Immune Complexes Shape the Pathogenicity of Autoantibodies in Systemic Autoimmune Diseases: Insights From an <scp>FcγRIIIA</scp> ‐Reporter Assay

OBJECTIVE: Immune complexes (ICs), formed by autoantigen and autoantibody, play a pathogenic role in systemic autoimmune diseases through stimulation of Fcγ receptors (FcγR). However, studies investigating bioactivity of circulating ICs across various diseases remain limited. We aimed to quantify bioactivity of serum ICs using an FcγR-reporter cell assay and examine their association with disease activity. METHODS: We assessed the bioactivity of serum ICs using the FcγRIIIA-reporter assay. Serum samples were obtained from healthy controls (n = 56), infectious disease controls (n = 12), systemic lupus erythematosus (SLE) (n = 175), Sjögren disease (n = 71), mixed connective tissue disease (n = 22), idiopathic inflammatory myopathies (n = 73), systemic sclerosis (n = 107), and rheumatoid arthritis (n = 51). RESULTS: The bioactivity of ICs was significantly elevated across various systemic autoimmune diseases and associated with disease activity. In SLE, bioactivity of ICs was notably elevated compared with other diseases. The bioactivity in patients with SLE reflected disease activity with sensitivity of 81% and specificity of 69%. In patients with low anti-double-stranded DNA antibody levels, those with high IC bioactivity were at higher risk of clinical symptoms including nephritis, arthritis, and skin involvement, providing additive value in assessing SLE activity. Longitudinal analysis also showed that the FcγRIIIA-reporter assay more sensitively reflected flares than conventional serological markers, and those who achieved a low FcγRIIIA-reporter response within the initial 3 months tended to achieve remission at 24 months (90% vs 75%, P = 0.56). CONCLUSIONS: The FcγRIIIA-reporter assay enables precise quantification of pathogenic bioactivity of ICs in various systemic autoimmune diseases, providing complementary information to existing serological markers.