We describe a new mechanism responsible for Systemic Lupus Erythematosus (SLE). In humans with SLE and in two SLE murine models, there is marked enrichment of isolevuglandin (isoLG)-adducted proteins in monocytes and dendritic cells (DCs). We found that antibodies form against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduces transcription of all C1q subunits. Treatment of SLE prone mice with the specific isoLG scavenger 2-hydroxybenzlyamine (2HOBA) ameliorates parameters of autoimmunity including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowers blood pressure, attenuates renal injury, and reduces inflammatory gene expression uniquely in C1q expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE.
David M. Patrick, Néstor de la Visitación, Jaya Krishnan, Wei Chen, Michelle J. Ormseth, C. Michael Stein, Sean S. Davies, Venkataraman Amarnath, Leslie J. Crofford, Jonathan M. Williams, Shilin Zhao, Charles D. Smart, Sergey Dikalov, Anna Dikalova, Liang Xiao, Justin P. Van Beusecum, Mingfang Ao, Agnes B. Fogo, Annet Kirabo, David G. Harrison