Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease and presents a major clinical unmet need. It is characterised by significant clinical and transcriptomic heterogeneity. Lupus begins in early adulthood with 90% of affected individuals being women; it is chronic and incurable. It has been postulated that what we call SLE may in fact consist of several diseases each brought about by a different pathogenic pathway. Current approaches to treatment including the use of “precision therapies” are not administered in a personalised manner, because we do not fully understand the underlying pathogenic mechanism. In the last two decades, important lessons have been learnt from inborn errors of immunity caused by damaging germline variants in single genes that present clinically as increased susceptibility to infections. We have applied a similar approach to systemic autoimmunity and searched for novel – including de novo – and ultrarare coding variants in individuals suffering from severe SLE. This has led to the discovery of multiple disease-causing gene variants in genes not previously known to cause human lupus, that have been validated through their introduction in mice. The novel bespoke mouse models are revealing novel insights into pathogenic pathways and illuminating targeted therapies. Intriguingly, most pathways appear to converge in a central one that requires TLR7-MyD88 signaling, which suggests that lupus may in fact be one disease driven by increased nucleic acid signaling, with protean clinical manifestations.