Autoantibodies in systemic sclerosis display a proinflammatory Fc glycosylation signature independent of systemic inflammation.

Reduced IgG Fc galactosylation, reflected by elevated agalactosylated (G0) glycoforms, is a hallmark of autoimmune diseases and correlates with systemic inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Whether similar glycosylation alterations occur in disease-specific autoantibodies in the absence of systemic inflammation remains unknown. IgG Fc glycosylation was analyzed in systemic sclerosis (SSc), a disease characterized by fibrosis, vasculopathy, and autoimmunity rather than overt systemic inflammation. Anti-centromere protein B antibody-positive (ACA+) and anti-topoisomerase I antibody-positive (ATA+) SSc patients were studied in a discovery (n = 69) and validation dataset (n = 58), with age- and sex-matched healthy donors (HDs; n = 30 per dataset) as controls (total n = 187). Total and antigen-specific IgG were affinity-purified and analyzed by liquid chromatography-mass spectrometry. Fc glycosylation traits were quantified, and associations with CRP and ESR assessed. Compared with HDs, total IgG1 in SSc exhibited reduced galactosylation (p ≤ 0.01) and sialylation, and increased bisection. These alterations were more pronounced in antigen-specific IgG1, with both anti-CENP-B and anti-TOP1 IgG1 displaying increased fucosylation and bisection; and reduced galactosylation and sialylation compared with total IgG1 (all p ≤ 0.002). Anti-CENP-B IgG1 showed higher bisection than anti-TOP1 IgG1 (p = 0.001), whereas antigen-specific IgG2/3 and IgG4 glycoforms were predominantly detected in ATA+ patients. Despite significantly elevated autoantigen-specific G0 glycoform frequencies compared with total IgG1 (p < 0.0001 to p = 0.013), no significant correlations with CRP or ESR were observed (rs < 0.24 for all). Findings were confirmed in the validation dataset. Autoantigen-specific IgG1 in SSc exhibits a proinflammatory Fc glycosylation profile in the absence of systemic inflammation, suggesting disease-specific or localized mechanisms underlying Fc glycan remodeling.