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Progesterone and Autoimmune Disease
Abstract
Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-α) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg's immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations.
... Figure 1 illustrates the main immunomodulatory effects of P4. This specific immunosuppressive action of P4 is associated with the inhibition of the Th1 and Th17 pathways, which can shorten the active course of some chronical autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis [65]. Hormone Figure 1. ...
... Figure 1 illustrates the main immunomodulatory effects of P 4 . This specific immunosuppressive action of P 4 is associated with the inhibition of the Th1 and Th17 pathways, which can shorten the active course of some chronical autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis [65]. Hormone replacement therapy (HRT) can also be an example of the anti-inflammatory action of P 4 since this hormone reverses the menopausal CD4/CD8 ratio, as well as limits the general peri-and postmenopausal inflammatory state [66]. ...
... In addition to its own inhibition of T-cell activation, P 4 has a significant effect on dendritic cells, NK cells, and macrophages ( Figure 1C). In macrophages, P 4 decreases the expression of iNOS, NO, and TNFα and the release of prothrombotic factors [65]. In dendritic cells, P 4 decreases CD40, CD80, CD86, TNF-α, IL-1β, IL-6, and IL-12 and increases IL-10, IL-8, and CD11c [39]. ...
The specific regulation of inflammatory processes by steroid hormones has been actively studied in recent years, especially by progesterone (P4) and progestins. The mechanisms of the anti-inflammatory and immunomodulatory P4 action are not fully clear. The anti-inflammatory effects of P4 can be defined as nonspecific, associated with the inhibition of NF-κB and COX, as well as the inhibition of prostaglandin synthesis, or as specific, associated with the regulation of T-cell activation, the regulation of the production of pro- and anti-inflammatory cytokines, and the phenomenon of immune tolerance. The specific anti-inflammatory effects of P4 and its derivatives (progestins) can also include the inhibition of proliferative signaling pathways and the antagonistic action against estrogen receptor beta-mediated signaling as a proinflammatory and mitogenic factor. The anti-inflammatory action of P4 is accomplished through the participation of progesterone receptor (PR) chaperones HSP90, as well as immunophilins FKBP51 and FKBP52, which are the validated targets of clinically approved immunosuppressive drugs. The immunomodulatory and anti-inflammatory effects of HSP90 inhibitors, tacrolimus and cyclosporine, are manifested, among other factors, due to their participation in the formation of an active ligand–receptor complex of P4 and their interaction with its constituent immunophilins. Pharmacological agents such as HSP90 inhibitors can restore the lost anti-inflammatory effect of glucocorticoids and P4 in chronic inflammatory and autoimmune diseases. By regulating the activity of FKBP51 and FKBP52, it is possible to increase or decrease hormonal signaling, as well as restore it during the development of hormone resistance. The combined action of immunophilin suppressors with steroid hormones may be a promising strategy in the treatment of chronic inflammatory and autoimmune diseases, including endometriosis, stress-related disorders, rheumatoid arthritis, and miscarriages. Presumably, the hormone receptor- and immunophilin-targeted drugs may act synergistically, allowing for a lower dose of each.
... Progesterone receptors are present in many tissues outside reproductive organs, including the brain, breast, vascular endothelium, lung, and bone. In the immune system, intracellular progesterone receptors have been documented in human mast cells, NK cells, and macrophages, whereas extracellular progesterone receptors have been detected in CD4 þ and CD8 þ T cells (83,84). Binding of progesterone to intracellular progesterone receptors leads to nuclear localization of the receptor, interaction with coregulatory proteins and chromatin, and activation or suppression of target genes (85). ...
... Binding of progesterone to intracellular progesterone receptors leads to nuclear localization of the receptor, interaction with coregulatory proteins and chromatin, and activation or suppression of target genes (85). Extracellular progesterone receptors, upon activation, interact with inhibitory G-coupled protein receptors that are thought to be responsible for the rapid, nongenomic effects of progesterone (84,86). The specific effects of progesterone signaling are not fully understood. ...
Recently, there has been increased recognition of the importance of sex as a biological factor affecting disease and health. Many preclinical studies have suggested that males may experience a less favorable outcome in response to sepsis than females. The underlying mechanisms for these differences are still largely unknown but are thought to be related to the beneficial effects of estrogen. Furthermore, the immunosuppressive role of testosterone is also thought to contribute to the sex-dependent differences that are present in clinical sepsis. There are still significant knowledge gaps in this field. This mini-review will provide a brief overview of sex-dependent variables in relation to sepsis and the cardiovascular system. Preclinical animal models for sepsis research will also be discussed. The intent of this mini-review is to inspire interest for future considerations of sex related variables in sepsis that should be addressed to increase our understanding of the underlying mechanisms in sepsis-induced cardiovascular dysfunction for identification of therapeutic targets and improved sepsis management and treatment.
... Progesterone is the main active ingredient of oral contraceptive pills and a precursor to many steroid hormones such as cortisone, playing an essential role in the human life [5,6]. Since Ruseel Marker discovered steroid sapogenins in Mexican yams could be turned into the hormone progesterone in a single step, the progesterone is still used today as a raw material for the production of many drugs, utilized in clinical treatment to save countless people from the suffering of various diseases [7][8][9][10][11]. The pharmacological activities of compounds depend on molecular structures, and in turn, specific steric structures may also bring attractive physical properties, such as piezoelectricity or ferroelectricity (necessary conditions for crystallisation in non-centrosymmetric or polar point groups) [12]. ...
Progesterone and its derivatives attracted widespread interest because of their applications in medicine, health care and birth control, which is the main active ingredient of contraceptive pills known as one of the five chemistry discoveries that changed human life. Although the research of pharmacological effects on contraceptive pill-related compounds has been around for decades, their ferroelectricity has long been overlooked. Here, we report that 4-androsten-3-one-5-ene-17-carboxylic acid, a derivative of progesterone, is an organic single-component ferroelectric, as confirmed by the polarization–electric field hysteresis loops. It crystallizes in the monoclinic space group P21 with a polar packing structure and undergoes a reversible structural phase transition at a high temperature of 489 K. Thermal analysis revealed that its ferroelectricity can persist up to 533 K, giving a wide working temperature range. As the first ferroelectric in steroid biomaterials, 4-androsten-3-one-5-ene-17-carboxylic acid shows great potential in applications for flexible devices, biomedical devices, bio-machines and so on.
... The conflict with the results of previous published study [49] may be attributed to the differences in the used animal, drug-delivery way, and PRG dosage. High concentrations of PRG have been reported to exert immunomodulatory functions that inhibit the autoimmune response, while low concentrations may have the opposite effect [50]. Administration of high level of PRG could match the physiological serum levels of PRG in pregnant mice, thereby rescuing letrozole-induced implantation failure [51,52]. ...
Background
Autoimmune uveitis (AU) is the most common ophthalmic autoimmune disease (AD) and is characterized by a complex etiology, high morbidity, and high rate of blindness. AU remission has been observed in pregnant female patients. However, the effects of progesterone (PRG), a critical hormone for reproduction, on the treatment of AU and the regulatory mechanisms remain unclear.
Methods
To this end, we established experimental autoimmune uveitis (EAU) animal models and constructed a high-dimensional immune atlas of EAU-model mice undergoing PRG treatment to explore the underlying therapeutic mechanisms of PRG using single-cell RNA sequencing.
Results
We found that PRG ameliorated retinal lesions and inflammatory infiltration in EAU-model mice. Further single-cell analysis indicated that PRG reversed the EAU-induced expression of inflammatory genes (AP-1 family, S100a family, and Cxcr4) and pathological processes related to inflammatory cell migration, activation, and differentiation. Notably, PRG was found to regulate the Th17/Treg imbalance by increasing the reduced regulatory functional mediators of Tregs and diminishing the overactivation of pathological Th17 cells. Moreover, the Id2/Pim1 axis, IL-23/Th17/GM-CSF signaling, and enhanced Th17 pathogenicity during EAU were reversed by PRG treatment, resulting in the alleviation of EAU inflammation and treatment of AD.
Conclusions
Our study provides a comprehensive single-cell map of the immunomodulatory effects of PRG therapy on EAU and elaborates on the possible therapeutic mechanisms, providing novel insights into its application for treating autoimmune diseases.
... Progesterone is the main active ingredient of oral contraceptive pills and a precursor to many steroid hormones such as cortisone, playing an essential role in the human life [5,6]. Since Ruseel Marker discovered steroid sapogenins in Mexican yams could be turned into the hormone progesterone in a single step, the progesterone is still used today as a raw material for the production of many drugs, utilized in clinical treatment to save countless people from the suffering of various diseases [7][8][9][10][11]. The pharmacological activities of compounds depend on molecular structures, and in turn, speci c steric structures may also bring attractive physical properties, such as piezoelectricity or ferroelectricity (necessary conditions for crystallisation in non-centrosymmetric or polar point groups) [12]. ...
Progesterone and its derivatives attracted widespread interest because of their applications in medicine, health care and birth control, which is the main active ingredient of contraceptive pills known as one of the five chemistry discoveries that changed human life. Although the research of pharmacological effects on contraceptive pill-related compounds has been around for decades, their ferroelectricity has long been overlooked. Here, we report that 4-androsten-3-one-5-ene-17-carboxylic acid, a derivative of progesterone, is an organic single-component ferroelectric, as confirmed by the polarization − electric field hysteresis loops. It crystallizes in the monoclinic space group P 2 1 with a polar packing structure and undergoes a reversible structural phase transition at a high temperature of 489 K. Thermal analysis revealed that its ferroelectricity can persist up to 533 K, giving a wide working temperature range. As the first ferroelectric in steroid biomaterials, 4-androsten-3-one-5-ene-17-carboxylic acid shows great potential in applications for flexible devices, biomedical devices, bio-machines and so on.
... Progesterone induces the dedifferentiation of Tregs but suppresses the differentiation of Th17 cells via suppressing the production of IL-17A, IL-17F, and IL-21, as well as the expression of RORc in human cord blood cells. Furthermore, progesterone can also suppress the phosphorylation of STAT3 in response to IL-6 [165]. Overall favors Th2/Treg activities but suppresses Th1/Th17 activities, which is particularly advantageous for the acceptance of an allogeneic fetus during pregnancy [166]. ...
Atopic dermatitis (AD) or atopic eczema is an increasingly manifested inflammatory skin disorder of complex etiology which is modulated by both extrinsic and intrinsic factors. The exposome includes a person’s lifetime exposures and their effects. We recently reviewed the extrinsic exposome’s environmental risk factors that contribute to AD. The periods of pregnancy, infancy, and teenage years are recognized as crucial stages in the formation of AD, where the exposome leads to enduring impacts on the immune system. However, research is now focusing on the interactions between intrinsic pathways that are modulated by the extrinsic exposome, including genetic variation, epigenetic modifications, and signals, such as diet, stress, and microbiome interactions. As a result, immune dysregulation, barrier dysfunction, hormonal fluctuations, and skin microbiome dysbiosis are important factors contributing to AD development, and their in-depth understanding is crucial not only for AD treatment but also for similar inflammatory disorders.
... Progestins are used to treat several disorders, including endometriosis, irregular uterine bleeding, and menopausal symptoms, in addition to contraception [74]. It can be used to treat autoimmune conditions including lupus and multiple sclerosis [75]. ...
Microbe bioengineering has the potential to improve the nutritional value and health benefits of food products. Modifying microbial cells to produce specific proteins or compounds that can improve human health is one approach. Penicillin and recombinant insulin are two examples of this. The production of recombinant insulin by genetically modified E. coli bacteria has transformed diabetes treatment by providing a consistent and cost-effective source of insulin. Previously, insulin was extracted from the pancreas of animals, which was an expensive process that frequently resulted in impurities that could cause adverse reactions. Bioengineered insulin is now the standard diabetes treatment, providing a safe and effective method of controlling blood glucose levels. Bacteria, for example, can be genetically modified to produce vitamins like B12, which are difficult to obtain from plant sources. Likewise, yeasts can be genetically modified to produce β-carotene, a precursor to vitamin A that is required for vision, immune function, and skin health. Overall, bioengineered microorganisms have the potential to provide significant health benefits by producing essential compounds and proteins. Because of ongoing advances in genetic engineering techniques and understanding microbial metabolism, the possibilities for improving human health through bioengineering are limitless.
