Kallikreins: unravelling the genetics of autoimmune glomerulonephritis.

Human disease gene discovery has entered a new era where genome-wide associations (GWA), and high throughput sequencing technologies are providing a first survey of the complex genetic architecture of common diseases. Immune-mediated glomerulonephritis, a shared pathological feature of systemic lupus erythematosus (SLE), systemic vasculitis and Goodpasture syndrome, displays a strong genetic component and, unlike other autoimmune diseases, GWA studies describing genetic variation associated with immune-mediated glomerulonephritis have not been yet reported. Gene identification for autoimmune glomerulonephritis has benefited, on the other hand, from the successful use of experimental rodent models as they provide an unparalleled resource for the genetic investigation of autoimmunity characterized by end-organ kidney damage. The recent study published in Journal of Clinical Investigation by Liu et al. is an excellent example of the use of rodent models for positional cloning followed by association studies in human lupus nephritis [1]. Transcriptome analysis of the renal cortex of anti-GBM antibody-induced glomerulonephritis (nephrotoxic nephritis—NTN) in NTN-resistant and NTN-susceptible strains allowed the identification of a largely down-regulated gene family, the kallikreins (Klk) mapping to chromosome 7. Klk gene expression, protein amount and enzyme activity were markedly reduced following NTN induction in susceptible strains of mice such as DBA/1, 129/SvJ and NZW, and the pharmacological inhibition of bradykinin receptor B2, the biological target of Klk (and bradykinins), exacerbated glomerulonephritis in NTN-resistant BALB/c mice, suggesting a protective role for the activity of these serine esterases in murine nephritis. Genetic investigation of complex traits in rodent models aims to establish linkage of a given trait to a discrete chromosomal location in order to identify quantitative trait loci (QTL) in a segregating population. A QTL is a discrete chromosomal region controlling a quantitative trait such as clinical measurements (e.g. proteinuria, blood urea nitrogen) or a cell phenotype (e.g. T-cell activation). In general, QTLs correspond to relatively large chromosomal segments that may contain hundreds of genes. Finding the causative variant often requires specific genetic tools such as congenic strains. By repeatedly backcrossing one strain onto another, it is possible to produce mice that have a particular genomic region from one strain and the remainder of their genome from the other. The effect of the introgressed genetic region derived from one strain (generally corresponding to a QTL) can then be specifically tested on the genetic background of the other strain. Liu et al. strengthened their results by generating congenic strains where the introgression of Klk loci on chromosome 7 from NZW strain onto the genetic background of B6 led to severe nephritis. Importantly, in a separate study by the same group, a gene transfer approach by systemic adenoviral delivery in congenic mice demonstrated the protective role of this gene in experimentally induced autoimmune glomerulonephritis [2]. Sequencing analysis of the five most differentially expressed Klk genes in mice identified polymorphisms in the promoter regions, and reporter assays on the Klk1b3 promoter showed that genetic variants in this promoter affect gene expression. To translate their findings to humans, the authors performed three independent association studies and showed a genetic association of SNPs located within human Klk1 gene and the Klk3 promoter region with lupus and lupus nephritis. The recent advances in genomic technologies allowing testing of elevated numbers of genetic variations, such as single nucleotide polymorphisms (SNPs), in cases and controls have revolutionized common disease genetics [3]. The genetic dissection of SLE has resulted in the identification of >20 genetic loci associated with host immune responses [4]. Lupus nephritis and anti-GBM disease share a common pathophysiology where intrinsic or planted kidney antigens are the driving force of mechanisms involving an interaction between primary immune responses and intrinsic kidney factors [5]. In addition to this complex genetic architecture, modest sample sizes obtained from both autoimmune disorders have been a major obstacle