Abstract

 Rheumatoid Arthritis (RA) (OMIM ID: 180300) is an inflammatory autoimmune disease caused by immune reaction against the proliferating synovial fibroblasts. Nonsuppurative proliferation of synoviocytes frequently progresses to destroy the articular cartilages and underlying bone, resulting in permanent disability. Using system biology approach, candidate genes obtained from OMIM (Online Mendelian Inheritance in Man) and its interacting proteins were prioritized on the basis of three Gene Ontology terms (Molecular Function, Cellular component, and Biological Process) employing FunSimMat (Functional Similarity Matrix). Among the many, four prioritized proteins NFκBIL1, HCST, MICA, and MICB were selected. Amongst the prioritized genes, literature review suggested that NFκBIL-1 (Nuclear Factor-κ of B-cell Inhibitor Like protein-1) (UniProtKB ID: Q9UBC1) competes against SR (Ser-Arg) protein, ASF/SF2, in negatively regulating CD45RO gene expression in CD4 T-cells, whose overproduction would lead to cytokine outburst, thus leading to an immunological attack. ASF/SF2 mediated splicing variant, CD45RA, otherwise would have prevented overproduction of these cytokines. Overproduced cytokines such as TNF-α, IL-6, IL-15 simultaneously induces inflammatory stress in the synovial membrane and activates stress induced MICA/B (UniProtKB ID: Q29983/Q29980) through downstream signaling following TNFR1-TRAF mediated signaling pathway. Synovial expression of MICA/B enables interaction with its ligand NKG2D associated with DAP10 (UniProt KB ID: Q9UBK5) amply present on CD8+ αβ T-cells, CD4+γδ T-cells, and NK cells, thus promoting cytolysis of MICA/B expressing synoviocytes along with further production of cytokines TNF-α and IL-15. Hence, alteration in NFκBIL-1 promoter induces MICA/B expression that leads in production of cytokines could be a probable cause of chronic RA.
 Int. J. Appl. Sci. Biotechnol. Vol 6(4): 332--338
Highlights
Rheumatoid arthritis (OMIM ID: 180300) is a systemic, chronic inflammatory disease and is a long lasting autoimmune disorder occurring in women (3 to 5 times) commonly than in men
OMIM gene name was synchronized with HGNC number, and Ensemble number provided by HGNC was hyperlinked to generate UniProtKB ID
The expanded seed proteins were queried into three Protein-Protein Interaction (PPI) database in order to obtain the interacting proteins
Summary
Rheumatoid arthritis (OMIM ID: 180300) is a systemic, chronic inflammatory disease and is a long lasting autoimmune disorder occurring in women (3 to 5 times) commonly than in men. The resultant is an exceeding amount of CD45RO over CD45RA on T-cell surface, a Tyrosine phosphorylase enzyme which play a significant role in downstream signaling for activation of transcription factors (AP1, NF-κB, and NFAT) that express cytokines such as TNF-α (An et al, 2013). This triggers downstream signalling in the interacting lymphocytes, leading to cytolysis of MICA/B presenting cells along with further production of cytokines (Groh et al 2003).
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