Mitigated Tregs and Augmented Th17 Cells and Cytokines are Associated with Severity of Experimental Autoimmune Neuritis

Abstract

Experimental autoimmune neuritis (EAN), an animal model of human GuillainBarr e syndrome, has long been considered as a T helper (Th) 1 cell-mediated autoimmune disorder. However, deficiency of IFN-c, a signature Th1 cytokine, aggravated EAN, with features of elevated production of IL-17A, despite an alleviated systemic Th1 immune response. We hypothesized that Th17 cells and their cytokines might play a pathogenic role in EAN. To further clarify the roles of these Th and regulatory T cell (Treg) cytokines in the pathogenesis of EAN and their interrelationship, we investigated the expression of Th1/Th2/Th17/ Treg cytokines in EAN in this study. We found that the levels of Th17 cells and IL-17A in cauda equina (CE)-infiltrating cells and splenic mononuclear cells (MNCs) as well as in serum paralleled the disease evolution, which increased progressively during the initiation stage and reached higher value at the peak of EAN. The same pattern was also noticed for the expression of IL-22. The diverse expression profiles of FoxP3, IL-17 receptors A and C were seen in CE-infiltrating cells and splenic MNCs in EAN. These findings indicate a major proinflammatory role of Th17 cells and IL-17A in the pathogenesis of EAN. Therapeutic interventions may be focused upon inhibiting Th17 cells and their cytokines in the early phase of EAN, so as to delay and suppress clinical signs of the disease, which has relevance for future studies on pathogenesis and treatment of GBS in humans.

Expression of interleukin‐17 in primary Sjögren's syndrome and the correlation with disease severity: A systematic review and meta‐analysis

“…Meanwhile, IL‐17 can increase the expression of various pro‐inflammatory cytokines, which may in turn aggravate inflammation and cause organ destruction . In addition, IL‐17 could stimulate the release of matrix metalloproteinases, destroying components of the extracellular matrix and resulting in compromised function of the exocrine glands . In recent years, several articles have explored the aberrant expression of IL‐17 in patients with pSS.…”

PR‐957, a selective inhibitor of immunoproteasome subunit low‐MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing T h 17‐cell differentiation and regulating cytokine production

“…Overall, though, studies of T h 17 cells and EAN have obviously challenged the classic T h 1/2 paradigm more and more. IL-17 cells and T h 17 are indeed involved in the progression of GBS and EAN (43)(44)(45)(46)(47). In this study of rats with EAN, we investigated the infiltration of T h 1, -2, -17, and T reg cells into the spleen by using flow cytometry and into sciatic nerves by means of immunofluorescence.…”

Experimental autoimmune neuritis

“…Th1 cells are crucial for triggering antigen‐specific autoimmune neuritis. Mononuclear phagocytes and Th17 cells, T lymphocytes that produce a recently characterized pro‐inflammatory cytokine, interleukin (IL)‐17, play an important role in destroying PNS myelin . Actually, a macrophage‐elicited model of EAN failed to produce severe EAN .…”