Autoreactive-prone CD21lo B cells increased in scleroderma patients with interstitial lung disease

Abstract

Abstract Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by fibrosis of the skin and vital organs. The pathogenesis of SSc is unknown, but detection of autoantibodies in >90% of SSc patients suggests that B lymphocytes play a role. Therefore, we explored B cell phenotypes in SSc patients using fluorescence cytometry and the multi-dimensional unsupervised analysis tool viSNE. We found that compared to healthy controls, SSc patients had significantly higher proportions of an autoreactive-prone B cell subset identified by low expression of CD21 (CD21lo). Previously, circulating CD21lo B cells were shown to express autoantibodies and were increased in other autoimmune diseases. When considering the clinical phenotypes of the SSc patients, we found that the frequency of CD21lo B cells was only increased in SSc patients with interstitial lung disease (ILD). ILD is a complication of SSc that is associated with increased morbidity and mortality. To our knowledge, this is the first time that a peripheral blood B cell subset has been identified in association with ILD in patients with a systemic autoimmune disease. We investigated the signaling properties of these anergic cells and found lower expression of Bruton’s tyrosine kinase (BTK) in CD21lo B cells compared to normal B cells. This was surprising, as BTK is thought to be overexpressed in autoimmunity, but may indicate that the anergic state is due in part to suppression of BTK-mediated signaling. Our data suggest that CD21lo B cells should be investigated for their role in SSc pathogenesis, and for their utility as a biomarker of ILD. In addition, these findings demonstrate a potential mechanism by which B cell depleting therapy may specifically benefit SSc patients with ILD.