Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from <i>Actinomyces</i>.

Abstract

Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with <i>α</i>3_127-148 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected. To investigate whether microbes might activate autoreactive T and B lymphocytes <i>via</i> molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity. On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human <i>α</i>3_127-148. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from <i>Actinomyces</i> species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat <i>α</i>3_127-148. B7 induced T cell activation from human <i>α</i>3_127-148-immunized rats. T cell responses to B7 were detected in rats immunized by <i>Actinomyces</i> lysate proteins or recombinant proteins. We confirmed B7's pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in <i>α</i>3_135-145-immunized mice. Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from <i>Actinomyces</i> induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.