90% of all large B220+/CD25+/slgM− cells have at least one H chain locus VHDHJH rearranged; half of them have also the second locus VHDHJH rearranged and are thus large pre-B II cells. Rearrangements of at least one allele of the kL chain loci become detectable
in 65% of the small B220+/CD25+/slgM− cells, 67% of the immature B and >75% of the mature B cells. The ratio of kL to λL gene rearrangements in all three subpopulations
is ˜10:1, indicating that the kL/λL ratio is established as soon as rearrangements are made.
Because of positive and negative selection to molecules of the major histocompatibility complex (MHC), only a small proportion of the massive numbers of T cells generated in the thymus are selected for export. Immature thymocytes have a rapid turnover, and it has long been assumed that most thymocytes die in situ, presumably from apoptosis. This has yet to be proved, however, and conventional staining techniques have shown only minimal evidence of cell death in the normal thymus. Using a method for detecting cells with DNA strand breaks, we now present direct evidence for apoptosis in the normal thymus. In sections of thymus from adult mice, apoptotic cells are scattered throughout the cortex and are engulfed locally by F4/80+ macrophages. Apoptosis in the thymic cortex is not reduced in MHC-deficient mice, which suggests that T-cell death is primarily a reflection of lack of positive selection rather than negative selection. Direct evidence for apoptosis due to negative selection was obtained by crossing a V beta 5 transgenic line to I-E+ and I-E- mice: I-E+ mice are known to eliminate V beta 5+ T cells in the thymus whereas I-E- mice do not. In marked contrast to I-E- mice, the medulla of I-E+ V beta 5 transgenic mice contains dense aggregates of apoptotic cells; these cells are engulfed by a distinct population of F4/80- MAC-3+ macrophages. Negative selection of V beta 5+ cells is thus restricted to the medulla.
This chapter focuses on the progress of early B cell development from pluripotent stem cells to surface immunoglobulin-positive (sIg+) B cells. The main emphasis is on work done with mice. B cell development in humans, sheep, rabbits, chicken, frogs, and fish presents similarities and differences. Early development of cells along the B lymphocyte lineage pathway is marked by: (1) successive gene rearrangements in H chain, (2) by selective expression of surface-located and intracellular markers in L chain loci, (3) by differential proliferation potential in vitro on stromal cells in the presence of cytokines, and (4) by a differential capacity to populate the B cell compartments of severe combined immune deficient (SCID) mice. The chapter provides molecular processes involved in immunoglobulin gene rearrangements, selective expression of markers and their potential functions, and proliferative and differentiating capacities of progenitors and precursors. When VH and VL gene segments are rearranged, the resulting repertoire of VH/VL combinations expressed in immunoglobulin molecules on the surface of B cells is exposed to selective processes. B lymphocyte development occurs in multiple body sites during pre- and postembryonic development, prenatally in embryonic blood, yolk sac, embryonic placenta, liver, and omentum, and postnatally in blood, spleen, and, most of all, bone marrow.
Rearrangements of the IgH locus with JH joined to reading frame 2 of DH are greatly underrepresented in B cells. These rearrangements encode the truncated heavy chain D mu. In pre-B cells, we found D mu protein expressed on the cell surface and assembled into a complex with surrogate light chains, Ig alpha, and Ig beta. Cross-linking of either mu m- or D mu m- containing pre-B cell receptors triggered signal transduction reactions. In contrast, when expressed in mature B cell lines, D mu was not detected on the cell surface and did not efficiently bind kappa immunoglobulin light chains, but did associate with Ig alpha and Ig beta. These results characterize the interactions of D mu chain with other components of the B cell antigen receptor complex and suggest possible mechanisms by which D mu expression may interfere with B cell development.
Allelic exclusion at the IgH locus was examined in B lineage cells of wild-type mice and mice unable to express the surrogate light chain molecule lambda 5 using a single-cell PCR approach. By analyzing B precursor cells containing two VHDHJH rearrangements, we found that in wild-type animals, cells are allelically excluded as soon as mu chains are expressed. Furthermore, we provide evidence that in cells expressing D mu proteins VH-->DHJH rearrangement is inhibited. In contrast, in the absence of lambda 5 protein, B precursor cells were allelically "included", indicating that allelic exclusion at the IgH locus requires expression of the pre-B cell receptor either containing a mu chain or a D mu chain. However, although mu chain double-producing B precursor cells are generated in lambda 5-deficient mice, such cells were not detected among surface immunoglobulin positive B cells.
