Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies 2933

Abstract Description Misfolded proteins, complexed with HLA-II at low levels of invariant chain, are transported to the cell surface without peptide processing. These misfolded protein-HLA-II complexes, termed neo-self antigens, differ antigenically from normal proteins and are often targets of autoantibodies in autoimmune diseases. Ro52, an intracellular Fc receptor, is a target antigen for autoimmune diseases like dermatomyositis and Sjogren’s’ syndrome. We investigated the role of HLA-II in Ro52 presentation and found that Ro52 forms a unique complex with IgG and HLA-DR on the cell surface, which becomes an autoantibody target. Analyzing sera from 120 patients with inflammatory myopathies using flow cytometry, we found anti-Ro52/IgG/HLA-DR autoantibodies prevalent in anti-MDA5 antibody-positive dermatomyositis and anti-synthetase syndrome. Absorption with recombinant Ro52 did not eliminate antibody recognition of the Ro52/IgG/HLA-DR complex in sera from patients with dermatomyositis, suggesting anti-neo-self antibody specificity. Furthermore, changes in anti-Ro52/IgG/HLA-DR antibody titers over time correlated with disease status in patients with these two inflammatory myopathies.These findings suggest that anti-Ro52/IgG/HLA-DR complex autoantibodies may contribute to the pathogenesis of specific inflammatory myopathy subtypes, potentially informing novel diagnostic and therapeutic approaches. Funding Sources Japan Society for the Promotion of Science (JSPS) KAKENHI [grant number JP15K15419, JP18K08296, JP18H02829, JP21K08344, JP24K11492] and the Japan Agency for Medical Research and Development (AMED) [grant number J20ek0410053h0003, JP23ek0410088, JP24gm1810006, JP223fa627002]. Topic Categories Basic Autoimmunity (BA)