Genetically Determined Severity of Anti-Myeloperoxidase Glomerulonephritis (1)
Necrotizing crescentic glomerulonephritis (NCGN) is induced in mice by injecting anti-MPO IgG, and is mediated by neutrophils, enhanced by neutrophil priming, modulated by Fc gamma receptor engagement, and requires alternative complement pathway activation.
129S6/ SvEv (129S6) mice had 47 to 90% (mean 63.7%) compared to 4 to 23% in B6 (mean 9.5%). NOD, AJ, and DBA2 mice were resistant to NCGN induction.
Rag2/ B6 mice transplanted with 129S6 BM developed 79% crescents (69% to 85%), which is similar to Rag2/ 129S6 mice. Rag2/129S6 mice that received BM from B6 mice had 17% crescents (9% to 22%) similar to Rag2/ B6.
Anti-MPO IgG caused more activation of neutrophils from 129S6 compared to neutrophils from B6 or 129S1 mice, which correlated with NCGN severity in these strains, and demonstrated that genetic differences influence neutrophil activation by anti-MPO.
The most relevant model to ours is induced in Wistar Kyoto (WKY) rats by immunization with human MPO, which results in anti-MPO antibodies that cross-react with rat MPO and cause NCGN. Unlike WKY rats, Lewis, Wistar Furth, and Brown Norway rats immunized with human MPO do not develop NCGN, even though they develop comparable levels of anti-MPO to WKY rats.