The development of the thymus depends initially on epithelial-mesenchymal and subsequently on reciprocal lympho-stromal interactions. The genetic steps governing development and differentiation of the thymic microenvironment are unknown. With the use of a targeted disruption of the whn gene, which recapitulates the phenotype of the athymic nude mouse, the WHN transcription factor was shown to be the product of the nude locus. Formation of the thymic epithelial primordium before the entry of lymphocyte progenitors did not require the activity of WHN. However, subsequent differentiation of primitive precursor cells into subcapsular, cortical, and medullary epithelial cells of the postnatal thymus did depend on activity of the whn gene. These results define the first genetically separable steps during thymic epithelial differentiation.
Interactions between stromal cells and thymocytes play a crucial role in T cell development. The thymic stroma is complex and consists of epithelial cells derived from the pharyngeal region during development, together with macrophages and dendritic cells of bone marrow origin. In addition, fibroblasts and matrix molecules permeate the whole framework. It is now apparent that these individual stromal components play specialized roles at different stages of T cell differentiation. Thus, at the early CD4 ⁻ 8 ⁻ stage of development, T cell precursors require fibroblast as well as epithelial cell interactions. Later, at the CD4 ⁺ 8 ⁺ stage, as well as providing low avidity TCR/MHC-peptide interactions, thymic epithelial cells have been shown to possess unique properties essential for positive selection. Dendritic cells, on the other hand, are probably efficient mediators of negative selection, but they may not be solely responsible for this activity.
Alongside the functional roles of stromal cells, considerable progress is being made in unraveling the nature of the signaling pathways involved in T cell development. Identification of the pre-T cell receptor (pre-TCR) and associated signaling molecules marks an important advance in understanding the mechanisms that control gene rearrangement and allelic exclusion. In addition, a better understanding of the signaling pathways that lead to positive selection on the one hand and negative selection on the other is beginning to emerge.
Many issues remain unresolved, and some are discussed in this review. What, for example, is the nature of the chemotactic factor(s) that attract stem cells to the thymus? What is the molecular basis of the essential interactions between early thymocytes and fibroblasts, and early thymocytes and epithelial cells? What is special about cortical epithelial cells in supporting positive selection? These and other issues are ripe for analysis and can now be approached using a combination of modern molecular and cellular techniques.
T lymphocytes differentiate from hematopoietic stem cells that settle in the microenvironment of the thymus. The earliest stages of mouse alpha/beta T-cell differentiation occurring before surface expression of the TCR include three important events: proliferation, commitment to the T lineage, and rearrangement and expression of the TCR loci. Recent evidence suggests that the survival as well as differentiation of early thymocytes depends critically on molecular signals such as those generated by the recently described pre-TCR complex.
In the thymus, positive and negative selection shape the T cell repertoire. It has previously been shown that positive selection, like negative selection, is the result of the interaction of the TCR with self-peptides bound to MHC. However, little is known about the number or nature of the self-peptide ligands that mediate positive selection in vivo. We devised a novel assay with enhanced sensitivity for low affinity TCR ligands to identify self-peptides that may be biologically relevant. At least eight K(b)-bound self-peptides were detected by this assay using thymocytes bearing the OT-I TCR (specific for OVAp/K(b)). The sequence of one of these peptides was determined using the recently developed technique of membrane preconcentration-capillary electrophoresis-tandem mass spectrometry. This peptide, CP alpha1, has limited sequence similarity to OVAp, yet was found to induce positive selection of OT-I thymocytes in fetal thymic organ culture.
Gene targeting experiments have demonstrated that the expression of immunoglobulin heavy chain in the pre-B cell receptor (pBCR) and of heavy and light chains in the B cell antigen receptor (BCR) marks checkpoints in early B cell development that the cells have to pass to survive. To investigate whether the persistence of mature B cells in the peripheral immune system also depends on BCR expression, we have generated a transgenic mouse in which the BCR can be inducibly ablated through V region gene deletion. Ablation leads to rapid death of mature B lymphocytes, which is preceded by down-regulation of MHC antigens and up-regulation of CD95 (Fas) and can be delayed by constitutive bcl-2 expression.
