Crescentic nephritis--is it in your genes?

Crescentic glomerulonephritis is frequently associated with a rapid clinical course and poor outcome, particularly if treatment is delayed. The severity of the renal injury and the suboptimal treatment modalities for this disease have provided considerable impetus to studies of the underlying immuno-pathogenic mechanisms. Well-documented variation in susceptibility to crescentic glomerulonephritis between inbred strains of rodents has strongly suggested the influence of genetic predisposing factors in animal models. In mice, susceptibility to crescentic disease in strains showing strong Th1 responses to nephritogenic antigens indicates that genetic factors may operate (in part) through regulation of adaptive T helper subset responses [1,2]. Recent elegant work by Professor Cook and others from Imperial College London has identified genetic factors controlling innate immune responses [3,4] and intrinsic renal cell biology [5] that contribute to the exquisite susceptibility of Wistar Kyoto (WKY) rats to development of crescentic glomerulonephritis. The work of Behmoaras et al. published recently in Nature Genetics [4] demonstrates that a polymorphism in the promoter region of Jund, the gene for the AP-1 transcription factor JunD, accounts for a significant component of the susceptibility of WKY rats to crescentic glomerulonephritis. It expands previous work by this group that identified seven genetic susceptibility loci (named Crgn1–7) and characterized one major locus (Crgn1) that augments macrophage activation via copy number polymorphisms of an Fcγ receptor gene-related sequence (Fcgr3-rs) [3]. They used an approach involving backcrossing of susceptible WKY rats with resistant Lewis rats and selective intercrossing of their F2 offspring (introgression) to evaluate quantitative trait loci (QTLs) for susceptibility to crescentic