Lymphocyte Subsets and the Role of Th1/Th2 Balance in Stressed Chronic Pain Patients

Department of Anesthesiology, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany.
NeuroImmunoModulation (Impact Factor: 1.88). 02/2007; 14(5):272-80. DOI: 10.1159/000115041
Source: PubMed

ABSTRACT The complex regional pain syndrome (CRPS) and fibromyalgia (FM) are chronic pain syndromes occurring in highly stressed individuals. Despite the known connection between the nervous system and immune cells, information on distribution of lymphocyte subsets under stress and pain conditions is limited.
We performed a comparative study in 15 patients with CRPS type I, 22 patients with FM and 37 age- and sex-matched healthy controls and investigated the influence of pain and stress on lymphocyte number, subpopulations and the Th1/Th2 cytokine ratio in T lymphocytes.
Lymphocyte numbers did not differ between groups. Quantitative analyses of lymphocyte subpopulations showed a significant reduction of cytotoxic CD8+ lymphocytes in both CRPS (p < 0.01) and FM (p < 0.05) patients as compared with healthy controls. Additionally, CRPS patients were characterized by a lower percentage of IL-2-producing T cell subpopulations reflecting a diminished Th1 response in contrast to no changes in the Th2 cytokine profile.
Future studies are warranted to answer whether such immunological changes play a pathogenetic role in CRPS and FM or merely reflect the consequences of a pain-induced neurohumoral stress response, and whether they contribute to immunosuppression in stressed chronic pain patients.