MOUNTAINEERS have from time to time reported cases of rapid death attributed to pneumonia, occurring most often in healthy, active persons engaged in strenuous activity at altitudes from 14,000 feet upward. Most of the reports, by nonmedical authors, have appeared in lay publications. The course of the disease has been too fulminating and has not responded to adequate antibiotics to be typical of pneumonia. Consequently, some physician climbers have suspected another cause such as acute pulmonary edema. In 1959 I had the unusual opportunity of seeing such a case within reach of hospital facilities, and this single case is presented . . .
Secretory immunoglobulin A (sIgA) is the major immunoglobulin of the mucosal immune system. Whereas the suppressive effect of heavy training on mucosal immunity is well documented, little is known regarding the influence of hypoxia exposure on sIgA during altitude training. This investigation examined the impact of an 18-day Living high-training low (LHTL) training camp on sIgA levels in 11 (six females and five males) elite cross-country skiers. Subjects from the control group (n=5) trained and lived at 1,200 m of altitude, whereas, subjects from the LHTL group (n=6) trained at 1,200 m, but lived at a simulated altitude of 2,500, 3,000 and 3,500 m (3x6-day, 11 h day(-1)) in hypoxic rooms. Saliva samples were collected before, after each 6-day phases and 2 weeks thereafter (POST). Salivary sIgA, protein and cortisol were measured. There was a downward trend in sIgA concentrations over the study, which reached significance in LHTL (P<0.01), but not in control (P=0.08). Salivary IgA concentrations were still lower baseline at POST (P<0.05). Protein concentration increased in LHTL (P<0.05) and was negatively correlated with sIgA concentration after the 3,000 and 3,500 m-phase and at POST (P<0.05 all). Cortisol concentrations were unchanged over the study and no relationship was found between cortisol and sIgA. In summary, data were strongly suggestive of a cumulative negative effect of physical exercise and hypoxia on sIgA levels during LHTL training. Two weeks of active recovery did not allow for proper sIgA recovery. The mechanism underlying this depression of sIgA could be mediated by neural factors.
The purpose of this study was to investigate the changes in T-lymphocyte subsets in soccer players during "living high--training low" (LHTL) for 28 days in comparison to equally trained control players. Sixteen male soccer players were randomly assigned into two groups. The LHTL group lived in normobaric hypoxic rooms, simulating an altitude of 3000 m for 10 hours per night for 28 days. The control group lived at sea level. Both LHTL and control groups trained together at sea level and completed the same training schedules. The blood samples were collected prior to the trial (baseline) and at 1, 14, 21 and 28 days of the trial, respectively. Lymphocyte subsets were quantitated using the recommended flow cytometry method. The results showed that the relative changes from the baseline in the CD4 (+)/CD8 (+) ratio, in both LHTL and control groups, followed a similar downward trend during the trial. However, the trend was more pronounced in the LHTL group. In the LHTL group, significant differences were seen at both 14 and 28 days compared to the baseline. In addition, a significant difference was also observed between the groups at 14 days. During LHTL, hypoxia may augment the effect which training may have on T-lymphocyte subsets after 14 days, even when training was not performed under hypoxic condition. The long term effect of LHTL was unknown at this time and needs further investigation.
One hundred years ago the birth of immunology was made official by the Nobel Prize award to Elie Metchnikoff and Paul Ehrlich. Metchnikoff discovered phagocytosis by macrophages and microphages as a critical host-defense mechanism and thus is considered the father of cellular innate immunity. Ehrlich described the side-chain theory of antibody formation and the mechanisms of how antibodies neutralize toxins and induce bacterial lysis with the help of complement and thus is considered one of the fathers of humoral adaptive immunity. Despite many discordant discussions in the initial phase after these discoveries, innate and adaptive responses are now known to be complementary partners in producing robust immunity.
Comparative evaluation of studies of the action of different Immunol Invest Downloaded from informahealthcare.com by University of Notre Dame Australia on 05/07/13 For personal use only. High Altitude and Immune Response 233 levels of hypoxia on the human immunobiological status
- T K Krupina
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- N P Lichacheva
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T and B components of immunity in the presence of acute mountain sickness
- M M Mirrakhimov
- M I Kitaev
- A G Khamzamulin Tokhtabaev
- S M Pogrebitskiy
Natural killer Cells. Encyclopedia of Immunology
- T L Whiteside
Neuroimmuno humoral changes associated with altitude training (abstr)
- P N Uchakin
- E P Gotovtseve
- B Levine
- J Stray-Gundersen
- Whiteside T. L