... Because endogenous progesterone (pregn-4-ene-3,20-dione, P4) levels are >40 times higher in the luteal versus the follicular phase of the human menstrual cycle, 86 it has been identified as the likely mediator of luteal immunosuppression, both in the FRT and systemically. [87][88][89][90] While dampening immunity after ovulation helps to allow successful implantation of a fertilized embryo in the uterus, the immunosuppressive activity of high endogenous P4 levels may on the flip side limit the response to vaccination or increase the risk of infection. The former has been suggested by mouse studies, 91 the latter for HIV and chlamydia trachomatis risk during the luteal phase in women. ...
Tissue‐resident memory T cells (TRM) are considered to be central to maintaining mucosal barrier immunity and tissue homeostasis. Most of this knowledge stems from murine studies, which provide access to all organs. These studies also allow for a thorough assessment of the TRM compartment for each tissue and across tissues with well‐defined experimental and environmental variables. Assessing the functional characteristics of the human TRM compartment is substantially more difficult; thus, notably, there is a paucity of studies profiling the TRM compartment in the human female reproductive tract (FRT). The FRT is a mucosal barrier tissue that is naturally exposed to a wide range of commensal and pathogenic microbes, including several sexually transmitted infections of global health significance. We provide an overview of studies describing T cells within the lower FRT tissues and highlight the challenges of studying TRM cells in the FRT: different sampling methods of the FRT greatly affect immune cell recovery, especially of TRM cells. Furthermore, menstrual cycle, menopause, and pregnancy affect FRT immunity, but little is known about changes in the TRM compartment. Finally, we discuss the potential functional plasticity of the TRM compartment during inflammatory episodes in the human FRT to maintain protection and tissue homeostasis, which are required to ensure reproductive fitness.
... This may occur at the ovarian/endometrial level. Progesterone is primarily an anti-inflammatory hormone and is present in the ovaries [63]. During the premenstrual period, progesterone levels drop dramatically, leading to an influx of inflammatory cells into the local endometrial environment, which eventually leads to the shedding of functional endometrium during menstruation [64]. ...
Background:
It has been more than 2 years since the 2019 novel coronavirus disease (COVID-19) pandemic destabilized the world, adversely affecting not only physical health, but also mental health. During this time, frontline medical workers were at a greater health risk, especially female medical workers. Changes or abnormalities in the menstrual cycle-an important indicator of women's health-may jeopardize female reproductive functioning. Considering that emotional health and sleep status may be related to the menstrual cycle, this study aimed to investigate the association between menstrual cycle changes, anxiety, sleep dysfunction, and other factors among female medical workers during the COVID-19 pandemic.
Methods:
A cross-sectional survey was conducted by distributing online questionnaires to female medical workers in China from February to May 2022. The study included 160 women aged 18-45 years old. The questionnaires covered data related to the participants' sociodemographic characteristics, medical and reproductive history, and lifestyle. The Rating Scale for Clinical Manifestations of Menopathy (SCMM), Self-Rating Anxiety Scale (SAS), and Sleep Dysfunction Rating Scale (SDRS) were utilized. Data were analyzed using chi-square tests, t-tests, and linear regression analysis.
Results:
A total of 160 female medical staff were randomly selected in this research, of whom seven scored less than 3 points, 85 scored 3-11 points, and 68 scored more than 11 points on the total score of the SCMM. Compared to pre-pandemic scores, scores of dizziness and tinnitus were significantly higher during the COVID-19 pandemic. Scores corresponding to the following clinical symptoms were also higher during the pandemic: Menopathy, including hypaphrodisia, dim complexion, abnormal urination, languidness, dim menstruation, thin menstruation, dysmenorrhea, and empty or saggy lower abdomen (p < 0.05). However, pre-pandemic scores of vaginal bleeding quantity were significantly higher than those found during the COVID-19 pandemic (p < 0.05). Scores of vaginal bleeding quantity were significantly lower in cabin hospitals than other types of hospitals, and a similar finding was observed for vaginal bleeding duration (all p < 0.05). Moreover, the findings of the univariable and multivariable linear regression analysis revealed a link between consistent exercise, the underlying illness, the SDRS score, the SAS score, and the total score of SCMM (p < 0.05).
Conclusions:
In this study, we found that menstruation in female medical workers was affected by the COVID-19 pandemic. Furthermore, regular exercise and good physical condition were protective factors, while anxiety and insomnia were risk factors for menstrual abnormalities.
... Dienogest binds to the progesterone receptor, reduces systemic gonadotropin production, and exerts local antiproliferative and anti-inflammatory effects on endometriotic lesions when administered continuously, which is extremely selective for progesterone receptors (PGRs) and limits blood estrogen levels by stopping ovulation. Additionally, it encourages death and inhibits the growth of endometriotic cells [13][14][15]. ...
Introduction: Endometriosis is a severe disorder marked by endometrial tissue outside the uterus and linked to infertility, although typically manifesting as discomfort in the form of dysmenorrhea, dyspareunia, and pelvic pain. Dienogest is indicated as a first-line hormone treatment for endometriosis-related discomfort. The aim of this study is to analyze the efficacy of Dienogest on treating pelvic pain and dyspareunia compared to placebo or combined oral contraceptives (COC) in women with endometriosis. Methods: A systematic search is conducted in PubMed, ScienceDirect, and Google Scholar. The PRISMA 2020 rules were used to screen the articles that were obtained. For the review, studies that examined how using dienogest in improving endometriosis were exposed to were taken into consideration. In a meta-analysis utilizing a random-effects model, odds ratios with their 95% confidence intervals (CI) were provided. Results: Five studies that met the criteria for inclusion were determined to be pertinent to the association between using dienogest in improving endometriosis (n=711). The Dienogest group had substantially improve pelvic pain with a mean difference of 1.01 (95% CI 1.2, 0.82; p<0.00001) and dyspareunia with a mean difference of 0.58 (95% CI 1.09, 0.08; p=0.02) compared to placebo. Compared to combined oral contraceptives, COC had substantially improves dyspareunia with a mean difference of 0.99 (95% CI 0.62, 1.37; p<0.00001) and pelvic pain with a mean difference of 1.15 (95% CI 0.23, 0.83; p=0.01). Conclusion: Dienogest should be considered as an alternate treatment for endometriosis-related symptoms. In double-blind research, DNG efficacy was compared to placebo.
... Progesterone (P4) is a small amount of C21 steroid hormone secreted by the corpus luteum, which plays a diagnostic role for threatened abortion, habitual abortion [1][2][3], and other amenorrhea [4,5]. The detection of P4 has been one of the main physicochemical indexes of water, milk, mammalian blood, and body fluids, which exhibited the focus in current research. ...
Progesterone (P4) is an important biomarker of various diseases. When P4 level exceeds the normal value, the human body produces a series of problems, including carcinogenic risks. Developing the method for P4 monitoring with accurate, inexpensive, and fast becomes an important topic for researchers. In recent years, the abundance of new materials and synthesis technologies has developed P4 biosensors. Based on functional materials, this paper reviews the recent decade literatures and summarizes the latest progress and applications in enhancing detection of P4. In this study, the functional materials used to manufacture P4 biosensors are mainly divided into three categories: metal and metal-oxide nanomaterials, composite material, and other materials. A composite material refers to a combination of two or three types of materials, including carbonaceous nanomaterials, metal nanomaterials, polymers, and biological materials. The other materials mainly include a combination of special compounds, biomaterials, luciferin materials, and quantum dot materials, of which one or two. The introduction of these new functional materials improves the sensitivity and selectivity of P4 detection. Moreover, this study provides ideas for the future research on improving the performance of P4 biosensor. The future study should put more attentions on enzyme catalysis amplification, cyclic amplification, and DNA isothermal amplification strategies.
... This protective mechanism allows for energy resources to be diverted from reproduction to immune response [46]. This could also explain the menstrual cessation or irregularity reported amongst women experiencing long-term symptoms of Ebola infection (post-Ebola syndrome; possibly analogous to long COVID-19) [47]. Alternatively, or in addition, at the ovarian/endometrial level there could be more specific interactions between the reproductive system and SARS-CoV-2 infection. ...
The coronavirus disease no longer seems to represent an insurmountable global problem. This is thanks to the advent of coronavirus vaccines, which have alleviated the most serious symptoms associated with this disease. On the other hand, there are still many extrapulmonary symptoms of COVID-19, and among these also those of a gynecological nature. At the moment, there are several questions in this field, one above all concerns the causal link between COVID-19, vaccines and
gynecological alterations. Furthermore, another important aspect is represented by the clinical impact of post-COVID-19 gynecological alterations on the female population which, to date, would seem to be mainly due to their duration, even if the extent of these symptoms is still poorly understood.
Furthermore, it is not possible to foresee eventual long-term aggravations, or more serious symptoms caused by other viral variants that may arrive in the future. In this review, we focus on this theme and attempt to reorganize the different pieces of a puzzle which, to date, does not seem to have shown us its complete picture.
... However, progesterone opposes estradiol in its immunomodulatory effects. Estradiol is, in many cases, viewed as an enhancer of immune processes while progesterone is considered immunosuppressive and may have the ability to neutralize the effect of estrogens (72). For example, while estradiol may enhance SLE severity by modulating T helper cell cytokine secretion, progesterone has been shown to ease pro inflammatory signaling by inhibition of Th1 and Th17 cells (73). ...
The majority of autoimmune diseases affect more women than men, suggesting an important role for sex hormones in regulating immune response. Current research supports this idea, highlighting the importance of sex hormones in both immune and metabolic regulation. Puberty is characterized by drastic changes in sex hormone levels and metabolism. These pubertal changes may be what forms the gulf between men and women in sex bias towards autoimmunity. In this review, a current perspective on pubertal immunometabolic changes and their impact on the pathogenesis of a select group of autoimmune diseases is presented. SLE, RA, JIA, SS, and ATD were focused on in this review for their notable sex bias and prevalence. Due to both the scarcity of pubertal autoimmune data and the differences in mechanism or age-of-onset in juvenile analogues often beginning prior to pubertal changes, data on the connection between the specific adult autoimmune diseases and puberty often relies on sex hormone influence in pathogenesis and established sex differences in immunity that begin during puberty.
... This may occur at the ovarian/endometrial level. Progesterone is primarily an antiin ammatory hormone found in the ovary [32]. Before menstruation, progesterone levels drop sharply, which causes an in ux of in ammatory cells into the local endometrial environment, which ultimately causes the functional endometrium to shed at menstruation [33]. ...
Objective
Coronavirus disease 2019 (COVID-19) can affect women 's health. This study aimed to investigate the association between Menopathy, COVID-19 pandemic-related anxiety, sleep dysfunction and other factors among female medical staff.
Methods
A cross-sectional study was conducted via administrating online questionnaires to female medical staff in China from February to May 2022. The study includes 160 women aged between 18–45 years old. The questionnaires contain sociodemographic characteristics, medical and reproductive history, lifestyle information of participants, Rating Scale for Clinical Manifestation of Menopathy (SCMM), Self-Rating Anxiety Scale (SAS), and Sleep Dysfunction Rating Scale (SDRS). Data were analyzed using chi-square, t-tests, and linear regression analysis.
Results
A total of 160 female medical staff were randomly selected in this research, 7 of whom scored less than 3 points, 85 of whom scored more than 2 points and less than 12 points, and 68 of whom scored more than 11 points on the total score of SCMM. The score of dizziness and tinnitus was significantly higher during than before the COVID-19 pandemic, and scores of its following clinical symptoms of Menopathy: hypaphrodisia, dim complexion, abnormal urination, languidness, dim menstruation, thin menstruation, dysmenorrhea, and empty or saggy lower abdomen (p < 0.05). However, the score of vaginal bleeding quantity was significantly higher before than during the COVID-19 pandemic (p < 0.05). The score of vaginal bleeding quantity of the female medical staff was significantly lower in the cabin hospitals than others, and the same is true for vaginal bleeding duration (all p < 0.05). Besides, the findings of the univariable and multivariable linear regression analysis revealed a link between consistent exercise, the underlying illness, the SDRS score, the SAS score, and the total score of SCMM (p < 0.05).
Conclusions
In this study, we found that menstruation in female health staff was affected by the COVID-19 epidemic, where regular exercise and good physical condition were protective factors, while anxiety and insomnia were risk factors for regular menstruation.
