Novel cause of monogenic lupus illuminates disease pathogenesis

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease of uncertain aetiology and awell-established genetic basis. Females are nine times more likely to be affected than males. SLE isthought to be polygenic, although an increasing number of monogenic causes are being described. Todate, there is no cure for this disease and current treatments often fail to treat the most seriousmanifestations. Better understanding of disease pathogenesis is critical for identification of moreeffective therapies. We have performed whole genome sequencing of probands with severechildhood-onset disease and have identified a novel cause of monogenic SLE. After identifying a denovo mutation in a proband, we subsequently identified additional SLE patients with damagingvariants in the same gene.
Using CRISPR/cas9 we have generated a mouse model carrying the orthologous de novo variant.These mice develop lupus-like disease with an increased female to male bias. Disease and cellularmanifestations include ANAs, thrombocytopenia, splenomegaly, increased Tfh cells, spontaneousgerminal centres, activated CD4 and CD8 T cells, reduced marginal zone B cells and B1a cells, andaccumulation of plasmablasts.
We have also identified an epistatic interaction between the de novo variant and a second rare variantpresent in the proband and validated this in mice: Mice carrying both human variants develop a moresevere phenotype. Insights into the mechanism underpinning lupus development will be presented.These discoveries and bespoke mouse models of human lupus provide an opportunity to trial targetedtherapies that may be effective in the patients