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

Award Number: K99AI196240
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Characterizing autoreactive B cells and their roles in the pathogenesis of SLE using immune organoids - Project Summary 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $127,926 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	1	3/30/2026	NEW	$127,926
														Subtotal = $127,926

Grand Total All Awards = $127,926

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

Award Number: K99AI196240

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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