The Contribution of Pathogenic Genetic Variants to the Development of Autoimmunity and Kidney Disease

Abstract

Irreversible damage or reduction in kidney function is termed chronic kidney disease (CKD). CKD is highly prevalent and is increasing in incidence, with projections for this to become one of the top five leading causes of death worldwide. This is particularly true for Indigenous Australians who experience a disproportionate burden of kidney disease with onset 30 years younger than other Australians.

An important cause of CKD is autoimmune glomerulonephritis (GN) which is the second most common cause of end-stage kidney disease (ESKD) worldwide. Despite this, the development of new therapeutic treatment strategies has been limited, and current therapy relies on aggressive, broad-spectrum immunosuppression. In contrast, personalised medicine approaches target therapy to the specific dysregulated immune pathway in individual patients and promises improved efficacy with reduced risk of excessive immunosuppression. We use an established pipeline that incorporates analysis of genetic variants, immunophenotyping, and transcriptomics to identify therapeutic targets in autoimmunity.

Single nucleotide variants (SNV) in humans are associated with the development of autoimmunity, GN, and CKD. The genetic risk in these disorders generally does not obey Mendelian inheritance patterns but rather more complex patterns of genetic inheritance. To investigate the role of rare SNVs in human autoimmune disease, we compared the burden of rare SNVs in the endosomal Toll-like receptor (eTLR) pathway. The eTLR pathway is important for identification of RNA and DNA viruses and is implicated in the development of systemic lupus erythematosus (SLE). We find that rare SNVs in the eTLR pathway are enriched among individuals with SLE, an autoimmune disease that causes GN in half of affected individuals. These results support a role for rare single nucleotide polymorphisms in complex diseases.

We found 5 rare missense SNVs in the TNFAIP3 gene among the Indigenous Australian inhabitants of the Tiwi Islands. TNFAIP3 is an important negative regulator of inflammation including that arising from the eTLR pathway and has been associated with the development of autoimmunity and kidney disease. The Indigenous Australian inhabitants of the Tiwi Islands are a genetically distinct Indigenous Australian group and experience the highest rate of CKD in the world. We find that several of these TNFAIP3 variants fail to suppress inflammatory NFKB signalling. A mouse model of the most damaging of these SNVs worsens GN when crossed to an important mouse model of autoimmunity. This suggests that this TNFAIP3/Tnfaip3 variant is less able to regulate kidney inflammation following an inciting immune response. The dysregulation of inflammatory signalling arising from this variant is therefore a putative molecular target for novel therapy development.

Previously this group has identified several rare SNVs in the Src-B family kinase gene BLK that were enriched among individuals with SLE. BLK was previously thought to be a redundant gene, yet SNVs in BLK are associated with the development of many autoimmune diseases; suggesting that it has important unrecognised roles in the immune system. Using a mouse model carrying a Blk SNV orthologous to that from a patient with SLE, we identify an unexpected role for Blk in licensing the development of GN in several mouse models. This is the target on ongoing drug development efforts aiming to reproduce the impact on protein function seen with this SNV.

In summary, we identify two novel molecular targets in kidney disease through the analysis of rare genetic variants. By targeting inflammatory TLR signalling pathways mediated by TNFAIP3, we have identified the first potential novel therapeutic strategy targeting kidney disease in Indigenous Australians. Furthermore, the development of a specific inhibitor of BLK has the potential to improve treatment options for a range of autoimmune kidney diseases. Show more