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    • "Further, stress hormones are known to influence the production of Th1 and Th2 cytokines and thus, help determine which type of immune response prevails (Elenkov and Chrousos 1999). Deregulation of Th1/Th2 cytokines has been reported to be involved in the pathogenesis of many diseases including autoimmune diseases, sleep disturbance, major depression, and other disorders (Schwarz et al. 2001; Kaufmann et al. 2007). The glucocorticoid-induced tumor necrosis factor receptor (GITR) is constitutively expressed in regulatory T cells (Tregs) at a higher level than in other T cells (McHugh et al. 2002; Shimizu et al. 2002) and activated T cells can also up-regulate GITR expression (Shevach and Stephens 2006). "
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    ABSTRACT: Alterations to the immune system caused by stress have been considered to markedly increase the risk for immune-related diseases such as cancer and autoimmune disorders. We investigated the potential anti-stress effects of the histamine 4 receptor (H4R) agonist, 4-methylhistamine (4-MeH), in a murine stress model. Mice were placed in 50 ml conical centrifuge tubes for 12 h followed by a 12 h rest. The effects of treatment with 4-MeH (30 mg/kg, i.p, twice daily) for 2 days were assessed. At 2 days after physical restraint, mice were sacrificed and tissues harvested. We evaluated the effects of 4-MeH treatment on CD4+ T cell production, and intracellular IFN-γ and IL-4 expression in these cells. We also assessed IL-1β, IFN-γ, TNF-α, and IL-4 mRNA expression as well as IFN-γ, TNF-α, GITR, Ox40 and IL-4 protein expression in the spleen. The results showed that 4-MeH treatment of stressed mice results in a substantial increase in the CD4+ T cells as well as in IFN-γ production by these cells. Compared to both untreated and stressed controls. In contrast, IL-4 expression decreased significantly following 4-MeH treatment of mice. Moreover, stimulation of the H4R resulted in up-regulated expression of IL-1β, IFN-γ and TNF-α mRNAs and decreased the expression of IL-4. Western blot analysis confirmed decreased protein expression of IFN-γ, TNF-α, GITR, Ox40 and increased IL-4 in the SC group and treatment of mice with 4-MeH reversed these effects. Our results confirm the significant impact of chronic stress on T cell function and production of Th1/Th2 mediators H4R.
    Immunobiology 10/2014; DOI:10.1016/j.imbio.2014.10.014 · 3.04 Impact Factor
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    • "Although results are mixed, two published meta-analyses indicate that depression is accompanied by a lymphopenia and reduced natural killer cell (NK) counts (Herbert and Cohen, 1993a; Miller, 2010; Zorrilla et al., 2001). For somatization syndromes and associated conditions such as insomnia or pain disorders, there is some evidence for reduced counts of lymphocytes including whole T cell counts, suppressor T cells and T helper cells (Kaufmann et al., 2007; Rief et al., 2001a, 2001b; Savard et al., 2003). Previous research indicates that exercise and physical activity have beneficial effects across several physical and mental-health outcomes (Penedo and Dahn, 2005). "
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    ABSTRACT: Background Previous research indicates that physical activity may alter the number of immune cells. We examined whether increasing or decreasing the level of physical activity affects circulating lymphocyte and monocyte counts in patients with somatization syndromes and patients with major depression. Methods Thirty-eight participants with major depression, 26 participants with somatization syndromes and 47 healthy controls participated in the study. Using an experimental within-subject design, participants were involved in 1 week of increased physical activity (daily exercise sessions) and 1 week of reduced physical activity. Counts of total lymphocytes, lymphocyte subsets and monocytes were determined before and after each trial. Linear mixed models adjusted for sex, body mass index, age, fitness status and the order of trials were used for longitudinal data analysis. Results One week of exercise increases the number of monocytes in healthy controls (p<.05), but not in patients with somatization syndromes or patients with major depression. In addition, after 1 week of exercise, depressive symptoms were reduced in patients with major depression (p<.05) while somatoform symptoms were reduced (p<.05) in both clinical groups. Baseline comparisons and mixed models indicated reduced T helper cell counts in patients with somatization syndromes. Limitations Relatively small sample size. The time of physical activity was relatively short and restricted to low-graded exercise. Conclusions This study demonstrates a blunted mobilization of monocytes by exercise in both patients with somatization syndromes and patients with major depression. In addition, even one week of exercise reduces somatoform and depressive symptoms.
    Journal of Affective Disorders 09/2014; 166:156–164. DOI:10.1016/j.jad.2014.04.060 · 3.38 Impact Factor
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    • "All seven studies had a modified CEMB level of 3d [10,12,18,21,22,24,31]. One study reached a NOS score of 4 [12], two studies of 3 [24,31], and four studies of 2 [10,18,21,22]. Applying W-MeQS three studies were of medium methodological quality [10,21,31] and four were of low quality [12,18,22,24]. "
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    ABSTRACT: To perform a systematic review and meta-analysis on cytokine levels in patients with fibromyalgia syndrome (FMS). Through December 2010 we systematically reviewed the databases PubMed, MEDLINE, and PsycINFO and screened the reference lists of 22 review articles for suitable original articles. Original articles investigating cytokines in patients with FMS were included. Data were extracted by two independent authors. Differences of the cytokine levels of FMS patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed applying methodological scores: modified Center of Evidence Based Medicine, Newcastle-Ottawa-Scale, and Würzburg Methodological Quality Score. Twenty-five articles were included investigating 1255 FMS patients and 800 healthy controls. Data of 13/25 studies entered meta-analysis. The overall methodological quality of studies was low. The results of the majority of studies were not comparable because methods, investigated material, and investigated target cytokines differed. Systematic review of the selected 25 articles revealed that FMS patients had higher serum levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8, and higher plasma levels of IL-8. Meta-analysis of eligible studies showed that FMS patients had higher plasma IL-6 levels compared to controls (SMD = -0.34 [-0.64, -0.03] 95% CI; p = 0.03). The majority of investigated cytokines were not different between patients and controls. The pathophysiological role of cytokines in FMS is still unclear. Studies of higher quality and with higher numbers of subjects are needed.
    BMC Musculoskeletal Disorders 10/2011; 12(1):245. DOI:10.1186/1471-2474-12-245 · 1.72 Impact Factor
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