Anti-glomerular basement membrane (GBM) disease is associated with HLADRB1*1501 and characterized by circulating autoantibodies against the GBM. A recent study by Zhao Cui and colleagues reports that a microbial peptide can activate autoreactive T and B cells and contribute to the pathogenesis of this disease.
“Infections can initiate most forms of glomerulonephritis but the specific pathogens and pathways that lead to autoimmunity and inflammatory activation are unclear,” says Cui. “Anti-GBM disease is the classical model of autoimmune glomerulonephritis, and the autoantigen and critical amino acids have been identified. We used bioinformatics tools to search for pathogen peptides that may mimic the critical amino acids of the autoantigen and activate autoreactive lymphocytes. This method helped us to narrow down the candidate microbial peptides from thousands to 36, which made the subsequent laboratory experiments feasible.”
The researchers identified antibodies against nine of the candidate microbial peptides in serum samples from patients with anti-GBM disease. Immunization with one of these nine peptides, B7 derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM and crescent formation in Wistar Kyoto rats and in humanized HLADR15 transgenic mice via cross-reactivity of lymphocytes.
“Our findings implicate a role for infection and molecular mimicry in the pathogenesis of anti-GBM disease,” concludes Cui. “Similar mechanisms might also be found in other autoimmune forms of glomerulonephritis. However, molecular mimicry is just one of many pathways between infections and glomerulonephritis and further investigations are needed to define these pathways and develop preventive approaches.”
Gu, Q. et al. Experimental antiglomerular basement membrane GN induced by a peptide from Actinomyces. J. Am. Soc. Nephrol. 31, 1282–1295 (2020)
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Carney, E.F. Role of infection and molecular mimicry in the pathogenesis of anti-GBM disease.
Nat Rev Nephrol (2020). https://doi.org/10.1038/s41581-020-0311-8