... Isso pode ocorrer no nível ovariano e no endométrio. A progesterona é predominantemente anti-inflamatória(Hughes, 2012). Os níveis de progesterona caem antes da menstruação, com um fluxo de células inflamatórias para o ambiente endometrial que leva à descamação do endométrio na menstruação(Maybin & Critchley, 2015). ...
Desde que foi decretada em dezembro de 2019, a pandemia da COVID-19 tomou enormes proporções. Neste contexto em que todos os aspectos da vida humana foram afetados, torna-se importante, no âmbito da saúde feminina, compreender quais os impactos da COVID-19 no ciclo menstrual, visto sua importância na vida das mulheres. O objetivo deste trabalho foi buscar estudos capazes de descrever as mudanças no ciclo menstrual observadas devido à COVID-19 e a fisiopatologia que está ligada a essas alterações, bem como suas consequências. Um ciclo menstrual normal é um indicador de boa saúde, ao passo que distúrbios no ciclo menstrual podem indicar condições subjacentes.. Diferentes tipos de células encontradas nas gônadas mostram a expressão da enzima conversora de angiotensina 2 (ECA2) e serina protease transmembrana subtipo 2 (TMPRSS2), que fornecem vias de entrada fundamentais para o vírus SARS-CoV-2 na célula. Além disso, os efeitos biológicos sistêmicos da infecção por COVID-19 podem influenciar no eixo hipotálamo-hipófise-adrenal, aumentando o estresse e, consequentemente, o cortisol, exercendo um efeito global sobre o funcionamento do corpo. A revisão sistemática demonstrou que a COVID-19 influencia, de maneira reversível, no aumento ou diminuição na duração do ciclo, irregularidade menstrual, aumento do fluxo menstrual, escapes intermenstruais e sintomas mais intensos no período pré-menstrual, como dor abdominal e aumento da tensão pré-menstrual. Além disso, o impacto da pandemia na saúde mental e no comportamento sexual podem afetar a reprodução humana, sendo assim, a pandemia foi associada a um declínio na satisfação sexual, menor libido e menor frequência sexual.
... 1β IL-1β, IL-10, TNF * ND: No data.[12,14,44,[46][47][48][49][50][51][52]. ...
Sex has been universally acknowledged as a confounding factor in every type of biological study, while there are strong sex differences in morbidity along the lifespan. Humans have almost identical genomes (99.2%), yet minor variance in their DNA produces remarkable phenotypic diversity across the human population. On the other hand, metagenomic analysis of the human microbiome is more variable, depending on the sex, lifestyle, geography, and age of individuals under study. Immune responses in humans also exhibit variations, with an especially striking sexual dimorphism, which is at play in several other physiologic processes. Sex steroids have noticeable effects on the composition of the human microbiome along the lifespan, accompanied by parallel changes in immunity and the stress response. Gut microsex/genderome, a recently coined term, defines the sexually dimorphic gut microbiome. Apart from the sex steroids, the stress hormones are also at play in the proliferation of microbes. This review summarizes the concept of gut microsex/genderome under the prism of recent studies on the interrelations of the sexually dimorphic microbiome with immunity and stress.
... Progesterone inhibits macrophage growth, IL6 generation, and peripheral antibody production [82]. Oscillations in progesterone levels during pregnancy and the ovulatory cycle are thought to be linked to reversible immune system alterations [83]. ...
As the prevalence of endocrine dysfunction is increasing and is associated with many complications including polycystic ovary syndrome (PCOS) which, itself is a risk factor of thyroid dysfunction. Although the causality of this association is uncertain, the two conditions share a bidirectional relationship. Both syndromes share certain common characteristics, risk factors and pathophysiological abnormalities, which can be managed by lifestyle changes as well as pharmacological treatment. Polycystic appearing ovaries are a clinical feature of hypothyroidism as well as hyperthyroidism in a few case studies. Adiposity, evidence of deranged autoimmunity, increased insulin resistance and disturbed leptin levels are present in both the disease states, seeming to play a complex role in connecting these two disorders. Major endocrine pathways including hypothalamic-pituitary-thyroid axis (HPTA) and HP-gonadal axis are involved in parallel relationship of PCOS and thyroid dysfunction. This chapter helps to explore all the dimensions of the relationship between PCOS and thyroid dysfunction.
... Female-dominant autoimmune disease symptoms tend to decrease during menstruation and pregnancy, and increase after menopause (Hughes, 2012;Hughes and Choubey, 2014). PR is expressed by several immune cell types and is well known for its ability to suppress T cell activation during pregnancy (Arruvito et al., 2008;Shah et al., 2019;Szekeres-Bartho et al., 2001). ...
Synopsis
The cancer research field is finally starting to unravel the mystery behind why males have a higher incidence and mortality rate than females for nearly all cancer types of the non-reproductive systems. Here, we explain how sex – specifically sex chromosomes and sex hormones – drive differential adaptive immunity across immune-related disease states including cancer, and why males are consequently more predisposed to tumor development. We highlight emerging data on the roles of cell-intrinsic androgen receptor in driving CD8+ T cell dysfunction or exhaustion in the tumor microenvironment and summarize on-going clinical efforts to determine the impact of androgen blockade on cancer immunotherapy. Finally, we outline a framework of future research in cancer biology and immuno-oncology, underscoring the importance of a holistic research approach to understand the mechanisms of sex dimorphisms in cancer, so sex will be considered as an imperative factor for guiding treatment decisions in the future.
... The reduction in endogenous P4 that occurs with OC use may also contribute to effects on Treg cells. P4 acts to skew T cell differentiation away from proinflammatory Th1 and Th17 and toward protolerogenic Th2 and Treg cell phenotypes (39,67,68), promoting anti-inflammatory interleukin (IL) 10 expression over proinflammatory cytokines tumor necrosis factor, interferon-gamma (IFNG) and IL12 (36). Elevated P4 in the luteal phase of natural cycles is thought to embed Treg stability and promote uterine Treg cell accumulation in readiness for potential pregnancy (16,69) through systemic effects reflected in peripheral blood (70,71). ...
Regulatory T (Treg) cells are a specialized CD4 + T cell subpopulation that are essential for immune homeostasis, immune tolerance, and protection against autoimmunity. There is evidence that sex-steroid hormones estrogen and progesterone modulate Treg cell abundance and phenotype in women. Since natural oscillations in these hormones are modified by hormonal contraceptives, we examined whether oral contraception (OC) use impacts Treg cells and related T cell populations. T cells were analyzed by multi-parameter flow cytometry in peripheral blood collected across the menstrual cycle from healthy women either using OC or without hormonal contraception, and from age-matched men. Compared to naturally cycling women, women using OC had fewer Treg cells and an altered Treg cell phenotype. Notably, Treg cells exhibiting a strongly suppressive phenotype, defined by high FOXP3, CD25, Helios, HLADR, CTLA4 and Ki67, comprised a lower proportion of total Treg cells, particularly in the early-cycle and mid-cycle phases. The changes were moderate compared to more substantial differences in Treg cells between women and men, wherein women had fewer Treg cells - especially of the effector memory Treg cell subset - associated with more T helper type 1 (Th1) cells and CD8 + T cells and lower Treg: Th1 cell and Treg: CD8 + T cell ratios than men. These findings imply that OC can modulate the number and phenotype of peripheral blood Treg cells and raise the possibility that Treg cells contribute to the physiological changes and altered disease susceptibility linked with OC use.
... Studies indicate that progesterone mediates immunological effects distinct from estradiol and testosterone [58]. Progesterone appears to counteract many of the effects of estradiol, thereby ameliorating the risk of lupus-like disease [59]. ...
Humans are afflicted by a wide spectrum of autoimmune disorders, ranging from those affecting just one or a few organs to those associated with more systemic effects. In most instances, the etiology of such disorders remains unknown; a consequence of this lack of knowledge is a lack of specific treatment options. Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder; pathology is believed to be antibody-mediated, and multiple organs are targeted. Periods of disease “flares” are often followed by long periods of remission. The fact that SLE is more commonly observed in females, and also that it more particularly manifests in females in the reproductive age group, has quite naturally drawn attention to the potential roles that hormones play in disease onset and progression. This review attempts to shed light on the influences that key hormones might have on disease indicators and pathology. Databases (Google Scholar, PubMed) were searched for the following keywords (sometimes in certain combinations), in conjunction with the term “lupus” or “SLE”: autoantibodies, recurrent abortion, polycystic ovarian syndrome (PCOS), preeclampsia, pre-term delivery, estrogens, progesterone, androgens, prolactin, leptin, human chorionic gonadotropin (hCG). Cited publications included both research articles and reviews.
... These include compounds such as PAHs, phthalates, metalloestrogens, and alkylphenols [57], many of which act as ligands in estrogen receptors, thereby altering signaling activities [58]. Progesterone can contribute to the pathophysiology of MS by inhibiting T helper cells [59]. However, the components of air pollution mediating these harmful consequences in the CNS have not yet been fully characterized as in (Figure 1). ...
Epidemiology findings show that exposure to urban air pollutants as a source of oxidative stress and neuroinflammation is associated with the central nervous system (CNS) demyelinating diseases, such as multiple sclerosis (MS). An autoimmune response involving increased inflammation and demyelination in the CNS leads to the pathophysiology of MS, which is more common in adult young females. Particulate matter (PM), including fine particles (PM <2.5μm, PM 2.5) and very fine particles (PM <0.1μm, PM 0.1), transition metals, and ozone are of potent or oxidant capable of producing reactive oxygen species (ROS). Redox-sensitive pathways can be caused by oxidative stress, leading to various biological processes, including inflammation and other harmful outcomes in the brain. Exposure to diesel exhaust particles (DEPs) mediates significant alterations in myelination across various regions in the brain. There is also an increase in ROS production in the CNS of DEPs exposed mice. Thus, targeting neuroinflammation and oxidative stress can be a useful strategy to eliminate the obvious symptoms of CNS demyelinating diseases. Overall, in the current mini-review, we examined the exposure to air pollutants nanoparticles associated with the CNS demyelinating diseases, such as MS.
... MAPK integrates crosstalk with multiple signaling pathways, such as the Ras/MAPK pathway, ErbB pathway, and PI3K-Akt pathway. Together, these signaling pathways play a role in osteoblast growth, proliferation, apoptosis angiogenesis, and inflammation regulation [64][65][66][67][68][69]. There has been some evidence of a therapeutic role for SAN in hoof disease-related disorders. ...
Based on network pharmacological analysis and molecular docking techniques, the main components of M. cordata for the treatment of bovine relevant active compounds in M. cordata were searched for through previous research bases and literature databases, and then screened to identify candidate compounds based on physicochemical properties, pharmacokinetic parameters, bioavailability, and drug-like criteria. Target genes associated with hoof disease were obtained from the GeneCards database. Compound−target, compound−target−pathway−disease visualization networks, and protein−protein interaction (PPI) networks were constructed by Cytoscape. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed in R language. Molecular docking analysis was done using AutoDockTools. The visual network analysis showed that four active compounds, sanguinarine, chelerythrine, allocryptopine and protopine, were associated with the 10 target genes/proteins (SRC, MAPK3, MTOR, ESR1, PIK3CA, BCL2L1, JAK2, GSK3B, MAPK1, and AR) obtained from the screen. The enrichment analysis indicated that the cAMP, PI3K-Akt, and ErbB signaling pathways may be key signaling pathways in network pharmacology. The molecular docking results showed that sanguinarine, chelerythrine, allocryptopine, and protopine bound well to MAPK3 and JAK2. A comprehensive bioinformatics-based network topology strategy and molecular docking study has elucidated the multi-component synergistic mechanism of action of M. cordata in the treatment of bovine hoof disease, offering the possibility of developing M. cordata as a new source of drugs for hoof disease treatment.
... For example, studies testing the compensatory prophylaxis hypothesis have largely relied on menstrual cycle phase, pregnancy trimester, or levels of progesterone as a proxy for the activities of the immune system (e.g., Fessler et al. 2005;Fleischman and Fessler 2011;Jones et al. 2018). However, each of these factors have complex, pleiotropic effects on immune function (i.e., rather than uniformly impairing immunity; Hall and Klein 2017;Hughes 2012;Lorenz et al. 2015;Mor and Cardenas 2010;Saito et al. 2010), and considered in isolation, likely provide a poor index of one's current infection risk. ...
