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


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.

10 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
    • "Conversely, mice without B-and T-cells (RAG − / − ) have less pain behaviour after nerve lesions than wild-type mice, indicating the importance of lymphocytes for the development of pain (Costigan et al., 2009). The lymphocyte balance between TH1/TH2 is changed in CRPS reflecting a diminished Th1-response, perhaps in an attempt to counteract CRPS inflammation (Kaufmann et al., 2007). As CRPS occurs mostly after fractures, it is interesting to note that fracture healing is improved in animals lacking an adaptive immune system (Toben et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute Complex Regional Pain Syndrome (CRPS) is associated with signs of inflammation such as increased skin temperature, oedema, skin colour changes and pain. Pro-inflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-1beta, IL-6) are up-regulated, whereas anti-inflammatory cytokines (IL-4, IL-10) are diminished. Adaptive immunity seems to be involved in CRPS pathophysiology as many patients have autoantibodies directed against β2 adrenergic and muscarinic-2 receptors. In an animal tibial fracture model changes in the innate immune response such as up-regulation of keratinocytes are also found. Additionally, CRPS is accompanied by increased neurogenic inflammation which depends mainly on neuropeptides such as CGRP and Substance P. Besides inflammatory signs, sympathetic nervous system involvement in CRPS results in cool skin, increased sweating and sympathetically-maintained pain. The norepinephrine level is lower in the CRPS-affected than contralateral limb, but sympathetic sprouting and up-regulation of alpha-adrenoceptors may result in an adrenergic supersensitivity. The sympathetic nervous system and inflammation interact: norepinephrine influences the immune system and the production of cytokines. There is substantial evidence that this interaction contributes to the pathophysiology and clinical presentation of CRPS, but this interaction is not straightforward. How inflammation in CRPS might be exaggerated by sympathetic transmitters requires further elucidation.
    Autonomic neuroscience: basic & clinical 12/2013; 182. DOI:10.1016/j.autneu.2013.12.011 · 1.56 Impact Factor
Show more