Lupus IgA1 autoantibodies synergize with IgG to enhance pDC responses to RNA-containing immune complexes

Autoantibodies to nuclear antigens are hallmarks for diagnosis of the autoimmune disease systemic lupus erythematosus (SLE) and they contribute to SLE pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to key disease processes, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). Here, we show that individuals with SLE have IgA autoantibodies against most nuclear antigens assessed, largely correlating with the amounts of IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoproteins (Sm/RNPs), play a role in IC activation of pDCs. We found that pDCs express the IgA-specific Fc receptor, FcRI, and there was a striking ability of IgA1 isotype autoantibodies to synergize with IgG in RNA-containing ICs to generate robust pDC IFN responses. pDC responses to these ICs required both FcRI and FcRIIa, suggesting the most potent ICs for pDCs contained autoantibodies of both isotypes. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. In addition, binding of Sm/RNP ICs generated with IgA1-sufficient serum correlated to pDC FcRI expression, but not FcRIIa expression. pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcRI than pDCs from healthy control individuals, correlating with expression of IFN response genes. Taken together, our data indicate that IgA1 ANAs contribute to SLE pathology and warrant further investigation. Cross-sectional investigation of systematic lupus erythematosus subjects in relation to disease severity and levels of Fc receptors on pDCs and monocytes. One sample per subject, RNAseq from whole peripheral blood.