... The ovarian hormone progesterone is predominantly anti-inflammatory. 39 Progesterone levels fall dramatically before menstruation, with a resulting influx of inflammatory cells to the local endometrial environment that ultimately leads to the shedding of the functional endometrium at menstruation. 40 Intense vasoconstriction of the specialized endometrial spiral arterioles and activation of the local coagulation system act to limit menstrual blood loss. ...
... It is well known that the interaction between androgens and their receptor will lead to immunosuppressive responses on several cell types, such as macrophages, neutrophils, B and T cells [196]. So, androgens/ AR play a protective host role, that neutralize the pathways affected by estrogens and act on the immune responses [195,197]. Indeed, androgens promote the appearance of pro-inflammatory M2 macrophages but also anti-inflammatory neutrophils in favor of an inflammatory microenvironment favorable to tumor development [198]. On the other hand, estrogens have been described as immune stimulators, particularly on dendritic cells, macrophages, and B cells [199]. ...
Cancers are heterogeneous multifactorial diseases consisting of a major public health issue worldwide. Sex disparities are evidenced in cancer incidence, mortality, expression of prognosis factor, response to treatment, and survival. For both sexes, an interplay of intrinsic and environmental factors influences cancer cells and tumor microenvironment (TME) components. The TME cumulates both supportive and communicative functions, contributing to cancer development, progression, and metastasis dissemination. The frontline topics of this chapter are focused on the contribution of sex, via steroid hormones, such as estrogens and androgens, on the following components of the TME: cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), blood and lymphatic endothelial cells, and immunity/inflammatory system.
Introduction: Polycystic ovary syndrome (PCOS) is one of the women's most common endocrine disorders, which may be is associated with some autoimmune diseases such as autoimmune thyroiditis disorders (AIT). This study was performed with aim to evaluate the prevalence of autoimmune thyroiditis in women with PCOS by a systematic review and meta-analysis.
Methods: This review study was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. The research documents were collected by searching Persian-language databases such as Magiran, Sid, Iranmedex, and English-language databases such as Web of Science, Pubmed Scopus, and Google Scholar from January 1 until August 1, 2022. All studies were evaluated by the Newcastle-Ottawa scale at the four levels of selection, comparison, exposure, and outcome. Data analysis was performed with comprehensive meta-analysis (CMA) software (version 3.1).
Results: A total of 9 studies with 2290 participants were included in the meta-analysis. The prevalence of AIT in patients with polycystic ovary syndrome was 26.4% (95% CI: 21.3-32.2) and in healthy women was 11.7% (95% CI: 8.1-16.7). Subgroup studies demonstrated a higher prevalence of AIT in younger patients. Meta-regression analysis also showed a significant association between the study area and the prevalence of AIT.
Conclusion: There is a significant association between the increased prevalence of AIT in patients with PCOS. This shows the importance of evaluating and monitoring thyroid function in patients with PCOS.
A 1‐year 5‐month‐old, female, entire Parson Russell terrier was referred for investigations of focal epileptic seizures and behavioural changes. The clinical signs started 4 days after whelping its first litter. On presentation, the neurological examination was unremarkable. Neuroanatomical localisation was the forebrain. A brain magnetic resonance imaging showed bilateral, asymmetric, intra‐axial, T2‐weighted and fluid‐attenuated inversion recovery hyperintense, T1‐weighted hypointense, mildly to non‐contrast‐enhancing lesions in the piriform cortex. Cerebrospinal fluid analysis was within normal limits, and main infectious diseases were ruled out. Based on the presentation, findings and progression of clinical signs, a meningoencephalitis of unknown origin was suspected. In the present case, a positive response to immunosuppressive medication was observed. A well‐established link between pregnancy and immune‐mediated diseases, including meningoencephalitis, has been described in humans. This connection could have been the reason of the clinical signs, and this is supported by the recent pregnancy, presentation and positive response to immunosuppressive medication.
Background
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a remarkable predominance in female, suggesting that steroid hormones may be involved in the pathogenesis. However, steroid signature of SLE patients has not been fully explored.
Methods
A metabolic profiling analysis based on gas chromatography/mass spectrometry (GC/MS) with high sensitivity and reproducibility was employed to comprehensively reveal SLE-specific steroid alterations.
Results
More than 70 kinds of steroids in urine were detected by gas chromatography/mass spectrometry (GC/MS) to reveal SLE-specific steroid alterations. Principle component analysis demonstrated that the steroid profile was obviously distinguished between patients with SLE and controls. A lower level of total androgens was observed in patients, and nine androgens [dehydroepiandrosterone (DHEA), testosterone, Etio, androsterone, βαβ-Diol, Epi-An, Epi-DHT, 16α-OH-DHEA, and A-Diol] underwent significant decrease. Moreover, patients with SLE exhibited a slightly higher level of total estrogens than controls, and three estrogens (17-Epi-E3, 17α-E2, and E3) were remarkably increased. Furthermore, we identified the elevation of two sterols (Lan and Chol), and the reduction of one corticoid (11-DeoxyF) and two progestins (5α-DHP and 11β-OH-Prog) in patients.
Discussion
In this study, metabolic signature of urinary steroids associated with SLE was comprehensively defined by GC/MS for the first time, and steroid metabolism disorders were found in patients with SLE, especially the conversion of androgens to estrogens. Our findings will provide new insights for a deeper understanding of the mechanism of steroid hormones in the pathogenesis of SLE and will help to unravel the reason of sexual disparity in SLE.
Steroids are an important class of biomolecules with diverse roles and functions. Besides being important as structural and signaling molecules, these molecules hold promise against numerous disorders, including cardiovascular conditions, cancer, inflammation and autoimmune disorders. Many investigations have demonstrated that steroidal frameworks may provide lipid solubility, receptor selectivity or membrane binding properties to non-steroidal pharmacophores. However, the therapeutic use of steroids can be dangerous when they're used incorrectly. Additionally, misconceptions about steroids among athletes or recreational users can lead to steroid abuse and poor health outcomes. Steroids and their Medicinal Potential discusses the classification, distribution, biosynthesis, chemical synthesis and semi-synthesis of different steroids. The medicinal potential of each class is exhaustively discussed in different chapters. The latest advances and developments in steroid-based drug discovery are also discussed thoroughly. The book aims to address general questions and concerns about steroids, providing readers a useful resource on the subject. Key Features -Provides comprehensive coverage on all aspects of steroids including steroid chemistry, biochemistry, medicinal potential, drug discovery and advances in target-binding interactions of steroid-based drugs -Includes chapters dedicated to anabolic steroids and their abuse -Designed as an accessible source of information for understanding steroidal drugs with structured chapters -Includes references for advanced readers
Objective:
Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), namely granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis constitute a group of rare systemic vasculitides, affecting small vessels. Genders are equally affected, with symptoms most commonly presenting during and/or after the fifth decade of life, but AAV may also present in younger individuals. As advanced maternal age is becoming common and safe over the last decades, it is now more feasible for middle-aged women suffering from AAV to get pregnant. Although adverse pregnancy outcomes have been thoroughly investigated in other systemic diseases, the exact prevalence of pregnancy complications and unfavorable outcomes in pregnant women with AAV has not been systematically evaluated.
Methods:
We researched PubMed, Scopus, Cochrane Library and Cinahl databases until September, 2022. Three blinded investigators extracted data and assessed the risk of bias. Α random effects model was used for the analysis. The outcomes studied were pre-term delivery, intrauterine growth restriction (IUGR) neonates and disease flare.
Results:
We included six studies with 92 pregnancies in patients with AAV. The prevalence of pre-term delivery, IUGR neonates and disease flare were 18% (CI: 0.10-0.30, p=non-significant), 20% (CI: 0.11-0.33, p=non-significant) and 28% (CI: 0.09-0.59, p<0.01), respectively.
Conclusion:
The analysis demonstrated higher occurrence of adverse outcomes in pregnant women suffering from AAV accompanied by an increased risk of disease flare during pregnancy. These findings underline the importance of preconception counseling and the necessity of close monitoring in these patients similarly to other systemic inflammatory diseases.
Background:
Sex and gender have increasingly been recognized as significant risk factors for many diseases, including dermatological conditions. Historically, sex and gender have often been grouped together as a single risk factor in the scientific literature. However, both may have a distinct impact on disease incidence, prevalence, clinical presentation, severity, therapeutic response, and associated psychological distress.
Objectives and project description:
The mechanisms that underlie differences in skin diseases between males, females, men, and women remain largely unknown. The specific objectives of this review paper are:To highlight the biological differences between males and females (sex), as well as the sociocultural differences between men and women (gender) and how they impact the integumentary system.To perform a literature review to identify important sex- and gender-related epidemiological and clinical differences for various skin conditions belonging to a range of disease categories and to discuss possible biological and sociocultural factors that could explain the observed differences.To discuss dermatological skin conditions and gender-affirming treatments within the transgender community, a population of individuals who have a gender identity which is different than the gender identity they were assigned at birth.
Future impact:
With the rising number of individuals that identify as non-binary or transgender within our increasingly diverse communities, it is imperative to recognize gender identity, gender, and sex as distinct entities. By doing so, clinicians will be able to better risk-stratify their patients and select treatments that are most aligned with their values. To our knowledge, very few studies have separated sex and gender as two distinct risk factors within the dermatology literature. Our article also has the potential to help guide future prevention strategies that are patient-tailored rather than using a universal approach.
A 3‐year‐old, female, neutered, crossbreed dog was diagnosed with non‐regenerative immune‐mediated anaemia. Bone marrow cytology was hypercellular, with signs of maturation arrest and rubriphagocytosis. During the initial investigations, a suspected ovarian remnant was identified. The patient was stabilised with a packed red blood cell transfusion and started on immunosuppressive medication. The anaemia remained non‐regenerative and gradually worsened over the next 2 months. Due to lack of response, splenectomy and ovarian remnant excision was performed. Splenic histopathology revealed evidence of erythrophagia. Two weeks following surgery, complete blood count revealed mild reticulocytosis, and the patient subsequently achieved clinical remission. Twenty‐one months following splenectomy, the patient continued to do well. Splenectomy may be considered as an additional immune‐modulating option in refractory cases of canine non‐regenerative immune‐mediated anaemia.
The results of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial, the first large randomized controlled clinical trial comparing the HIV acquisition risk of women receiving DMPA, the levonorgestrel (LNG) implant, or the copper intrauterine device (IUD), did not reveal an increased risk of HIV acquisition for women on any of these three contraceptives. Our study results confirm that the two different progestin-based hormonal contraceptives DMPA and levonogestrel will not increase the risk for HIV infection.
The prevalence of metabolic syndrome is increasing day by day, owing to the sedentary lifestyle, unhealthy food habits, genetic factors, environmental influences and many other conspicuous variables. Skin, aptly considered to be a mirror of internal organs, often manifests with certain signs and symptoms, suggestive of a diagnosis of metabolic syndrome. In this chapter, we have attempted to touch upon the dermatological manifestations (both common and uncommon) of metabolic syndrome.KeywordsMetabolic syndromeDiagnosisSkin manifestations
Eczemas are a wide group of inflammatory skin disorders that can affect female patients of all ages. Depending on their etiopathogenic, they might be differentiated into atopic eczema, atopic eczema of pregnancy, contact dermatitis (both allergic and irritant), photocontact dermatitis, and dyshidrotic eczema. Atopic dermatitis has no significant differences between women and men, with the exception that atopic dermatitis being the most prevalent gestational dermatosis due to the physiological increase of Th2 response during this period. Allergic contact dermatitis seems to be more prevalent among female patients, probably due to higher exposure to allergens such as cosmetics or metals. Some specific considerations should be considered in treating eczemas in female patients, in particular referring to differences that rely on the pregnancy status.
