Understanding the complex interplay of genetic, immunologic, and environmental factors in rheumatoid arthritis pathogenesis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive joint destruction, systemic inflammation, and disability of patients. Its prevalence is steadily increasing worldwide. In Kazakhstan, the number of diagnosed cases has increased significantly, indicating the need for a deeper understanding of the mechanisms of the disease. This review presents an updated analysis of the immunogenetic factors contributing to RA pathogenesis. Genetic polymorphisms in HLA-DRB1, PTPN22, STAT4, CTLA4, and TRAF6 are implicated in immune dysregulation by promoting T-cell activation, Th17 differentiation, and cytokine overproduction, including IL-6, IL-17, and TNF-α. Dysregulation of transcription factors such as STAT3, GATA3, and FOXP3 further contributes to Treg/Th17 imbalance. Additionally, environmental triggers like smoking promote citrullination through PAD2/PAD4 activation, production of anti-citrullinated protein antibodies (ACPA), and immune complex formation. B-cell activation and the emergence of autoantibodies, including novel markers such as anti-CarP and anti-PAD4, sustain inflammation and enhance diagnostic precision, especially in seronegative cases. The review also emphasizes the role of epigenetic mechanisms, such as gene hypomethylation and altered microRNA expression, in modulating immune responses. A comprehensive understanding of these interconnected mechanisms offers new insights into early diagnosis, the identification of preclinical RA stages, and the development of targeted therapeutic strategies.Keywords: rheumatoid arthritis, pathogenesis, genes, autoantibodies, cytokines.