Tuesday, April 29, 2025
4/29/2025
Plasmacytoid dendritic cells and IgA autoantibodies in SLE - PROJECT SUMMARY Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women and is more prevalent among non-white individuals, including those of Black, Hispanic and Asian ancestries. Disease in SLE can target a variety of organs, including the skin, joints, kidneys, lung, brain, and cardiovascular system, which can make diagnosis difficult. SLE is characterized by the breakdown of tolerance to nuclear antigens; thus individuals with SLE have circulating anti-nuclear antibodies (ANAs) that recognize complex antigens such as nucleic acids, and DNA-associated or RNA-associated proteins, including histones or ribonucleoprotein (RNP) subunits. These ANAs form nucleic acid-containing immune complexes (ICs) that are recognized by and trigger inflammatory responses from Fc receptor (FcR)-expressing immune cells. In this way, ANA-ICs facilitate nucleic acid internalization and delivery to endosomes where the RNA and DNA sensing Toll-like receptors (TLR) 7 and 9 reside, thereby allowing aberrant responses to autologous nucleic acids in SLE. Plasmacytoid DCs (pDCs) abundantly express TLR7 and TLR9, and thus are key mediators of responses to nucleic acid-containing ICs by producing large quantities of type I IFNs, crucial cytokines in SLE. While most studies have focused on how IgG isotype ANAs contribute to SLE pathogenesis, we have discovered a critical role for IgA isotype autoantibodies in pDC responses to nucleic acid-containing ICs in SLE. We found that most individuals with SLE have a broad array of IgA autoantibodies to antigens to which they also have IgG. We showed that pDCs express the IgA- binding FcαRI in addition to the IgG-binding FcγRIIa. Using an innovative in vitro system employing serum from individuals with SLE to generate ICs with potent pDC stimulatory function, we found a novel and critical function for IgA1 antibodies in pDC type I IFN production in response to RNA-containing RNPs. FcαR and FcγRIIa acted synergistically to induce type I IFN production by facilitating internalization of ICs, and pDCs from individuals with SLE had higher IC internalization and FcαRI expression than those from HCs. Thus, we have uncovered an important role of IgA1 and FcαR in pDC responses in SLE that we will further study here. The premise of this proposal is that IgA anti-nuclear autoantibodies are important contributors to SLE pathogenesis through enhancement of pDC type I IFN production in response to nucleic acid-containing ICs. Here we will use primary human samples from individuals with SLE along with novel research tools we have developed to 1) determine the mechanisms underlying the potent synergy between IgA1 and IgG in Sm/RNP ICs, and 2) determine how IgA autoantibodies to nucleic acid-associated antigens relate to SLE. Together these studies will lead to a better mechanistic understanding of how IgA and IgA-producing B cells contribute to type I IFN production in SLE.
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