Дана оценка влияния прогестерона на лейкоцитарный состав крови в организме беременных телок и нетелей голштинской породы в зависимости от его триместра. Установлено, что наступление и развитие беременности сопровождается сдвигами в лейкоцитарном составе крови телок. При этом увеличивается как общее количество лейкоцитов и развивается «лейкоцитоз беременности», так и изменяется дифференциальный состав лейкоцитарных клеток. В лейкограмме уменьшается число эозинофилов и лимфоцитов и увеличивается нейтрофилов и моноцитов. При этом колебания числа нейтрофилов и лимфоцитов происходят в пределах границ нормы. При наступлении беременности уровень прогестерона в сыворотке крови телок резко повышается, по сравнению с небеременными в 2,93–4,83 раза. Оценка зависимости лейкоцитарного состава крови беременных телок и нетелей от триместра беременности (I фактор) и концентрации прогестерона (II фактор) показывает, что не только данные факторы обладают статистической значимостью, но и их двухфакторных взаимодействия «Триместр беременности × Лейкоцитарные клетки» и «Прогестерон × Лейкоцитарные клетки», что подтверждается преобладанием Fрасчетное над Fкритическое.
Background/purpose
Delayed healing of the extraction socket is not uncommon when tooth extraction is performed on patients taking prednisolone. This study aimed to identify specific dosage of prednisolone and factors associated with delayed healing of the extraction socket in patients taking prednisolone.
Materials and methods
This single-center retrospective study included 80 patients who underwent tooth extraction under local anesthesia and were taking prednisolone orally. Patients were divided into the nondelayed healing group (n = 50) and delayed healing group (n = 30), and their background and dosage of prednisolone were compared.
Results
The dosage of prednisolone was significantly higher in the delayed healing group than in the nondelayed healing group. A receiver operating characteristics curve analysis resulted in moderate accuracy when the cutoff value was set at 8.0, with 67% sensitivity, 76% specificity, and 0.765 area under the curve. The multivariate logistic regression analysis revealed that prednisolone dosage >8.0 mg/day (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.79–41.6) and osteosclerotic changes beyond the alveolar bone around the tooth to be extracted (OR, 10.3; 95% CI, 2.81–37.8) in X-ray imaging had significant effects on delayed healing.
Conclusion
The results of this study suggested that delayed healing following tooth extractions in patients taking prednisolone was related to a dosage of 8.0 mg/day or higher and osteosclerotic changes.
Multiple sclerosis (MS), Neuromyelitis optica spectrum disorder (NMOSD) and Myelin-Oligodendrocyte-Glycoprotein antibody associated disorder (MOGAD) are demyelinating disorders of the central nervous system (CNS) of autoimmune origin. Here, we summarize general considerations on sex-specific differences in the immunopathogenesis and hormonal influences as well as key clinical and epidemiological elements.
Gender-specific issues are widely neglected starting with the lacking separation of sex as a biological variable and gender comprising the sociocultural components.
As for other autoimmune diseases, female preponderance is common in MS and NMOSD. However, sex distribution in MOGAD seems equal.
As in MS, immunotherapy in NMOSD and MOGAD is crucial to prevent further disease activity. Therefore, we assessed data on sex differences of the currently licensed disease-modifying treatments for efficacy and safety. This topic seems widely neglected with only fragmented information resulting from post-hoc analyses of clinical trials or real-world post-marketing studies afflicted with lacking power and/or inherent sources of bias.
In summary, biological hypotheses of sex differences including genetic factors, the constitution of the immune system and hormonal influences are based upon human and preclinical data, especially for the paradigmatic disease of MS whereas specific data for NMOSD and MOGAD are widely lacking. Epidemiological and clinical differences between men and women are well described for MS and to some extent for NMOSD, yet, with remaining contradictory findings. MOGAD needs further detailed investigation. Sex-specific analyses of safety and efficacy of long-term immunotherapies need to be addressed in future studies designed and powered to answer the pressing questions and to optimize and individualize treatment.
The fatal outcomes of COVID-19 are related to the high reactivity of the innate wing of immunity. Estrogens could exert anti-inflammatory effects during SARS-CoV-2 infection at different stages: from increasing the antiviral resistance of individual cells to counteracting the pro-inflammatory cytokine production. A complex relationship between sex hormones and immune system implies that menopausal hormone therapy (MHT) has pleiotropic effects on immunity in peri- and postmenopausal patients. The definite immunological benefits of perimenopausal MHT confirm the important role of estrogens in regulation of immune functionalities. In this review, we attempt to explore how sex hormones and MHT affect immunological parameters of the organism at different level (in vitro, in vivo) and what mechanisms are involved in their protective response to the new coronavirus infection. The correlation of sex steroid levels with severity and lethality of the disease indicates the potential of using hormone therapy to modulate the immune response and increase the resilience to adverse outcomes. The overall success of MHT is based on decades of experience in clinical trials. According to the current standards, MHT should not be discontinued in COVID-19 with the exception of critical cases.
Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease and has a female predominance of around 3:1. The relationship between sex hormones and RA has been of great interest to researchers ever since Philip Hench's observations in the 1930's regarding spontaneous disease amelioration in pregnancy. Extensive basic scientific work has demonstrated the immunomodulatory actions of sex hormones but this therapeutic potential has not to date resulted in successful clinical trials in RA. Epidemiological data regarding both endogenous and exogenous hormonal factors are inconsistent, but declining estrogen and/or progesterone levels in the menopause and post-partum appear to increase the risk and severity of RA. This review assimilates basic scientific, epidemiological and clinical trial data to provide an overview of the current understanding of the relationship between sex hormones and RA, focusing on estrogen, progesterone and androgens.
Purpose of review:
As perspectives on sex and gender identity have evolved, there has been an increase in the practice of transgender medicine. Within rheumatology, however, there is a dearth of information about rheumatic disease in transgender and gender diverse (TGGD) individuals. This is important, as sex hormones affect the etiopathogenesis and expression of autoimmune diseases. We therefore sought to identify TGGD patients with rheumatic disease, review their clinical courses, and appraise existing literature about this population.
Recent findings:
Of 1053 patients seen at the Los Angeles County and University of Southern California Medical Center from 2019 through 2021, five transgender men and two transgender women with rheumatic disease were identified. Most patients' disease courses were not overtly impacted by gender affirming hormone therapy (GAHT). Six of seven patients had psychosocial barriers to care. Our systematic review found 11 studies with 11 transgender women and two transgender men. In 12 of 13 patients, GAHT possibly modulated the patients' rheumatic disease.
Summary:
Our observations suggest GAHT need not be a strict contraindication in TGGD patients with rheumatic disease. TGGD patients often face significant psychosocial barriers. Additional information about this population and empathy toward their health disparities are needed.
Sex bias in autoimmune disease (AID) prevalence is known, but the role of estrogen in disease progression is more complex. Estrogen can even be protective in some AIDs; but in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc), estrogen, its metabolites, and its receptors have been demonstrated to play critical, localized inflammatory roles. Estrogen is instrumental to the fibrosis seen in RA, SLE, SSc and other disease states, including breast cancer and uterine leiomyomas. Fibrotic diseases tend to share a common pattern in which lymphocyte–monocyte interactions generate cytokines which stimulate the deposition of fibrogenic connective tissue. RA, SLE, SSc and thyroid eye disease (TED) have very similar inflammatory and fibrotic patterns—from pathways to tissue type. The thorough investigations that demonstrated estrogen’s role in the pathology of RA, SLE, and SSc could, and possibly should, be carried out in TED. One might even expect to find an even greater role for estrogen, and sex steroid homeostasis in TED, given that TED is typically sequalae to Graves’ disease (GD), or Hashimoto’s disease (HD), and these are endocrine disorders that can create considerable sex steroid hormone dysregulation. This paper highlights the pathophysiology similarities in 4 AIDs, examines the evidence of sex steroid mediated pathology across 3 AIDs and offers a case study and speculation on how this may be germane to TED.
Perimenopause is linked to increased migraine (Mg), especially menstrual Mg (MMg), influenced by hormonal changes. Compared to nonmenstrual attacks, menstrual attacks are more disabling and less responsive to treatment. Women with perimenstrual estrogen withdrawal have been linked to Mg during menstruation, whereas Mg during perimenopause has been linked to unpredictable fluctuations in estrogen levels. It has been widely established that female sex hormones play a role in Mg, but how it occurs remains unclear. This narrative review was identified using Medline and PubMed searches between 1946 and 2021. Search terms included "headache," "migraine," "menstrual migraine," "menstruation," "menopause," "perimenopause," "estrogen," and "progesterone." This article focuses on the candidate genes and female hormones that play a role in MMg. More study is necessary to understand better the environmental components that play a critical role in disease development. Currently, there is insufficient clinical evidence to support the function of menstrual Mg. The specific research facts examined MMg unique candidate genes and female hormonal factors that support their association and found MMg etiologic processes for generating an early diagnostic marker.
Inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract, is a global health care problem. Compelling evidence shows sex differences regarding the prevalence, pathophysiology, clinical presentation, and treatment outcome of IBD. Sex hormones, including estrogen, progesterone, and androgen, have been proposed to have a role in the pathogenesis of sexual dimorphism in IBD. Clinical and experimental data support the modulatory effects of sex hormones on various clinical characteristics of the disease, including intestinal barrier dysfunction and mucosal immune activation. Additionally, the potential role of sex hormones in the modulation of gut microbiota is attracting increasing attention. Here, we discuss the sex dimorphic disease profile and address the potential mechanisms involved in the sex-specific pathogenesis of IBD. Improved understanding of these sex differences in the clinic could improve the knowledge of patients with IBD with heterogeneous disease profiles.
Polycystic ovary syndrome (PCOS) is an endocrine disorder that frequently affects women of reproductive age. In PCOS, the incidence of thyroid diseases has increased in addition to reproductive and metabolic problems. To compare thyroid nodule, volume, autoimmunity, and thyroid function tests of euthyroid PCOS and its phenotypes. The files of 178 patients with PCOS aged 18-45 years and 92 patients with no disease who were matched for body mass index were retrospectively scanned. Women with PCOS were divided into four phenotypes, ABCD, according to the Rotterdam guideline, as determined using thyroid ultrasonography (USG) of all participants, and PCOS phenotypes, as well as thyroid-stimulating hormone (TSH), fT4, fT3 thyroid peroxidase (anti-TPO), and thyroglobulin (anti-Tg) thyroid volume, nodule number, and nodule diameter were noted. Anti-TPO titer and prevalence, fT3, and thyroid volume were higher in the PCOS group compared with the control group (p=0.004, p=0.023, p=0.001, and p=0.001, respectively) in terms of anti-Tg levels, presence of nodules, and the number of nodules. There was no statistical difference between the PCOS group and the healthy controls. The number of nodules of 1 cm and above was found to be higher only in patients with PCOS compared with the control group (p=0.018). When the phenotypes were examined, thyroid dysfunction features were found in phenotype A, which was the most prominent. Thyroid autoimmunity, thyroid volume, and the number of nodules larger than 1 cm increased in patients with PCOS compared with controls. This situation is thought to be caused by the reproductive and metabolic properties of PCOS because thyroid dysfunction was detected more in phenotype A, which is called the full phenotype. Therefore, all patients with PCOS, especially phenotype A, should be evaluated for the presence of nodules with autoimmunity using USG, even if there are no symptoms, and thyroid functions.
Epidemiology studies suggest that exposure to ambient air pollution is associated with demyelinating diseases in the central nervous system (CNS), including multiple sclerosis (MS). The pathophysiology of MS results from an autoimmune response involving increased inflammation and demyelination in the CNS, which is higher in young (adult) females. Exposure to traffic-generated air pollution is associated with neuroinflammation and other detrimental outcomes in the CNS; however, its role in the progression of pathologies associated with demyelinating diseases has not yet been fully characterized in a female model. Thus, we investigated the effects of inhalation exposure to mixed vehicle emissions (MVE) in the brains of both ovary-intact (ov+) and ovariectomized (ov−) female Apolipoprotein (ApoE−/−) mice. Ov + and ov− ApoE−/− mice were exposed via whole-body inhalation to either filtered air (FA, controls) or mixed gasoline and diesel vehicle emissions (MVE: 200 PM μg/m³) for 6 h/d, 7 d/wk., for 30 d. We then analyzed MVE-exposure mediated alterations in myelination, the presence of CD4+ and CD8+ T cells, reactive oxygen species (ROS), myelin oligodendrocyte protein (MOG), and expression of estrogen (ERα and ERβ) and progesterone (PROA/B) receptors in the CNS. MVE-exposure mediated significant alterations in myelination across multiple regions in the cerebrum, as well as increased CD4+ and CD8+ staining. There was also an increase in ROS production in the CNS of MVE-exposed ov− and ov + ApoE−/− mice. Ov− mice displayed a reduction in cerebral ERα mRNA expression, compared to ov + mice; however, MVE exposure resulted in an even further decrease in ERα expression, while ERβ and PRO A/B were unchanged across groups. These findings collectively suggest that inhaled MVE-exposure may mediate estrogen receptor expression alterations associated with increased CD4+/CD8+ infiltration, regional demyelination, and ROS production in the CNS of female ApoE−/− mice.
