Generation of a novel CD30+ B cell subset producing GM-CSF and its possible link to the pathogenesis of systemic sclerosis

Abstract

Summary Systemic sclerosis (SSc) is a T helper type 2 (Th2)-associated autoimmune disease characterized by vasculopathy and fibrosis. Efficacy of B cell depletion therapy underscores antibody-independent functions of B cells in SSc. A recent study showed that the Th2 cytokine interleukin (IL)-4 induces granulocyte–macrophage colony-stimulating factor (GM-CSF)-producing effector B cells (GM-Beffs) in humans. In this study, we sought to elucidate the generation mechanism of GM-Beffs and also determine a role of this subset in SSc. Among Th-associated cytokines, IL-4 most significantly facilitated the generation of GM-Beffs within memory B cells in healthy controls (HCs). In addition, the profibrotic cytokine transforming growth factor (TGF)-β further potentiated IL-4- and IL-13-induced GM-Beffs. Of note, tofacitinib, a Janus kinase (JAK) inhibitor, inhibited the expression of GM-CSF mRNA and protein in memory B cells induced by IL-4, but not by TGF-β. GM-Beffs were enriched within CD20+CD30+CD38−/low cells, a distinct population from plasmablasts, suggesting that GM-Beffs exert antibody-independent functions. GM-Beffs were also enriched in a CD30+ fraction of freshly isolated B cells. GM-Beffs generated under Th2 conditions facilitated the differentiation from CD14+ monocytes to DC-SIGN+CD1a+CD14−CD86+ cells, which significantly promoted the proliferation of naive T cells. CD30+ GM-Beffs were more pronounced in patients with SSc than in HCs. A subpopulation of SSc patients with the diffuse type and concomitant interstitial lung disease exhibited high numbers of GM-Beffs. Together, these findings suggest that human GM-Beffs are enriched in a CD30+ B cell subset and play a role in the pathogenesis of SSc.

In‐depth peripheral CD4+ T profile correlates with myasthenic crisis

“…These include induction of anti‐inflammatory cytokine production, activation of apoptosis, and interference with the signal transduction machinery by induction of suppressors of cytokine signaling. To be noticed, Th2‐related cytokines, IL‐4 and IL‐13, were significantly decreased in 6 months off‐ventilation, which were previously characterized as the inducers in pathogenic antibody production 39,40 …”

“…To be noticed, Th2-related cytokines, IL-4 and IL-13, were significantly decreased in 6 months off-ventilation, which were previously characterized as the inducers in pathogenic antibody production. 39,40 There are some limitations in our study. First, this study is mainly correlative.…”

Defective Early B Cell Tolerance Checkpoints in Patients With Systemic Sclerosis Allow the Production of Self Antigen–Specific Clones

“…We cannot rule out the possibility that autoantibodies may also emerge from the activation of mature naive B cells, which also contained antinuclear-reactive clones in patients with SSc or other autoimmune diseases. Impaired early B cell tolerance checkpoints and the production of autoreactive B cells may also favor autoimmunity via the secretion of proinflammatory cytokines such as granulocyte-macrophage colony-stimulating factor in SSc and MS (33,34) or IL-6 in SSc and RA (21,35). B cell production of lymphotoxin β may also favor tertiary lymphoid organ formation (36).…”

Role of B-Cell in the Pathogenesis of Systemic Sclerosis

“…These cells belong to the memory B-cell subset and strongly produce IL-6 and TNF-α. These cells have been reported to be increased in SSc patients, especially in dcSSc and associated with ILD, suggesting their role in the pathogenesis of SSc ( 102 ).…”