Reflections on B Cells in SLE & Lupus Nephritis

CHICAGO—At this year’s ACR Convergence, Shaun Jackson, MD, PhD, gave the Dubois Memorial Lecture, named for Edmund L. Dubois, MD, a pioneer in systemic lupus erythematosus (SLE) research. Dr. Jackson, an attending physician in pediatric rheumatology and nephrology and principal investigator at Seattle Children’s Hospital Research Institute’s Center for Immunity and Immunotherapies, spoke on the evolving understanding of the role of B cells in SLE, with insights on related therapeutic and research questions.

Role of B Cells in SLE

Rheumatology interest in B cells in SLE pathophysiology goes back several decades. Researchers hoped that a 2012 phase 3 lupus nephritis study of rituximab, a B cell–depleting anti-CD20 monoclonal antibody, would yield a new therapeutic option; however, the heavily publicized trial failed.¹ Dr. Jackson, then early in his work studying the role of B cells in lupus nephritis, remarked that this wasn’t a very auspicious start to his career.

The reasons for the trial’s failure were probably multifaceted, with other trials showing some mixed success; many rheumatologists still used the therapy off label, especially for non-responsive or severe disease.² It’s now thought that the somewhat poor response of such B cell–depleting therapies in many autoimmune diseases may be due to the persistence of autoreactive B cells outside the blood, in lymphatic tissues or other organs.³

Dr. Shaun W. Jackson

“Things have changed enormously over the last 12 or 13 years,” said Dr. Jackson. He pointed to the U.S. Food & Drug Administration’s approval of obinutuzumab, another anti-CD20 B cell–depleting monoclonal antibody, in October 2025. He also emphasized the recent transformative work on the power of B cell depletion in the context of chimeric antigen receptor (CAR) T cell therapy, pioneered in human subjects by Georg Schett, MD, a rheumatologist at the University Hospital Erlangen, Germany.^3,4

Mouse Models

Dr. Jackson traced developments in understanding B cells in SLE through a series of studies in mouse models. For example, he showed how knocking out certain genes in B cells alone could either significantly promote SLE or protect against it, depending on the gene involved, e.g., those linked to toll-like receptors 7 and 9, interferon γ, interleukin (IL)-6 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.^5-9

“There’s a central role for dysregulated signaling [in SLE], particularly on the B cell receptor, toll-like receptors and cytokine receptor pathways, which seem to be very important for the initiation of lupus,” Dr. Jackson said. He noted that although immunology textbooks often illustrate T cells finding B cells, B cells may play more of the central role in orchestrating breaks in T cell tolerance, perhaps by helping concentrate antigens for presentation to T cells.