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

Assess the impact of rs2201841 and rs2275913 single nucleotide polymorphism of host genes IL-23R and IL-17A respectively on susceptibility of rheumatoid arthritis .

Determine serum levels of IL-23 and IL-17A using ELISA test to investigate their correlation to rheumatoid arthritis disease activity .

Compare the 4 biomarkers IL-23R and IL-17A genetic polymorphism and levels of IL-23 and IL-17A as predictors of rheumatoid arthritis susceptibility and disease 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) .

SNP is a single base pair mutation at a specific locus, usually consisting of two alleles (where the rare allele frequency is \> 1%). The genetic factors account for 50-60% of all RA cases (13) . Some researchers have reported the relationship between IL-23R gene polymorphisms and RA risk but got no consistent results . Therefore, this study will search the role of IL-23R gene rs11209026 polymorphisms in individual susceptibility to RA . Many different genetic variants with functional gene polymorphisms may play a culprit role in the underlying pathogenetic mechanisms (14) .

IL-23R gene variants increase susceptibilities to autoimmune disease in patients with psoriasis, inflammatory bowel disease, and multiple sclerosis (15) . IL-17A is a promising target for anti-cytokine therapy in autoimmune arthritis (16).

In recent years, the associations between IL-17A polymorphisms and RA risk have been studied in various populations by many researchers, (17) with the most frequent variant being IL-17A rs2275913 .

The IL-17A rs2275913 polymorphism is located in the promoter region of the IL-17A gene, and cells with the 197A positive allele (genotypes GA/AA) secreted more IL-17A than cells with the 197A negative allele (18) .

Hence, the IL-17A rs2275913 polymorphism results in more efficient secretion of IL-17A, which may be a potential mechanism by which this polymorphism can increase the risk of developing RA. Many studies hypothesized that rs2201841 and rs2275913 SNP of IL-23R and IL-17A genes respectively have good prediction role for RA susceptibility and severity . Genetic and experimental data support the concept that the activation of IL-23/IL-17 axis contributes to the development of a series of inflammatory rheumatic diseases, including, rheumatoid arthritis (RA). It rapidly became a critical target of research to determine predictors of severity to guide therapeutic intervention .

Eligibility Criteria:
Inclusion Criteria:

* A total of 45 Patients fulfilling the 2010 Classification Criteria of the American college of Rheumatology/European League against Rheumatism (ACR / EULAR) will be included in the study.

The patients will be recruited from department of Physical medicine, Rheumatology \& Rehabilitation, Assiut University Hospital.

Exclusion Criteria:

* Patients with other connective tissue diseases (e.g. SLE, systemic sclerosis (SS), BD,...etc), associated autoimmune diseases, chronic liver or kidney diseases, or genetic diseases will be excluded from the study.