Association of Defective Regulation of Autoreactive Interleukin‐6–Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis

Objective Systemic sclerosis ( SS c) has the highest case‐specific mortality of any rheumatic disease, and no effective therapy is available. A clear manifestation of SS c is the presence of autoantibodies. However, the origin of autoantibody‐producing B lymphocytes, their mechanisms of activation and autoantibody production, and their role remain unclear. This study was undertaken to identify mechanisms that contribute to pathogenic B cell generation and involvement in SS c and to assess the altered distribution and function of B cells in SS c patients. Methods Multicolor flow cytometry was performed to determine B cell subset distribution, cytokine production, and tolerance induction in SS c patients and healthy controls. Cytokine production following stimulation of the cells ex vivo was determined by multiplex assay. Results A range of defects in B lymphocyte tolerance and cytokine production in SS c were noted. There was evidence of altered distribution of transitional B cell subsets, increased production of interleukin‐6 ( IL ‐6) and IL ‐8, and defective tolerance induction in SS c B cells. In addition, B cells from SS c patients had a reduced ability to produce IL ‐10 when stimulated through innate immune pathways. In contrast to healthy individuals, tolerance checkpoints in SS c patients failed to suppress the emergence of B cells that produce autoantibodies with specificity to the Scl‐70 antigen, which is strongly associated with SS c. These defects were paralleled by altered intracellular signaling and apoptosis following B cell receptor engagement. Conclusion Our findings provide new insights into mechanisms underlying defective B lymphocyte responses in patients with SS c and their contribution to disease.