Acquired immunologic genetic variation in lupus pathogenesis and heterogeneity

LRA’s Lupus Innovation Award will help Dr. Satpathy study the immune cells of people with lupus using two novel technologies that the team recently developed to find somatic mutations. Somatic mutations are changes in our genetic makeup that accumulate throughout a person’s life. Recent studies suggest that somatic mutations in immune cells may contribute to the development of lupus and how the disease affects each person differently (heterogeneity). However, these mutations have not been well understood because they are challenging to detect with current technology.

Using clinical samples from lupus patients and healthy individuals, Dr. Satpathy and team will look at somatic mutations in six different types of immune cells. They will focus particularly on how somatic mutations in the key type of immune cells – T cells – regulate lupus development.

What this study means for people with lupus

This pioneering study provides new technology to improve analysis of immune cells and how they regulate lupus development. Better understanding of how mutations in our genetic make-up affect the immune system will give researchers valuable information to improve lupus diagnosis and treatment.

Immune cells continually acquire ‘somatic’ mutations, which are technically challenging to detect and remain to be characterized in lupus and other autoimmune diseases. Together with recent studies linking autoimmune phenotypes in blood disorders and cancer to somatic variation, we recently identified numerous lupus-associated, lineage-restricted mutations in immune cells. Accordingly, our long-term goal is to determine how somatic variation modulates the immune system in health and autoimmune disease. The objective of the proposed research is to use novel single-molecule and single-cell genomic technologies we have developed to systematically analyze somatic mutations in immune cells. We hypothesize that somatic variation in immune cells contributes to the pathogenesis and clinical heterogeneity of lupus. We will use human clinical samples from lupus and unaffected control subjects to test this hypothesis in two parallel aims. In Aim 1, we will survey the dynamics of somatic variation in sorted lymphoid and myeloid cell populations during lupus flares and quiescent disease using bulk short-read and single-molecule sequencing. This includes generating lineage-resolved catalogues of protein-coding variation integrated with germline polymorphism, inferred pathogenicity, and clonal dynamics. In Aim 2, we will use single-cell whole genome and transcriptome sequencing to simultaneously detect mutations and gene expression in pathologic T cell subsets in lupus. This includes analyses of lineage and occurrence patterns of somatic mutations to estimate their timing of origin and associated endogenous and exogenous mutational processes. This study will pioneer a suite of genomic technologies for somatic variant discovery to implicate somatic mutations in lupus pathogenesis and heterogeneity, generate first-in-class catalogues of human immunogenetic mosaicism, and yield new insights into the molecular mechanisms of gene-environment interactions and clinical heterogeneity in autoimmunity. These outcomes promise to establish acquired genetic variation as a molecular basis for defining lupus heterogeneity and enabling patient stratification, thereby empowering precision rheumatology.