Distinct T cell chromatin landscapes in scleroderma subtypes

Abstract

Systemic sclerosis (SSc; scleroderma) is a poorly understood autoimmune rheumatic disease that primarily affects women. The clinical hallmark is hardening of the skin, but internal organ dysfunction is the leading cause of death. Diagnosis and treatment are complicated by heterogeneity within the disease including variable lethality, fibrosis severity, serum autoantibody production, and internal organ involvement. Important gaps remain in our knowledge of the exact molecular and cellular pathways underlying distinct SSc subtypes. Herein, we identify genome-wide chromatin accessibility profiles of peripheral CD4+ T cells to distinguish and better understand the observed heterogeneity in SSc patients. We identify a link between serum anticentromere autoantibody (ACA) subtype and elevated levels of T helper 2 (Th2) cells and increased chromatin access at gene loci encoding fibrosis-driving Th2 cytokines IL4, IL13, and IL4 receptor. Biological sex followed by autoantibody subtype are the predominant variables associated with differences in CD4+ T cell epigenomic profiles, while mycophenolate mofetil treatment appeared to have no effect. These results suggest new mechanistic basis and therapeutic strategies to address SSc, especially the ACA+ subtype that is associated with pulmonary arterial hypertension.

Xist ribonucleoproteins promote female sex-biased autoimmunity

“…Our discovery of seropositivity towards multiple XIST-associating proteins in autoimmune patients introduces a novel antigen set with great clinical potential for enhancing diagnostics and disease monitoring, as autoantigens are often detected prior to or early in disease onset 61,62 . In addition to serving as effective biomarkers for disease, studies in SSc have also demonstrated the effectiveness of autoantigen analysis in patient stratification and identifying pathogenic pathways 63,64 .…”