Characterizing autoreactive B cells and their roles in the pathogenesis of SLE using immune organoids

Systemic lupus erythematosus (SLE) is a complex autoimmune disease driven by the breakdown of B cell tolerance and the production of autoreactive antibodies. We recently identified the presence of autoreactive B cells in spleens from healthy individuals and observed a 20-fold increase in spleens derived from SLE patients. This proposal will investigate a critical gap in understanding how autoreactive B cells transition from a tolerogenic state to a pathogenic one through: (i) analysis of dysregulated transcriptional pathways in spheromer-sorted autoreactive B cells derived from SLE patients, (ii) investigation of human-specific TLR7 mutants in mediating autoreactive B cell activation using immune organoids, and (iii) characterization of proinflammatory monocytes triggered by bacterial peptidoglycans in SLE. We will test the hypothesis that autoreactive B cells in SLE have distinct transcriptomic profiles and increased somatic hypermutation frequencies compared to healthy donors. We further hypothesize that amplified TLR7 signaling due to gene mutations and proinflammatory monocytes activated by bacterial peptidoglycans are pathognomonic for distinct SLE disease subtypes and characteristics. Aim 1 will characterize the transcriptomic and B cell receptor (BCR) profiles of autoreactive B cells from lupus patients. Aim 2 will investigate the autoimmune response in immune organoids expressing the TLR7Y264H mutant. Aim 3 will examine the ability of proinflammatory monocytes from SLE and healthy monocytes primed by peptidoglycan to trigger autoreactive B cell activation. The success of the proposed studies will elucidate the mechanisms by which autoreactive B cells become pathogenic and cause SLE, fundamentally transforming our understanding of SLE and potentially leading to novel therapeutic strategies. Project Number: 1K99AI196240-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Xin Chen | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $127,926 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 IIDA-T (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99AI19624001