Elucidating genetic pathways in SLE and stratifying patients via whole genome sequencing

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Twin studies indicate a strong genetic contribution to lupus, yet often the pathogenic variant remains unknown. Using next generation sequencing technologies (WES/WGS) it is now possible to identify rare/novel gene variants that cause disease. We previously used WES to identify a genetic variant in TREX1 as a cause of cerebral SLE; providing proof of principle that rare genetic variants do contribute to complex autoimmunity. It also revealed the patient to be a prime candidate for tailored therapies targeting type-I interferons. Using our validated bioinformatics pipeline and methodology, we have now identified two other cohorts of patients with genetic variants that impair thymic tolerance and toll-like receptor (TLR) 2 signaling, respectively. Biochemical assays on patient PBMCs or overexpression in cell lines confirmed the variants impair protein function. Furthermore, flow cytometry identified endophenotypes in the patients' PBMCs that may explain disease pathogenesis. These endophenotypes and the mechanisms by which they drive SLE pathogenesis are being evaluated in mice with CRIPSR/Cas9- engineered patient-specific alleles. Our data suggests the first cohort have defects in thymic epithelial cells and developing thymocytes that combine to affect central tolerance, characterized by impaired regulatory T cells. In contrast, in the second cohort, we identified a pathway that primarily affects myeloid cells and neutrophils to cause SLE through production of type-I interferon. Thus by understanding the precise genetic mechanisms that contribute to SLE pathogenesis, our data is able to stratify patients and through a personalized approach, identify tailored therapeutic options.