The tumor microenvironment (TME) is a complex infrastructure composed of stromal, epithelial, and immune cells embedded in a vasculature ECM. The microenvironment surrounding mammary epithelium plays a critical role during the development and differentiation of the mammary gland, enabling the coordination of the complex multihormones and growth factor signaling processes. Progesterone/progesterone receptor paracrine signaling interactions in the microenvironment play vital roles in stem/progenitor cell function during normal breast development. In breast cancer, the female sex hormones, estrogen and progesterone, and growth factor signals are altered in the TME. Progesterone signaling modulates not only breast tumors but also the breast TME, leading to the activation of a series of cross-communications that are implicated in the genesis of breast cancers. This chapter reviews the evidence that progesterone and PR signaling modulates not only breast epitheliums but also the breast TME. Furthermore, crosstalk between estrogen and progesterone signaling affecting different cell types within the TME is discussed. A better understanding of how PR and progesterone affect the TME of breast cancer may lead to novel drugs or a therapeutic approach for the treatment of breast cancer shortly.
Multiple sclerosis (MS) and rodent models of the disease including experimental autoimmune encephalomyelitis, cuprizone intoxication and lysophosphatidyl-choline induced demyelination show altered levels of circulating sex steroids and changes in the biosynthesis of nervous system localized steroidogenesis (neurosteroidogenesis). Therapy with progesterone, estrogens, androgens or direct stimulation of neurosteroidogenesis show beneficial effects for brain and spinal cord neuropathology of MS models due to the reduction of reactive astrocytes and microglia, down regulation of the expression of proinflammatory markers, improved myelin formation from oligodendrocyte precursors and better clinical scores and behavioral performances. Steroid effectiveness is explained in part by activation of classical nuclear receptors, membrane receptors and modulation of GABAA receptors expressed by several cell types from different CNS regions. Because resolving inflammation is crucial for treatment of MS and related animal models, treatment with natural or synthetic steroids or with molecules targeting neurosteroidogenesis may open further therapeutic opportunities for neuroinflammatory diseases.
Because of the young age at onset and preponderance in women, many patients with systemic lupus erythematosus (SLE) will need specialized management of their reproductive health. While most women with SLE can successfully bear children, the potential hazards of SLE in pregnancy demand that these pregnancies be carefully planned to limit the risks of pregnancy loss, preterm birth, and disease flares. As fertility is not impaired in most women with SLE, effective contraception is required to enable sexually active, heterosexual women to avoid pregnancy when they either do not wish to conceive or are at high risk for pregnancy complications. SLE can also bring complexity to the management of menopausal symptoms. Fortunately, both the American College of Rheumatology and the European League Against Rheumatism have published guidelines for the management of reproductive health issues in women with rheumatic disease, as well as the management of rheumatic disease during pregnancy (Sammaritano et al., 2020; Andreoli et al., 2017; Gotestam Skorpen et al., 2016). With this guidance, more patients living with SLE will be able to fulfill their own reproductive goals.
The immunological targets of estrogen at the molecular, humoral, and cellular level have been well documented, as has estrogen's
role in establishing a gender bias in autoimmunity and cancer. During a healthy immune response, activation-induced deaminase
(AID) deaminates cytosines at immunoglobulin (Ig) loci, initiating somatic hypermutation (SHM) and class switch recombination
(CSR). Protein levels of nuclear AID are tightly controlled, as unregulated expression can lead to alterations in the immune
response. Furthermore, hyperactivation of AID outside the immune system leads to oncogenesis. Here, we demonstrate that the
estrogen–estrogen receptor complex binds to the AID promoter, enhancing AID messenger RNA expression, leading to a direct
increase in AID protein production and alterations in SHM and CSR at the Ig locus. Enhanced translocations of the c-myc oncogene
showed that the genotoxicity of estrogen via AID production was not limited to the Ig locus. Outside of the immune system
(e.g., breast and ovaries), estrogen induced AID expression by >20-fold. The estrogen response was also partially conserved
within the DNA deaminase family (APOBEC3B, -3F, and -3G), and could be inhibited by tamoxifen, an estrogen antagonist. We
therefore suggest that estrogen-induced autoimmunity and oncogenesis may be derived through AID-dependent DNA instability.
Pregnancy is a highly regulated process, requiring strict control of the immune system in order to prevent rejection of the semiallogenic foetus. One aspect of pregnancy immunology that has been of great interest is the influence of female sex and pregnancy associated hormones, such as progesterone and oestrogen, on cells of the immune system. This review evaluates studies investigating the ability of these hormones to modulate the function of cells of both the innate and adaptive arms of the immune system and mechanisms by which immunity to infection can be altered due to increased levels of progesterone and oestrogen. Finally, the influence of pregnancy on the most common autoimmune diseases, on toxoplasmosis and on malaria is reviewed.
Plasmacytoid dendritic cells are specialized in the production of type I interferon (type I IFN), which promotes antiviral and antitumor responses, as well as autoimmune disorders. Activation of type I IFN secretion depends on the pattern recognition receptors TLR7 and TLR9, which sense microbial RNA and DNA, respectively. Type I IFN production is modulated by several receptors, including the type II C-type lectin domain family 4, member C (CLEC4C). The natural ligand of CLEC4C is unknown. To identify it, here we probed a glycan array with a soluble form of the CLEC4C ectodomain. We found that CLEC4C recognizes complex type sugars with terminal galactose. Importantly, soluble CLEC4C bound peripheral blood leukocytes and tumor cells that express glycans with galactose residues at the non-reducing ends. The positive and negative modulation of galactose residues on cell membranes was paralleled by the regulation of type I IFN secretion by plasmacytoid dendritic cells in co-culture experiments in vitro. These results suggest that the modulation in the expression of non-sialylated oligosaccharides by invading pathogens or transformed cells may affect type I IFN response and immune surveillance.
Estrogen treatment exerts a protective effect on experimental autoimmune encephalomyelitis (EAE) and is under clinical trial for multiple sclerosis therapy. Estrogens have been suspected to protect from CNS autoimmunity through their capacity to exert anti-inflammatory as well as neuroprotective effects. Despite the obvious impacts of estrogens on the pathophysiology of multiple sclerosis and EAE, the dominant cellular target that orchestrates the anti-inflammatory effect of 17β-estradiol (E2) in EAE is still ill defined. Using conditional estrogen receptor (ER) α-deficient mice and bone marrow chimera experiments, we show that expression of ERα is critical in hematopoietic cells but not in endothelial ones to mediate the E2 inhibitory effect on Th1 and Th17 cell priming, resulting in EAE protection. Furthermore, using newly created cell type-specific ERα-deficient mice, we demonstrate that ERα is required in T lymphocytes, but neither in macrophages nor dendritic cells, for E2-mediated inhibition of Th1/Th17 cell differentiation and protection from EAE. Lastly, in absence of ERα in host nonhematopoietic tissues, we further show that ERα signaling in T cells is necessary and sufficient to mediate the inhibitory effect of E2 on EAE development. These data uncover T lymphocytes as a major and nonredundant cellular target responsible for the anti-inflammatory effects of E2 in Th17 cell-driven CNS autoimmunity.
Progesterone, a key female sex hormone with pleiotropic functions in maintenance of pregnancy, has profound effects on regulation of immune responses. We report in this work a novel function of progesterone in regulation of naive cord blood (CB) fetal T cell differentiation into key T regulatory cell (Treg) subsets. Progesterone drives allogeneic activation-induced differentiation of CB naive, but not adult peripheral blood, T cells into immune-suppressive Tregs, many of which express FoxP3. Compared with those induced in the absence of progesterone, the FoxP3(+) T cells induced in the presence of progesterone highly expressed memory T cell markers. In this regard, the Treg compartment in progesterone-rich CB is enriched with memory-type FoxP3(+) T cells. Moreover, CB APCs were more efficient than their peripheral blood counterparts in inducing FoxP3(+) T cells. Another related function of progesterone that we discovered was to suppress the differentiation of CB CD4(+) T cells into inflammation-associated Th17 cells. Progesterone enhanced activation of STAT5 in response to IL-2, whereas it decreased STAT3 activation in response to IL-6, which is in line with the selective activity of progesterone in generation of Tregs versus Th17 cells. Additionally, progesterone has a suppressive function on the expression of the IL-6 receptor by T cells. The results identified a novel role of progesterone in regulation of fetal T cell differentiation for promotion of immune tolerance.
Chronic antigenic stimulation leads to gradual accumulation of late-differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8(+) T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8(+) CD28(-) or CD8(+) CD57(+) T lymphocytes. There is growing evidence that the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population is heterogeneous and composed of various functionally competing (cytotoxic and immunosuppressive) subsets thus the overall effect of CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell-mediated immunity depends on the predominance of a particular subset. Many articles claim that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells have lost their proliferative capacity during process of replicative senescence triggered by repeated antigenic stimulation. However recent data indicate that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells can transiently up-regulate telomerase activity and proliferate under certain stimulation conditions. Similarly, conflicting data is provided regarding CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell sensitivity to apoptosis, finally leading to the conclusion that this T-cell population is also heterogeneous in terms of its apoptotic potential. This review provides a comprehensive approach to the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population: we describe in detail its origins, molecular and functional characteristics, subsets, role in various diseases or conditions, associated with persistent antigenic stimulation.
Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). Although the presence of aPL is a necessary pre-condition, APS-associated clotting is seemingly triggered by an additional 'second hit', frequently related to innate inflammatory immune responses. β(2) glycoprotein I (β(2)GPI)-dependent aPL, the most important subset of these antibodies, mediate several--not necessarily alternative--thrombogenic mechanisms, mainly on the basis of their reactivity with β(2)GPI expressed on the membrane of cells that participate in the coagulation cascade. Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. Although one in vivo model of fetal loss suggests a mechanism of aPL-mediated acute placental inflammation, other models and the histopathological examination of APS placentae do not support a widespread inflammatory signature. β(2)GPI-dependent aPL are thought to recognize their antigen on placental tissues, inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation. Why antibodies with similar antigen specificity produce different clinical manifestations is not clear. Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question.
Oestradiol and the selective oestrogen receptor modulator (SERM) raloxifene have been shown to ameliorate collagen-induced arthritis (CIA) in rats and in mice. One aim was to investigate if raloxifene exerts its anti-arthritic and anti-osteoporotic effects during the induction or effector phase of arthritis. A second aim was to analyse if raloxifene activates the oestrogen response element (ERE) to produce its immune-modulator effects. CIA or collagen-antibody-induced arthritis (CAIA) was induced in ovariectomized DBA/1-mice. CIA was used for evaluation of treatment during the induction, and CAIA for the effector phase of arthritis and osteoporosis development. Raloxifene, oestradiol or vehicle was administered 5 days/week. The clinical disease was evaluated continuously. Bone marrow density (BMD) was analysed with peripheral quantitative computer tomography, paws were collected for histological examination, and sera were analysed for markers of bone and cartilage turnover and proinflammatory cytokines. Transgenic luciferase (Luc)-ERE mice were immunized with collagen (CII), and after 10 days injected once with raloxifene, oestradiol or vehicle before termination. Spleens were analysed for luciferase activity to measure ERE activation. Treatment with oestradiol or raloxifene during the induction phase of CIA failed to affect arthritis. Raloxifene did not hamper disease activity in CAIA, whereas oestradiol delayed the onset and ameliorated the severity. Both raloxifene and oestradiol preserved BMD in CAIA. CII-immunization increased the oestradiol-induced ERE activation in spleen, and raloxifene activated the ERE at about 25% the intensity of oestradiol. Further experiments are needed to elucidate the exact mechanisms behind this finding.
The non-classical HLA class I molecule HLA-G was initially shown to play a major role in feto-maternal tolerance. Since this discovery, it has been established that HLA-G is a tolerogenic molecule which participates to the control of the immune response. In this review, we summarize the recent advances on (1) the multiple structures of HLA-G, which are closely associated with their role in the inhibition of NK cell cytotoxicity, (2) the factors that regulate the expression of HLA-G and its receptors, (3) the mechanism of action of HLA-G at the immunological synapse and through trogocytosis, and (4) the generation of suppressive cells through HLA-G. Moreover, we also review recent findings on the non-immunological functions of HLA-G in erythropoiesis and angiogenesis.
