Pathogenic autoantibodies to IFN-gamma act through the impedance of receptor assembly and Fc-mediated response

Abstract

Anti-interferon (IFN)-y autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-y function, but their effects on IFN-y signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-gamma-reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (K-D < 10(-9) M) binding to IFN-y, but only eight neutralized IFN-gamma-STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I-III) for AIGAs on IFN-gamma. We found that site I mAb neutralized IFN-gamma by blocking its binding to IFN-gamma R1. Site II and III mAbs bound the receptor-bound IFN-gamma on the cell surface, abolishing IFN-gamma R1-1FN-gamma R2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody-IFN-gamma complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-gamma signaling and by eliminating IFN-gamma-responsive cells.