IL-21 is therefore an autocrine cytokine that regulates human Th17 cells in rheumatoid arthritis, and serves as a good target for treating this autoimmune disease.
Interleukin 22 (IL-22), a relatively new cytokine has been found to induce significant proliferation of human keratinocytes and fibroblast like synoviocytes (FLS) and thus plays an important role in the pathogenesis of autoimmune diseases like psoriasis and rheumatoid arthritis (RA) which are characterized by hyperproliferation of keratinocytes and FLS respectively.
IL-21 also affects different subtypes of T cells including T helper-17 (TH17), T follicular helper (TFH) and regulatory T (Treg) cells and thereby promotes the development of autoimmune disorders and inflammatory diseases.
Accordingly, SFN significantly inhibited the activation of untransformed human T-cells derived from healthy donors or RA patients, and downregulated the expression of the transcription factor RORγt, and the T<sub>H</sub>17-related cytokines IL-17A, IL-17F, and IL-22, which play a major role within the pathophysiology of many chronic inflammatory/autoimmune diseases.
Also, the studies on the production of IL-21 in human autoimmune diseases and its behaviour on human cells in vitro are revealing the potential of IL-21 to exacerbate cellular processes that determine the course of autoimmune diseases.
Although the early studies on IL-17 focused on Th17 cells, it was later demonstrated that γδ T cells were an important early source of IL-17 and IL-21 that helped amplify IL-17 production by Th17 cells in autoimmune diseases.
Co-expression of IL-22 and IL-17 has been identified and demonstrated to be involved in the immunopathogenesis of some autoimmune diseases as well as the defense against pathogenic infections in animal studies.
Compared with age-matched healthy controls, children with autoimmunity had lower numbers and frequencies of B10 cells (decreased by 39% and 48%, respectively), higher IFNγ levels, and lower IL-21 levels in serum.
Deregulated production of interleukin (IL)-17 and IL-21 contributes to the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
Finally, BXSB-Yaa mice, which develop a systemic lupus erythematosus-like disease, have greatly elevated IL-21, suggesting a role for IL-21 in the development of autoimmune disease.
Follicular helper T cells (Tfh), which play a pivotal role in B cell activation and differentiation in lymphoid structures, secrete IL-21 whose augmented secretion is a hallmark of several autoimmune diseases.
Furthermore, accumulating evidence has defined both protective and pathogenic properties of IL-22 in a number of conditions including autoimmune disease, infection, and malignancy.
IL22RA2 represents a compelling MS candidate gene due to the role of IL-22 in autoimmunity; however, rs17066096 does not map into any known functional element.
In particular the crucial role of NF-AT detected herein may form the basis of direct action of CsA on IL-22 expression by T cells, which may contribute to therapeutic efficacy of the drug in autoimmunity.