IgA and FcαR are critical components of plasmacytoid DC response to autoantibody-containing immune complexes in SLE.

Abstract

Abstract Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease characterized by the presence of circulating autoreactive anti-nuclear antibodies (ANAs). ANAs form immune complexes (ICs) upon binding to nuclear antigens and these ANA-ICs promote a feedforward loop by enhancing immune responses in cells that recognize ANA-ICs via Fc receptors (FcRs). Plasmacytoid dendritic cells (pDCs) are FcR expressing cells that promote SLE pathology. ANA-ICs deliver nucleic acids to endosomal TLR7 and TLR9. These TLRs induce type I IFN secretion and immune activation upon nucleic acid recognition. Type I IFNs, including IFNα, and interferon stimulated genes are correlated with SLE disease activity. IgG isotype facilitated ANA-IC internalization via FcgRIIA has been the most studied antibody-mediated route for IFNα production in pDCs. The importance of IgA isotype ANAs remains under investigated despite these autoantibodies being present in half of SLE patients. We show here the novel result that human pDCs express the IgA-specific FcαR (CD89) by flow cytometry, that pDCs from SLE patients express increased FcαR compared to pDCs from healthy controls, and that increased pDC FcαR expression in SLE correlates with hallmark IFNα gene set. Additionally, we found that IgA autoantibodies were a critical component of pDC ANA-IC activation when these ANA-IC were generated with serum from IgA autoantibody positive SLE donors complexed with smRNP nuclear antigen. Therefore, our study shows that IgA-containing immune complexes and FαRI are important contributors to pDC type I IFN production in SLE. Supported by LRA Lupus Mechanisms and Targets Award (JAH), R21AI154841 (JAH), and ITHS TL1 training grant (HRW).