Abstract
OBJECTIVES: The role of autoantibody-producing B cells in connective tissue diseases (CTD) has recently been highlighted by the successful treatment with CD19-targeting CAR T cells. Detrimental effects of autoantibodies are linked to the formation of deposited IgG complexes and the activation of immune cells via Fcγ receptors (FcγRs). The role of circulating immune complexes (cICs) as a link between adaptive and innate immunity has remained understudied. Clinical testing of cICs has been hindered by the lack of reliable detection methods. The aim of this study was to determine the potential of IgG-containing cICs to activate FcγRs (their bioactivity) using a new detection method. METHODS: A reporter cell platform was used to assess the presence and bioactivity of cICs in IgG-autoantibody-positive CTD patients (cross-section analysis) and in patients treated with CD19-CAR T cells (longitudinal analysis). RESULTS: The bioactivity of cICs in the cohort of patients with CTDs was significantly higher compared with healthy controls and patients with IgG-autoantibody-negative systemic inflammatory disease (psoriatic arthritis). Analyses of individual diseases revealed the presence of cICs in the sera of all CTDs, including systemic sclerosis (SSc) and primary Sjögren's syndrome, although there was significant heterogeneity among individuals. Within SSc, patients positive for anti-topoisomerase-I (Scl70) autoantibodies, diffuse cutaneous and lung involvement had significantly enhanced cIC bioactivity. Finally, the bioactivity of cICs was significantly reduced in CTD patients after CD19-CAR T cell therapy. CONCLUSIONS: Our study reveals the presence of FcγR-engaging cICs in CTDs and demonstrates that the bioactivity of cICs is correlated with clinical phenotypes and treatment outcomes.