Involvement of the IL-23/IL-17 axis and the Th17/Treg balance in the pathogenesis and control of autoimmune arthritis

Abstract

The T helper (Th) cell subsets are characterized by the type of cytokines produced and the master transcription factor expressed. Th1 cells participate in cell-mediated immunity, whereas Th2 cells promote humoral immunity. Furthermore, the two subsets can control each other. Thereby, Th1-Th2 balance offered a key paradigm in understanding the induction and regulation of immune pathology in autoimmune and other diseases. However, over the past decade, Th17 cells producing interleukin-17 (IL-17) have emerged as the major pathogenic T cell subset in many pathological conditions that were previously attributed to Th1 cells. In addition, the role of CD4+CD25+ T regulatory cells (Treg) in controlling the activity of Th17 and other T cell subsets has increasingly been realized. Thereby, examination of the Th17/Treg balance in the course of autoimmune diseases has significantly advanced our understanding of the pathogenesis of these disorders. The differentiation of Th17 and Treg cells from naïve T cells is inter-related and controlled in part by the cytokine milieu. For example, transforming growth factor β (TGFβ) is required for Treg induction, whereas the same cytokine in the presence of IL-6 (or IL-1) promotes the differentiation of Th17. Furthermore, IL-23 plays a role in the maintenance of Th17. Accordingly, novel therapeutic approaches are being developed to target IL-23/IL-17 as well as to modulate the Th17/Treg balance in favor of immune regulation to control autoimmunity.

Interleukin-17A Levels Increase in Serum of Children With Juvenile Idiopathic Arthritis

“…2 The negative correlation of osteoblastogenesis and the IL-17A level in the synovial fluid in children with juvenile idiopathic arthritis (JIA) confirms the role of IL-17A in the lesion in bone structures. 15 The destruction of bone structures is also influenced by various proinflammatory mediators induced by IL-17A, such as IL-6, prostaglandin E2, nitric oxide, and others.…”

“…1 IL-17A binds to its receptors -IL-17 receptor A/IL-17 receptor C-on synoviocytes, endothelial cells, fibroblasts and osteoblasts and stimulates production of pro-inflammatory cytokines, chemokines and other inflammatory mediators, and also, interacts synergistically with other proinflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor alpha. 2,3 In the initial phases of chronic arthritis, IL-17A affects synovial hypercellularity. 4 A study conducted on the culture of synovial fibroblasts has shown that IL-17A stimulates the production of the vascular endothelial growth factor, which is important in the angiogenesis and the consequent synovial proliferation.…”

Progress in interleukin‐2 therapy for rheumatic immune diseases by regulating the immune balance of T cells

“…The level of IL‐17 in the peripheral blood of RA patients was significantly higher than that of healthy people. IL‐17 could promote cell migration, activate osteoclasts and lead to inflammation and bone destruction …”

An imbalance between regulatory T cells and T helper 17 cells in acetylcholine receptor–positive myasthenia gravis patients

“…In contrast to tT reg cells, peripheral T reg cells express FOXP3 and CD25 only after activation and require the presence of TGF‐β . The regulatory mechanisms of T reg cells required to suppress effector cell proliferation are various, including cell–cell contact through the expression of the cytotoxic T lymphocytes–associated protein 4 (CTLA4), deprivation of IL‐2, expression of anti‐inflammatory cytokines (TGF‐β and IL‐10), or expression of granzyme A and activation of the perforin pathway …”