Our understanding of the genetic basis of systemic lupus erythematosus (SLE) has been rapidly advanced using large-scale, case-control, candidate gene studies as well as genome-wide association studies during the past 3 years. These techniques have identified more than 30 robust genetic associations with SLE including genetic variants of HLA and Fcγ receptor genes, IRF5, STAT4, PTPN22, TNFAIP3, BLK, BANK1, TNFSF4 and ITGAM. Most SLE-associated gene products participate in key pathogenic pathways, including Toll-like receptor and type I interferon signaling pathways, immune regulation pathways and those that control the clearance of immune complexes. Disease-associated loci that have not yet been demonstrated to have important functions in the immune system might provide new clues to the underlying molecular mechanisms that contribute to the pathogenesis or progression of SLE. Of note, genetic risk factors that are shared between SLE and other immune-related diseases highlight common pathways in the pathophysiology of these diseases, and might provide innovative molecular targets for therapeutic interventions.
The role of progesterone in modulating dendritic cell (DC) function following stimulation of different TLRs is relatively unknown. We compared the ability of progesterone to modulate murine bone marrow-derived DC cytokine production (IL-6 and IL-12) and costimulatory molecule expression (CD40, CD80, and CD86) induced by either TLR3 or TLR4 ligation and determined whether activity was via the progesterone receptor (PR) or glucocorticoid receptor (GR) by comparative studies with the PR-specific agonist norgestrel and the GR agonist dexamethasone. Progesterone was found to downregulate, albeit with different sensitivities, both TLR3- and TLR4-induced IL-6 production entirely via the GR, but IL-12p40 production via either the GR or PR. Of particular significance was that progesterone was able to significantly inhibit TLR3- but not TLR4-induced CD40 expression in bone marrow-derived DCs. Stimulation of the PR (with progesterone and norgestrel) by pretreatment of DCs was found to sustain IFN regulatory factor-3 phosphorylation following TLR3 ligation, but not TLR4 ligation. Overall, these studies demonstrate that progesterone can differentially regulate the signaling pathways employed by TLR3 and TLR4 agonists to affect costimulatory molecule expression and cytokine production.
Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that predominantly affects women. Previous findings that duplicated Toll-like receptor 7 (Tlr7) promotes lupus-like disease in male BXSB mice prompted us to evaluate TLR7 in human SLE. By using a candidate gene approach, we identified and replicated association of a TLR7 3'UTR SNP, rs3853839 (G/C), with SLE in 9,274 Eastern Asians (P(combined) = 6.5 x 10(-10)), with a stronger effect in male than female subjects [odds ratio, male vs. female = 2.33 (95% CI = 1.64-3.30) vs. 1.24 (95% CI = 1.14-1.34); P = 4.1 x 10(-4)]. G-allele carriers had increased TLR7 transcripts and more pronounced IFN signature than C-allele carriers; heterozygotes had 2.7-fold higher transcripts of G-allele than C-allele. These data established a functional polymorphism in type I IFN pathway gene TLR7 predisposing to SLE, especially in Chinese and Japanese male subjects.
Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease with a highly variable clinical course. Pediatric-onset SLE (pSLE) represents 10-20% of all SLE cases, and is associated with higher disease severity, including more-rapid damage accrual, than adult-onset SLE. As in adults, pSLE disease expression varies according to ethnicity, with a milder disease course in white patients. The majority of pSLE patients will have developed damage within 5-10 years of disease onset, most frequently involving the musculoskeletal, ocular, renal and neuropsychiatric systems. Owing to improvements in disease management and recognition over the past 20-30 years, patients now live longer, but as a result have increased disease damage. Premature atherosclerosis and osteoporosis have become increasingly prevalent morbidities in pSLE patients. Early atherosclerosis leads to a considerable rise in cardiovascular and cerebrovascular events, and failure to develop adequate peak bone mass during adolescence-a crucial period of bone accrual-is likely to lead to early osteoporosis and fractures. Patients with pSLE have an incurable, potentially devastating disease that occurs during a vulnerable period of psychosocial development, leading to specific and unique psychosocial stressors. Additional large, long-term follow-up studies in pSLE are needed to better understand the disease prognosis and to facilitate development of tailored treatments.
In a study of 151 normal, healthy individuals of both sexes varying in age from 1-70 yr, it was found that the relative incidence of agalactosyl (with both outer arms terminating in N-acetylglucosamine) N-linked oligosaccharides on total serum IgG decreased from birth to a minimum (at 25 yr of age) and then increased with age. The relative incidence of digalactosyl structures varied inversely to this, and the relative incidence of monogalactosyl structures was constant. Galactosylation of the N-linked oligosaccharides of the human serum IgG of normal individuals is therefore an age-related molecular parameter. Several reports have suggested that rheumatoid arthritis is associated with a decreased galactosylation of serum IgG (3-5). The normal variation in galactosylation with age as described here allows a true assessment of disease-associated changes in this parameter, and raises the possibility that one of the lesions in rheumatoid arthritis is an accelerated aging of the immune system. In addition, heterogeneity within age groups may be due to intrinsic differences in genetic endowment, or may reflect the impact of extrinsic factors (8).
This article is a tribute to the late Sir Peter Brian Medawar for his pivotal contribution in 1953 to the establishment of the field of Reproductive Immunology, with a brief and selective assessment of the progress made during the ensuing 50 years towards elucidation of the mechanisms responsible for the paradoxical survival of the conceptus as an intra-uterine allograft within the immunologically competent genetically alien female host. Medawar's succinct and stimulating theories have been central throughout the whole of this time and his basic conclusion, that the single most important factor ensuring the success of gestation is the anatomical separation of the fetus from its mother, remains substantially valid to this day. The extent to which other factors are of significance, particularly those relating to the relative roles of maternal adaptive and innate immune responses to the developing feto-placental unit, has yet to be fully defined.
PROBLEM: To study the effects of estradiol (E2) or progesterone on macrophage function in the presence of lipopolysaccharide (LPS). METHOD OF STUDY: Male rat peritoneal macrophages were treated in vitro with 0.1 μg/mL of LPS and E2 or progesterone. RESULTS: At 10−2 ng/mL, E2 significantly (P<0.05; n=6) enhanced tumor necrosis factor (TNF) release by LPS-treated macrophages. TNF release was significantly (P<0.05; n=6) inhibited by 102 ng/mL or 103 ng/mL of E2 and by progesterone at less than 10−3 ng/mL or greater than 10−1 ng/mL. E2 (10−4 and 10 ng/mL) and progesterone (10−6–10−4 ng/mL and 102 ng/mL) each significantly (P<0.05, n=8) enhanced H2O2 release by LPS-treated macrophages. E2 (<10−2 and >10 ng/mL) and progesterone (10−7–104 ng/mL) each significantly inhibited (P<0.05; n=6) NO2− release by LPS-treated macrophages. CONCLUSIONS: Exposure to LPS tended to diminish the effects of E2 and to enhance the effects of progesterone on the parameters determined here. Such LPS-associated alterations in the dose–response profile of macrophages to female sex hormones may contribute to gender-related differences in the immune response under normal and pathological conditions.
This review describes an improved characterization of early B-lymphocyte precursors in mice and the remarkable sensitivity of the same cells to hormones. The nuclear enzyme terminal deoxynucleotidyl transferase (TdT) was used as a marker to image and characterize bone marrow cells lacking all lineage-associated markers. Most early TdT+ precursors have a distinctive density of c-kit and express the interleukin-7Ra chain, as well as flt-3/flk2, but lack CD34. An understanding of those cell surface properties made it possible to obtain highly enriched, viable cells with the potential to give rise to CD19+ lymphocytes in culture. A series of other flow cytometry and culture experiments suggested a possible differentiation sequence for these early pro-B cells. This new model was used to advantage in our studies of sex steroids. It appears that early precursors represent a hormone-sensitive control point for determining numbers of new B lymphocytes that are produced within bone marrow. We also compare and contrast these findings with B lymphopoiesis in humans.
Prepubertal castration of female NZB/NZW (B/W) hybrid mice did not influence mortality, whereas prepubertal castration of male B/W mice caused premature death and enhanced autoantibody formation. Prepubertal castration combined with the administration of sustained estradiol-17-β (E-2) enhanced mortality and autoantibody development and promoted immune complex nephritis in both sexes. The enhanced mortality observed in castrated males was significantly reduced if they were treated with sustained progesterone (P). Mice of both sexes receiving P had the highest levels of autoantibodies. By contrast, sustained 5-α-dihydrotestosterone (DHT) and testosterone (T) suppressed these autoimmune parameters. The suppressive effect of androgens was not a nonspecific anabolic property, since danazol (a compound with attenuated masculinizing but intact anabolic properties) was ineffective in suppressing disease. AntiDNA antibody formation developed prematurely in males given cyproterone acetate, an antiandrogen. However, this metabolic blocker did not influence mortality or proteinuria. Unexpected early enhancement of mortality was observed in female and male mice castrated and given both E-2 and DHT (when compared to sham-operated controls or mice given E-2 alone). When castration was combined with the administration of both E-2 and P, mortality was enhanced in males but was similar to E-2 alone in females. Androgen therapy was also suppressive when it was delayed and given to female mice with more advanced disease. DHT given to intact 3-month-old or castrated 6-month-old B/W females significantly improved survival without affecting the serum levels of anti-DNA antibodies. These observations demonstrate that sex hormones significantly modify disease in B/W mice and may have therapeutic potential.
The IgG subclass distribution of thyroglobulin antibodies (TgAb) has been studied in Hashimoto and Graves’ patients by several investigators with conflicting results, in part explainable by methodological problems. We have recently developed a quantitative ELISA to measure in absolute terms the serum concentration of TgAb subclasses. The aim of the present study was to apply this method in a large series of patients with autoimmune as well as, for the first time, non-autoimmune thyroid diseases. We examined 28 patients with Hashimoto's thyroiditis, 30 with Graves’ disease, 21 with thyroid carcinoma and 18 with non-toxic goitre, all selected for the presence of TgAbs. The results indicated that TgAbs in thyroid diseases were not restricted to any particular isotype, but comprised all four IgG subclasses. IgG1 was represented similarly in the four groups. The same was true for IgG3, even though its contribution to the total antibody content was very small. IgG4 was the dominant subclass in patients with Graves’ disease, thyroid carcinoma and non-toxic goitre, probably reflecting a prolonged antigenic challenge. In Hashimoto's thyroiditis IgG2 was dominant, possibly because T helper lymphocytes infiltrating the thyroid are typically Th1 type.
Fetal microchimerism may have a role in development of autoimmune thyroid disorders. Using parity as a surrogate for increasing fetal cell exposure, we analyzed its association with thyroid peroxidase antibody levels.
Secondary analysis of serum thyroid analytes determined in 17,298 women from a population-based prospective study between 2001 and 2003. Sera were assayed for thyrotropin, free thyroxine, and antithyroid peroxidase antibodies. We analyzed the relationship between thyroid peroxidase antibodies and increasing parity.
The incidence of abnormally elevated thyroid peroxidase antibody levels (>50 IU/mL) increased with advancing parity, but was not significant after adjustment for maternal characteristics. However, at higher thyroid peroxidase antibody levels (>500 IU/mL), a significant relationship with advancing parity persisted after adjustments (P = .002).
Advancing parity is associated with an increased risk for high serum concentrations of antithyroid peroxidase antibodies. This suggests fetal microchimerism may play a role in development of autoimmune thyroid disorders.
Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease associated with multiple immunologic abnormalities. Prominent among these is upregulation of type I interferon (IFN)?a powerful immune adjuvant. IFN is, in part, produced in SLE in response to autoantigens in the form of self-nucleic acids and their associated nuclear proteins. Sources of these autoantigens include apoptotic and necrotic cells as well as neutrophils undergoing a specific form of cell death called NETosis. Although plasmacytoid dendritic cells are the main producers of IFN-a, other cells are important regulators of this process. Both genetic and environmental risk factors play a role in the development and pathogenesis of SLE. Further highlighting the importance of IFN, candidate gene and genome-wide association studies have identified a number of genes involved in type I IFN pathways associated with SLE. In this review, 3 monogenic deficiencies that result in lupus-like phenotypes and several polygenic variants that have been consistently associated with SLE are highlighted, and the relationship of these genes to IFN-a production is discussed. Clinical associations of the type I IFN pathway and the use of IFN-blocking agents as therapeutic agents in SLE are also reviewed.
