Systemic lupus erythematosus (SLE) is a severe and rare (less than 1 in 2000) autoimmune disease characterized by the presence of antibodies to nuclear self-antigens and a marked degree of clinical, and likely causal, heterogeneity. Current treatments rely on non-specific immunosuppression with serious side effects, making the discovery of targeted therapeutics an urgent priority. Familial aggregation and higher concordance rates between monozygotic twins (20–40%) relative to dizygotic twins and other full siblings (2–5%) suggest a major genetic component to the pathogenesis of SLE. SLE is generally considered as a multifactorial disease, and genome wide association studies (GWAS) have identified more than 30 convincing disease-associated loci. Although these GWAS have greatly added to our understanding of lupus pathogenesis, the identified genetic variants have so far proven to be of limited clinical utility, because almost all have odds ratios of less than 1.5. Familial forms of lupus also occur, and can be syndromic e.g. due to complement deficiencies leading to lupus in association with a predisposition to infections, and ACP5 mutations causing SLE and a skeletal dysplasia. Additionally, non-syndromic forms of the disease are increasingly being recognized e.g. most recently due to mutations in DNase1L3 and PRKCD. As one approach to improving our understanding of why some people develop lupus, we are interested in the identification of new genes in families with highly penetrant forms of SLE. Here, we propose a network of four translational research laboratories able to proceed from the identification of genes in SLE families by high-throughput sequencing (whole-exome sequencing), through to the interrogation of the affected biological pathways - using functional and in-depth phenotypic analyses in patients and family members, combined with functional genomics in mice. Our previous identification of mutations in ACP5, PRKCD and IFIH1 to cause Mendelian forms of lupus demonstrate that such an approach is feasible, and we have now obtained further encouraging preliminary results with the description of three candidate genes, whose function seems highly relevant to tolerance and autoimmunity. The definition of highly penetrant forms of SLE not only provides clues to disease causation in specific cases, it can also help to define general molecular concepts of immune tolerance/dysfunction in humans. Therefore, we can expect that a better understanding of the pathogenesis of SLE will eventually lead to improved treatments for this devastating disorder (‘translational medicine’). And if lupus is not a single disease entity, then different treatment regimens might be appropriate in different patients (‘personalized medicine’). By harnessing the very latest technologies, in particular - exome sequencing and large scale transcriptomics, with detailed immuno-phenotyping and state-of-the-art mouse modelling, our strategy is to identify new biological pathways implicated in SLE, going from gene identification to dissection of gene function both in the human and murine context. We firmly believe that this approach will lead to a step change in our understanding of autoimmunity. Our network comprises partners with expertise in immuno-rheumatology, immuno-genetics and autoimmunity from 3 different universities and 4 highly ranked research laboratories, so that we are confident of achieving our stated aims.