Bingfei Yu, PhD
University of Southern California
with Elizabeth Volkmann, MD, MS
University of California, Los Angeles
Project Overview
Systemic sclerosis (SSc) is a chronic autoimmune disorder with complex pathogenesis. Key features are fibrosis, vascular damage, and dysregulation of immune responses, including B cell tolerance breach reflected by autoantibody production. Like many other autoimmune diseases, SSc patients are predominantly female. Intriguingly, CD11c+ atypical B cells, a hallmark of B cell tolerance breach in autoimmune diseases, exhibit a strong female bias. Despite their abnormal expansion in SSc patients, the differentiation pathway, pathogenic mechanism, and female bias of CD11c+ atypical B cells remain poorly understood in SSc.
Dr. Yu’s long-term goal is to elucidate the mechanisms underlying the female bias in escaping peripheral B cell tolerance and its implications for SSc. The objective of this grant is to investigate the female bias in CD11c+ atypical B cells and explore their phenotypic and functional diversity in SSc patients. The preliminary data indicated a crucial role of a female-specific long non-coding RNA XIST in regulating the female-bias of CD11c+ atypical B cells.
Dr. Yu discovered that XIST is essential to prevent the escape of X-inactivation of immune genes, particularly TLR7, whose gene dosage could lead to the accumulation of CD11c+ atypical B cell. By developing an XIST escape score to infer XIST dysregulation across diverse disease state using published single-cell RNA-seq data, Dr. Yu identified XIST dysregulation in CD11c+ atypical B cells among patients with female-biased autoimmunity.
Given recent studies showing the accumulation of CD11c+ atypical B cells in SSc patients, Dr. Yu proposes that XIST dysregulation may facilitate the formation of these cells, thus accelerating the breach of B cell tolerance in SSc.
