Relation of IL23R and IL17A Gene Polymorphisms Plus Serum Levels of IL23 and IL17A to Rheumatoid Arthritis Susceptibility and Activity

Rheumatoid arthritis an autoimmune disease that is associated with progressive disability, systemic complications and socioeconomic costs. RA affects 0.5-1% of the human population making it one of the most common autoimmune disorders. The incidence of RA increases with age, affecting about 6% of the population over 65 years old. Women are more affected than men in a ratio of 3:1 (1) .

The synovitis in RA is characterized by massive cellular infiltration of the synovium consisting mainly of leukocytes such as T and B cells, macrophages, granulocytes and dendritic cells, together with the increased local production of proinflammatory cytokines and chemokines, eventually leading to the destruction of the joint and bone (2) .

Th-17 starts producing IL-17 and IL-22 which in turn stimulate fibroblast-like synoviocytes (FLS) to secrete IL-8, IL-6, CCL20 and CXCL8 causing inflammation, while the macrophages secreted TNF-α results in IL-23 production from FLS, forming a positive feedback loop that maintains the production of IL-17 and IL-22 from Th-17 (3) . Both IL-17 and IL-22 are able to induce osteoclast differentiation from osteoclast progenitor either directly, or by elevating Receptor activator of nuclear factor kappa-B ligand (RANKL) on CD4+ and Th-17 which upon ligation with the RANK receptor on osteoclast progenitor stimulates osteoclast differentiation. Osteoclasts are a main cause of bone erosion (4).

However, advances in understanding the pathogenesis of the disease have fostered the development of new therapeutics, with improved outcomes (5) . Overall, current treatment strategies for RA tend to involve targeting pro-inflammatory cytokines, and thereby the activation process of inflammation, rather than functioning to boost pathways that orchestrate the suppression and resolution of inflammation (6) .

IL-23 is a pro-inflammatory cytokine that belongs to the IL-12 family, together with IL-12, IL-27, IL-35, and IL-39 (7) .Its actions are mainly mediated by the CD4 T helper subset Th17, a distinct subpopulation of gamma/delta T cells (Tγδ17 cells), subsets of natural killer T (NKT) cells, and type 3 innate lymphoid cells (ILC3s) (8) The main role of IL-23 is to induce the differentiation of αβ T CD4+ naïve cells (Th0 cells) in T helper type 17 (Th17 cells), (9) which are considered pivotal players in autoimmunity (10) . The IL-23 receptor (IL-23R) is a heterodimeric receptor composed of 2 subunits: IL-12Rβ1, in common with the IL-12 receptor (IL-12R) and IL-23Rα, specific to IL-23 signaling (11). The Th17 subset of T-helper cells is pro-inflammatory, plays vital roles in host defense and is involved in the pathogenesis of RA primarily by secreting IL-17 (12) .