CD11b agonists offer a novel approach for treating lupus nephritis

Abstract

Lupus nephritis (LN) develops in more than a third of all systemic lupus erythematosus (SLE) patients and is the strongest predictor of morbidity and mortality. Increased circulating levels of type I interferon (IFN I) and anti-double stranded DNA (anti-dsDNA) and anti-RNA binding protein (anti-RNP) antibodies lead to increased glomerular injury via leukocyte activation and glomerular infiltration. Uncontrolled Toll-like receptor (TLR) signaling in leukocytes results in increased production of IFN I and anti-dsDNA antibodies. ITGAM gene codes for integrin CD11b, the α-chain of integrin heterodimer CD11b/CD18, that is highly expressed in leukocytes and modulates TLR-dependent pro-inflammatory signaling. Three nonsynonymous SNPs in the ITGAM gene strongly correlate with increased risk for SLE and LN and with IFN I levels. Here we review the literature on the role of CD11b on leukocytes in LN. We also incorporate conclusions from several recent studies that show that these ITGAM SNPs result in a CD11b protein that is less able to suppress TLR-dependent pro-inflammatory pathways in leukocytes, that activation of CD11b via novel small molecule agonists suppresses TLR-dependent pathways, including reductions in circulating levels of IFN I and anti-dsDNA antibodies, and that CD11b activation reduces LN in model systems. Recent data strongly suggest that integrin CD11b is an exciting new therapeutic target in SLE and LN and that allosteric activation of CD11b is a novel therapeutic paradigm for effectively treating such autoimmune diseases.