Complement system activation through classical, alternative, and lectin pathways in the pathogenesis of systemic autoimmune diseases

Abstract

The complement system serves as a critical effector mechanism of innate immunity while simultaneously bridging innate and adaptive immune responses. Dysregulated complement activation has been implicated in the pathogenesis of numerous systemic autoimmune diseases, contributing to tissue injury and perpetuating inflammatory cycles. This research investigated complement pathway activation patterns across major systemic autoimmune conditions including systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, and systemic sclerosis. A cross-sectional comparative research enrolled 186 patients with confirmed autoimmune diagnoses and 48 healthy controls at the Rheumatology Clinic of Monterrey Regional Medical Center between February 2022 and August 2023. Serum samples were analyzed for complement components C3, C4, and CH50 functional activity, along with activation markers including C3a, C5a, and soluble C5b-9. Patients with systemic lupus erythematosus demonstrated the most pronounced complement consumption, with C3 and C4 levels reduced to 58.4% and 42.7% of control values respectively. Elevated C3a concentrations indicating ongoing activation were observed across all autoimmune groups, with lupus patients showing 2.87-fold elevation compared to healthy controls. Classical pathway activation predominated in lupus and rheumatoid arthritis, while alternative pathway markers showed greater elevation in systemic sclerosis. These findings confirm differential complement pathway involvement across autoimmune diseases and support the potential utility of complement-targeted therapeutics in selected patient populations.