Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from .

BACKGROUND

Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with 3 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.

METHODS

To investigate whether microbes might activate autoreactive T and B lymphocytes 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.

RESULTS

On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human 3. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from 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 3. B7 induced T cell activation from human 3-immunized rats. T cell responses to B7 were detected in rats immunized by lysate proteins or recombinant proteins. We confirmed B7's pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in 3-immunized mice.

CONCLUSIONS

Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from 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.