To evaluate the possible biological role of pregnancy on the risk of autoimmune diseases we assessed associations between reproductive history and subsequent risk of autoimmune diseases characterized by female predominance and other autoimmune diseases. Our study cohort comprised 4.6 million Danes born since 1935 for whom a complete record of childbirths was available. Cohort members were followed for hospital contacts for 31 autoimmune diseases from 1982 to 2008. Female predominant autoimmune diseases were those with a female:male sex ratio >2:1. Ratios of first hospitalization rates were calculated using Poisson regression, adjusting for potential confounding by age, birth cohort, calendar period and marital status. During 45.5 million person-years of follow-up 102,260 women were hospitalized with one or more autoimmune diseases. Overall, compared with childless women, women with children were at a relative risk of 1.04 (1.02-1.06) for any autoimmune diseases, 1.11 (1.08-1.14) for female predominant and 0.97 (0.95-1.00) for other autoimmune diseases. Possibly biologically related associations with parity were found for Hashimoto thyroiditis (1.11; 1.00-1.24), Graves' disease (1.19; 1.14-1.24), erythema nodosum (1.15; 1.01-1.32), psoriasis (1.08; 1.01-1.15), sarcoidosis (1.17; 1.06-1.28) and systemic lupus erythematosus (0.83; 0.74-0.93). Especially the one-year postpartum period was associated with an increased risk of Hashimoto thyroiditis, Graves' disease and sarcoidosis. Overall, parity was associated with an 11% increased risk of female predominant autoimmune diseases. Pregnancies resulting in liveborn children therefore seem to contribute only little to the general female predominance in autoimmune diseases. However, for a number of autoimmune diseases; especially autoimmune thyroid diseases, erythema nodosum and sarcoidosis parity might somehow be involved in disease development.
After approximately 130 years since their discovery as rare granulocytes that circulate in blood, basophils are just now gaining respect as significant contributors in the pathogenesis underlying allergic inflammation and disease. While long known for secreting preformed and newly synthesized mediators and for selectively infiltrating tissue during immunoglobulin E (IgE)-mediated inflammation, their role has largely been viewed as redundant to that of tissue mast cells in functioning as effector cells. This line of thought has persisted even though it has been known in humans for approximately 20 years that basophils additionally produce relatively large quantities of cytokines, e.g. interleukin-4 (IL-4)/IL-13, that are central for the manifestations of allergic disease. Studies using novel IL-4 reporter mice have significantly added to the in vivo importance of basophils as IL-4 producing cells, with recent findings indicating that these cells also function as antigen-presenting cells essential in initiating T-helper 2 responses. If confirmed and translated to humans, these provocative findings will give new meaning to the role basophils have in allergic disease, and in immunology overall.
Microparticles (MPs) are small membrane-bound vesicles that display proinflammatory and prothrombotic properties. These particles can be released by macrophages stimulated by ligands of the Toll-like receptors (TLRs) in a process that depends on nitric oxide (NO) production. Since sex hormones can modulate macrophage responses, we investigated the effects of progesterone and estradiol on macrophage particle release in vitro, comparing the responses with those induced by the glucocorticoid dexamethasone. As a model system for particle release, RAW 264.7 cells were stimulated in vitro with poly(I:C), a ligand of TLR3. Microparticles were measured by flow cytometry, while NO was measured by the Griess reaction. As the results of these studies showed, progesterone but not estradiol can block particle release by RAW264.7 cells treated with poly(I:C); dexamethasone was also active. Furthermore, while progesterone and dexamethasone inhibited NO production under the same culture conditions, neither agent blocked the production of particles stimulated by the NO donors dipropylenetriamine NONOate {(z)-1-[N-(3-aminopropyl)-N-(3-ammoniopropyl)amino] diazen-1-ium-1,2-diolate} and (z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2-diolate. Studies using RU486 to assess the role of hormone receptors indicated that while this agent blocked the inhibition of particle and NO production by dexamethasone, it did not affect the inhibition by progesterone. Together, these results indicate that progesterone but not estradiol can inhibit particle release by stimulated macrophages and suggest a mechanism that may contribute to the immunomodulatory effects of this sex hormone.
Preterm birth has increased over the last decade. In 2006, 12.5% of all births in the United States occurred at fewer than 37 weeks gestation. This is associated with significant health care costs as well as related neonatal morbidity and mortality. In 2003, costs related to care for infants with preterm-birth or low-birth weight exceeded 11 billion dollars. This article reviews the literature on 17 alpha-hydroxyprogesterone caproate (17-P) and natural progesterone and concludes that 17-P is indicated for prevention of preterm birth in women with a documented history of a preterm birth before 37 weeks.
For decades, natural and synthetic glucocorticoids (GC) have been among the most commonly prescribed classes of immunomodulatory drugs. Their unsurpassed immunosuppressive and antiinflammatory activity along with cost-effectiveness makes these compounds a treatment of choice for the majority of autoimmune and inflammatory diseases, despite serious side effects that frequently accompany GC therapy. The activated GC receptor (GR) that conveys the signaling information of these steroid ligands to the transcriptional machinery engages a number of pathways to ultimately suppress autoimmune responses. Of those, GR-mediated apoptosis of numerous cell types of hematopoietic origin and suppression of proinflammatory cytokine gene expression have been described as the primary mechanisms responsible for the antiinflammatory actions of GC. However, along with the ever-increasing appreciation of the complex functions of the immune system in health and disease, we are beginning to recognize new facets of GR actions in immune cells. Here, we give a brief overview of the extensive literature on the antiinflammatory activities of GC and discuss in greater detail the unexpected pathways, factors, and mechanisms that have recently begun to emerge as novel targets for GC-mediated immunosuppression.
Antigen-presenting molecules vary between individuals of the same species, making it more difficult for pathogens to evade immune recognition and spread through the whole population. As a result of this genetic diversity, transplants between individuals are recognized as foreign and are rejected. This alloreactivity turns placental viviparity into a major immunological challenge. The maternal immune system has to balance the opposing needs of maintaining robust immune reactivity to protect both mother and fetus from invading pathogens, while at the same time tolerating highly immunogenic paternal alloantigens in order to sustain fetal integrity. Regulatory T cells are responsible for the establishment of tolerance by modulating the immune response, and uterine natural killer cells direct placentation by controlling trophoblast invasion. A variety of other cell types, including decidual stromal cells, dendritic cells, and immunomodulatory multipotent mesenchymal stromal cells, are found at the fetal-maternal interface. These cells conspire to establish a suitable environment for fetal development without compromising systemic immunity. Defects in any of these components can lead to gestational failure despite successful fertilization.
The autoimmunity that characterizes systemic lupus erythematosus (SLE) is mediated by chronically activated plasmacytoid dendritic cells (pDCs), leading to production of type I interferon (IFN), and B-cell-mediated production of autoantibodies, particularly those against self DNA and other nuclear components. Neutrophils have also been implicated as having a role in the pathogenesis of SLE, but the exact nature of their contribution remains unknown.
A sexual dysmorphism in the immune response has been described and females display an increased incidence of autoimmune diseases. Experimental data show that sex steroids influence immune cell development and have immunomodulatory effects. The distribution, the action (genomic and nongenomic), the sex and tissue-depending expression pattern of estrogen, progesterone and androgen receptors and their functional disruptions in corresponding receptor knockout animals will be discussed, pointing out the difference among sex steroid hormones. Recent advances indicate an immunomodulatory role of sex steroids in the pathogenesis of systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. The outcomes of the clinical trials will help to find the best use of sex steroids in combination with current therapeutic drugs in autoimmune diseases. Sex steroid receptor modulating drugs will provide new therapeutic approaches in these pathologies.
Sex hormones play an important role as modulators of the immune system. A growing body of evidence shows reciprocal relationship between sex steroids and the immune system. Since the innate immune response determines the type of adaptive immune response, hormonal effects on the innate immune response may affect subsequent adaptive immunity. The sex steroids estrogens, progesterone and testosterone regulate growth, differentiation, survival and function of many cell types involved in homeostasis and immunity. The presence of sex steroid receptors on immune cells indicates that sex steroids may exert their biological effects by binding to these receptors. Sex steroids and immunity are closely connected, and their mutual regulation is involved in the maintenance of immune balance. Understanding the mechanisms of action of sex steroids on immune cells is important for further progress in the development of novel therapies for chronic diseases associated to immune dysregulation. This review describes the effects of sex steroids on the different immune system cells, and the possible implications of these effects on the incidence of many diseases.
Synthetic progestins are used by millions of women as contraceptives and in hormone replacement therapy (HRT), although their molecular mechanisms of action are not well understood. The importance of investigating these mechanisms, as compared to those of progesterone, has been highlighted by clinical evidence showing that medroxyprogesterone acetate (MPA), a first generation progestin, increases the risk of breast cancer and coronary heart disease in HRT users. A diverse range of later generation progestins with varying structures and pharmacological properties is available for therapeutic use and it is becoming clear that different progestins elicit beneficial and adverse effects to different extents. These differences in biological activity are likely to be due to many factors including variations in dose, metabolism, pharmacokinetics, bioavailability, and regulation of, and/or binding, to serum-binding proteins and steroidogenic enzymes. Since the intracellular effects on gene expression and cell signaling of steroids are mediated via intracellular steroid receptors, differential actions via the progesterone and other steroid receptors and their isoforms, are likely to be the major cause of differential intracellular actions of progestins. Since many progestins bind not only to the progesterone receptor, but also to the glucocorticoid, androgen, mineralocorticoid, and possibly the estrogen receptors, it is plausible that synthetic progestins exert therapeutic actions as well as side-effects via some of these receptors. Here we review the molecular mechanisms of intracellular actions of old (MPA, norethisterone, levonorgestrel, gestodene) vs. new (drospirenone, dienogest, trimegestone) generation progestins, via steroid receptors.
Multiple sclerosis (MS) is an autoimmune disease characterized by recurrent episodes of demyelination and axonal lesion mediated by CD4(+) T cells with a proinflammatory Th1 and Th17 phenotype, macrophages, and soluble inflammatory mediators. Identification of Th17 cells led to breaking the dichotomy of Th1/Th2 axis in immunopathogenesis of autoimmune diseases such as MS, and its experimental model, experimental autoimmune encephalomyelitis (EAE). Th17 cells are characterized by expression of retinoic acid-related orphan receptor (ROR)γt and signal transducer and activator of transcription 3 (STAT3) factors. Th17-produced cytokine profile including interleukin (IL)-17, IL-6, IL-21, IL-22, IL-23 and tumour necrosis factor (TNF)-α, which have proinflammatory functions, suggests it as an important factor in immunopathogenesis of MS, because the main feature of MS pathophysiology is the neuroinflammatory reaction. The blood brain barrier (BBB) disruption is an early and central event in MS pathogenesis. Autoreactive Th17 cells can migrate through the BBB by the production of cytokines such as IL-17 and IL-22, which disrupt tight junction proteins in the central nervous system (CNS) endothelial cells. Consistent with this observation and regarding the wide range production of proinflammatory cytokines and chemokines by Th17 cells, it is expected that Th17 cell to be as a potent pathogenic factor in disease immunopathophysiology. Th17-mediated inflammation is characterized by neutrophil recruitment into the CNS and neurons killing. However, the majority of our knowledge about the role of Th17 in MS pathogenesis is resulted in investigation into EAE animal models. In this review, we intend to focus on the newest information regarding the precise role of Th17 cells in immunopathogenesis of MS, and its animal model, EAE.
Several studies have reported that the fine-tuning of regulatory T cells (Tregs) is required for a successful pregnancy and for the control of autoimmune diseases. Here, we review the mechanisms that control the expansion of Tregs, based on insights obtained from the study of women suffering unsuccessful pregnancies and on recent data from patients with autoimmune diseases or with chronic viral infections such as HCV. In particular, we review the role of endocrine factors and IL-2/STAT5 signalling in the impaired expansion of Tregs.