Profiling of immunomodulatory anti-cytokine autoantibodies associated with disease heterogeneity in a multiethnic Asian cohort

In this study, we present a comprehensive analysis of anti-cytokine autoantibodies (ACAAs)-autoimmune phenocopies that mimic genetic inborn errors of immunity (IEIs) and contribute to clinical variability during infections and autoimmune diseases. ACAAs were profiled in a multi-ethnic Asian cohort comprising healthy individuals and patients with diverse autoimmune and chronic health conditions. While ACAAs were infrequent in healthy individuals (< 3%), their prevalence was significantly higher in patients with autoimmunity and multimorbidity, reaching up to 10% for certain interferon (IFN) subtypes. A functional assessment revealed that Type I anti-IFN autoantibodies elicited the strongest neutralising activities. This correlated with a reduction in pSTAT1 levels in cytokine-induced reporter cells. These findings suggest that type I anti-IFN antibodies can dampen/abrogate interferon signalling and may influence disease outcomes. Overall, these results map the landscape of ACAA frequency and specificity in an Asian population and underscore their context-dependent roles as modulators of cytokine networks, with potential implications for disease susceptibility and severity.