Sex effect on the correlation of immunoglobulin G glycosylation with rheumatoid arthritis disease activity

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease which affects females more than males with a presence of autoantibodies. Immunoglobulin G (IgG) produced by adaptive arm has 2 functional domains, Fc and Fab. The Fc domain binds Fc gammareceptors and C1q proteins of the innate arm. Therefore, the IgG Fc domain serves as a bridge between the innate and adaptive armsand is regulated by an evolutionarily conserved N-glycosylation with variable structures. These glycans are classified as agalactosylatedG0, monogalactosylated G1, and digalactosylated G2, which are further modified by core-fucosylation (F) and bisecting N-acetylglucosamine (B) moieties such as G0F and G0FB. Interestingly, proinflammatory G0F is shown to be regulated by estrogen in vivo. Here,it is hypothesized that the regulation of G0F by estrogen contributes to sex dichotomy in RA by setting up the level of IgG-dependentinflammation and therefore, RA disease activity (Das28-CRP3). To investigate this hypothesis, IgG glycosylation was characterized inserum samples from active RA patients (n = 232) and healthy controls (n = 232) by serum N-glycan analysis using the high performanceliquid chromatography. According to the results, the IgG Fc glycan phenotype originates predominantly from the structure of G0F, andboth G0F and G0FB correlate with Das28-CRP3 in females, but not in males. In conclusion, IgG G0F-dependent inflammation differsin males and females, and these differences point to the differential regulation of inflammation by sex hormone estrogen via IgG glycosylation.