What Rheumatologists Should Know About B Cell Tolerance & Autoimmunity

“In recent years, B cells have been identified as major drivers of systemic auto­immunity emphasizing the importance of maintaining B cell tolerance,” says Shaun W. Jackson, MBChB, MD, a pediatric nephrologist and rheuma­tologist at Seattle Children’s and principal investigator at its Center for Immunity and Immunotherapies (CIIT). Dr. Jackson is also a professor of pediatrics at the University of Washington School of Medicine, Seattle, and an adjunct professor in its Department of Laboratory Medicine and Pathology.

Dr. Jackson is the co-author of a review that is part of a series on immunology for rheumatologists published in Arthritis & Rheumatology (A&R).¹ In this new installment, Dr. Jackson and co-author Sivasankaran M. Ponnan, PhD, a post­doctoral researcher in Dr. Jackson’s lab at CIIT, review the mechanisms employed by the immune system to create B cells that respond to diverse pathogens while preserving immune tolerance, and how these mechanisms shape the understanding of autoimmune pathogenesis.²

Insights for Rheumatologists 

“A key feature of B cell tolerance that may not be recognized by rheumatologists is that healthy individuals have autoreactive B cells as part of a normal B cell repertoire. For this reason, multiple overlapping mechanisms act in concert to prevent the activation of autoreactive B cells and the production of harmful autoantibodies,” Dr. Jackson explains. “This review describes these coordinated processes that ensure the formation of a diverse yet self-tolerant antibody repertoire.

Dr. Shaun W. Jackson

“Prior reviews have described how genetic variants impacting B cell signaling pathways contribute to loss of tolerance and autoimmune pathogenesis. A key takeaway from the current article is the important role that neoantigens (i.e., altered self) play in precipitating breaks in B cell tolerance,” Dr. Jackson says.

The review initially presents a clinical case of a patient with two rare diseases, Alport syndrome, a genetic disorder leading to slowly progressive kidney dysfunction and hearing loss, and de novo anti-glomerular basement membrane (GBM) disease, an autoimmune disorder leading to rapidly progressive glomerulonephritis. To clarify the immunopathology of the case, the authors examine the fundamentals of B cell tolerance, comprising central, peripheral and germinal center B cell tolerance. They discuss the regulatory role of T cells in B cell tolerance, clonal redemption and anergic B cell maintenance, and the disruptions to B cell tolerance in autoimmunity.

Along with a graphical abstract and over 60 references, the review includes two detailed figures and legends demonstrating the central and peripheral mechanisms of B cell tolerance, and the contribution of neoantigens to breaks in B cell tolerance.