And, in fact, substantiating the differential effect of stress hormones, the stress-induced Th2 shift may represent a major driving force for the onset and the clinical expression in Graves’ hyperthyroidism by suppressing cellular immunity and potentiating humoral immunity.
Several lines of evidence also indicate that a hyper- or hypo-activity of the stress system, or, alternatively, a dysfunctional hypothalamic–pituitary–adrenal (HPA) axis or sympathetic nervous system are involved in the pathogenesis of autoimmune diseases.
However, the question still remains, in some cases e.g. multiple sclerosis and psoriasis, why chronic stress contributes to the relapse of autoimmune activity.
The study published in the March 2013 issue of the European Journal of Immunology may provide some new insights into this phenomenon.
In this study, Idan Harpaz and colleagues from the Ben-Gurion Universityof the Negev, Beer Sheva, Israel, demonstrate that prolonged stress exposure – 24 days of chronic variable stress (CVS) – exacerbates, rather than ameliorates, experimental autoimmune encephalomyelitis (EAE) in female C57BL/6 mice.
This effect was prevented by blocking corticosterone (CORT) signaling. Of note, during basal, non-stressed conditions, females exhibited substantially higher CORT levels and an attenuated EAE than males. However, in females C57BL/6 mice, CVS induced a significantly worsened EAE and a shift toward proinflammatory Th1/Th17 immune responses and a decreased proportion of CD4+CD25+ Treg cells.
Thus, according to the the authors, the study suggests that whereas C57BL/6 female mice generally exhibit higher CORT levels and an attenuated form of EAE than males, they become less responsive to the immunosuppressive effects of CORT under chronic stress and thereby prone to a higher risk of destructive autoimmunity.
The authors discuss that these observations may indicate that while the HPA axis provides immunosuppression under basal conditions, prolonged exposure to chronic stress may result in an attenuated CORT response to stimuli, and CORT resistance in proinflammatory T-cell lineages. Through this mechanism, chronic stress may contribute to exacerbations of autoimmune diseases.
This is substantiated by a 2012 study, discussed here, indicating that chronic stress may induce glucocorticoid receptor resistance (GCR), which, in turn, interferes with appropriate regulation of inﬂammation.
The authors discuss that these observations may indicate that while the HPA axis provides immunosuppression under basal conditions, prolonged exposure to chronic stress may result in an attenuated CORT response to stimuli, and CORT resistance in proinflammatory T-cell lineages.
Through this mechanism, chronic stress may contribute to exacerbations of autoimmune diseases.
According to the authors, their results also suggest that patients suffering from autoimmune diseases may perhaps develop steroid resistance due to persistent glucocorticoids exposure.
A2015 reviewoutlines the idea that reduced active glucocorticoid receptor expression in airway neutrophils may be a mechanism that contributes to glucocorticoid resistance in glucocorticoid resistant asthma. Thus, the authors discuss some studies showing that IL-17A and IL-17F are associated with overexpression of the inhibitory β-isoform of the GR (GR-β) in neutrophils and other airway and blood cells.
These data suggest that Th17 cells are sufficient to promote many of the hallmark characteristics of asthma in vivo and this response is steroid insensitive (Figure 1). Taken together, these data suggest a role of IL-17 to recruit neutrophils to airways and, consequently, to mediate the steroid-resistant and severe asthma.
A 2016 study describes a gradient of glucocorticoid sensitivity among helper T cell cytokines. Thus, Th1, Th2, and Th17 cells have distinct glucocorticoid sensitivity:
Th1 cells are sensitive to glucocorticoid-induced apoptosis and cytokine suppression.
Th2 cells are sensitive to glucocorticoid suppression of cytokines but resistant to glucocorticoid-induced apoptosis.
Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression.
According to Jesus Banuelosa and Nicholas Z. Lua, the authors of this study, the Th subset-specific glucocorticoid sensitivity helps to explain varying degrees of glucocorticoid resistance in autoimmune disorders, asthma, and several other inflammatory disorders. For example, approximately 20% of patients with Crohn’s disease and up to 10% of asthma patients are resistant to glucocorticoids.
These authors propose that varying Th subsets in these diseases underlie the glucocorticoid responsiveness of patients. Both Th1 and Th17 cells play a major role in Crohn’s disease, rheumatoid arthritis, psoriasis, and multiple sclerosis while Th2 and Th17 cells contribute to asthma.
In fact, as Elisabetta Profumo discussed in 2017, here on BrainImmune, Th17 cells are refractory to glucocorticoid (GC)-mediated T cell suppression, with different degree of resistance in different diseases. Different subsets of Th17 cells with distinct GC sensitivity probably exist, and GC treatment for a long period could be responsible for the depletion of GC-sensitive T cells and the expansion of GC resistant subsets, thus worsening the condition of patients affected by inflammatory diseases.
In a 2018 study Juliana de Castro Kroner et al. wrote that human TH17 responses to glucocorticoids are not homogeneous. Thus, in patients with psoriasis, TH17 cells are successfully suppressed by GCs, whereas in patients with lupus erythematosus, TH17 cells are refractory to glucocorticoid treatment. This prompted these to investigate whether glucocorticoids are able to induce human TH17 cells.
The authors found that glucocorticoids promote intrinsic human TH17, thus glucocorticoids are promoters of TH17 differentiation, which is regulated by IL-2. Also, they provide further evidence that the response of memory T cells to glucocorticoid treatment is context-dependent. It is known that certain TH17 diseases are more glucocorticoid-sensitive than others, but here these authors show that in the absence of disease, TH17 cells are refractory to glucocorticoid-suppressive effects. The specific pathologic aspects that alter TH17 responses to glucocorticoid therapy remain to be clarified.