Shaun Jackson, MD, PhD, Principal Investigator at Seattle Children’s Research Institute’s Center for Immunity and Immunotherapies, was invited to give the Dubois Memorial Lecture at ARC Convergence on Sunday. The talk honors a pioneer in systemic lupus erythematosus (SLE), and fittingly, Dr. Jackson has spent his career investigating the role of B cells in the disease. He reviewed mechanistic insights from animal models, discussed translational findings in human disease, and presented an overview of the implications for current and emerging therapies.
“The legacy of B cell research in lupus traces back to the 1950s, when Edmond Dubois became interested in lupus after evaluating patients with a new blood test for the LE cell prep — a test that highlighted the role of antibodies and, by extension, B cells,” Dr. Jackson said.
Although the centrality of B cells in lupus pathogenesis was not fully appreciated at the time, it is now clear that B cells have played a pivotal role throughout the history of lupus research, he noted.
Recorded sessions at ACR Convergence 2025, including Memorial Lectures, will be available on demand to all registered meeting participants within 72 hours of the live presentation through October 31, 2026, by logging into the meeting website.
When Dr. Jackson completed his fellowship in 2012, the field was reeling from the negative results of the LUNAR trial, which showed that rituximab did not improve outcomes in lupus nephritis.
“This was a discouraging start for those of us focused on B cell immunology,” he said. “However, the past decade has seen remarkable progress, including the development of chimeric antigen receptor (CAR) T cell therapies and the recent approval of new agents for lupus nephritis. Our work over the last 10 years has consistently demonstrated the importance of B cells in lupus pathogenesis, both in animal models and in translational studies.”
Insights from Animal Models
Animal models have been invaluable in dissecting the mechanisms of lupus, Dr. Jackson noted. Early studies using knockout mice for toll-like receptor 7 (TLR7) and TLR9 revealed that these receptors have opposing effects on disease severity and autoantibody profiles.
“Our own experiments confirmed that B cell-intrinsic deletion of these genes recapitulates the global knockout phenotype, underscoring the central role of B cells,” he said. “We extended this approach to other genes — MyD88, MHC class II, interferon receptors, and cytokine production pathways — and consistently found that B cell-specific deletions mirrored the effects seen in global knockouts. This convergence of findings across multiple labs and models strongly supports the hypothesis that B cells are critical orchestrators of lupus pathogenesis.”
A particularly illustrative example he discussed is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Genetic variants in NCF1, a component of this complex, are associated with a threefold increase in lupus risk.
“While complete loss of function causes chronic granulomatous disease, partial loss increases lupus susceptibility,” Dr. Jackson said. “Our studies showed that B cell-specific deletion of NADPH oxidase components accelerates lupus in mice, suggesting that impaired clearance of apoptotic debris by B cells enhances autoantigen exposure and drives disease.”
Translational Insights: Spatial Transcriptomics
“Technological advances, such as single-cell spatial transcriptomics, have enabled us to study the immune landscape of lupus nephritis at unprecedented resolution,” Dr. Jackson explained.
His team analyzed pediatric kidney biopsies and found that lupus kidneys are infiltrated by diverse immune cells with a notable increase in B cells and plasma cells. Spatial analysis revealed that these cells cluster in tubulointerstitial “hotspots,” suggesting ongoing adaptive immune responses. Network analysis indicated that activated B cells (expressing human leukocyte antigen (HLA) molecules) are central nodes in these immune cell clusters, likely orchestrating local immune activation.
“Despite the centrality of B cells, rituximab often fails to deplete tissue-resident B cells and plasma cells, which may explain its limited efficacy in lupus nephritis,” he said. “CAR-T cell therapies targeting CD19 have shown promise, inducing rapid and sustained remission in refractory cases. Our own early experience with pediatric CAR-T cell therapy has been encouraging, though not all patients achieve complete renal remission, particularly those with longstanding chronic damage.”
Looking ahead, the field is exploring a range of novel approaches, including off-the-shelf CAR-T and CAR NK cells, in vivo gene delivery, and bispecific T cell engagers. There is also interest in targeting B cell maturation antigen (BCMA), which is highly expressed on plasma cells, to address pathogenic long-lived plasma cells that are resistant to CD19-directed therapies.
“Both animal and human studies underscore the central role of B cells in lupus pathogenesis. Ongoing advances in immunology and cell therapy hold great promise for transforming the management of lupus and related autoimmune diseases,” Dr. Jackson concluded.
Don’t Miss a Session
If you weren’t able to make it to a live session during ACR Convergence 2025 — or you want to revisit a session from the annual meeting — make plans to watch the replay. All registered participants receive on-demand access to scientific sessions after the meeting through October 31, 2026.