Genetic and functional dissection of tissue-infiltrating and age-associated B cells in murine lupus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to self- nucleic acids and associated protein antigens (Ags), driven by aberrant activation of innate and adaptive immunity. B cells, T cells and myeloid cells infiltrate tissues of lupus patients and mice, causing damage to multiple organ systems including the lung, liver and kidneys. B cells are essential for both the initiation and propagation of lupus disease in murine models. Human SLE is demonstrably B cell-driven, as reflected by the efficacy of FDA-approved and investigational therapeutic drugs including belimumab (anti-BAFF), B cell depleting antibodies, and anti-CD19 CAR T cells. However, these therapeutic approaches target all B cells, leaving patients partially immunocompromised. An approach targeting only the pathogenic subset(s) of B cells is highly desirable. A deeper understanding of which B cell subsets are pathogenic and how they mediate disease is necessary for designing such targeted therapeutic approaches. Over the past several years, a subset of B cells termed "age-associated B cells" (ABCs) was identified as a putative pathogenic autoreactive driver of lupus disease in mouse models and in human patients. These cells are defined by the expression of β2-integrins CD11c (Itgax) and/or CD11b (Itgam) and transcription factors Tbx21 and Zeb2, and are generated through an extrafollicular (EF) B cell response driven by TLR7/9 signals in the presence of IFNγ and IL-21. In addition to being associated with multiple autoimmune diseases, they are formed during infection and may play both protective and pathogenic roles in those settings. The identities, functions and heterogeneity of ABC-like cells and other B cell subsets that infiltrate organs in SLE are not well-defined, yet their evolving relevance in many disease contexts renders defining these an important task. We recently showed in the MRL/lpr lupus model that deletion of CD11c+ B cells reduced disease, including interstitial nephritis, suggesting that these cells promote activation and expansion of autoreactive T cells. What remains unclear is whether ABCs are the sole non-redundant drivers of disease or whether instead they play partial or even dispensable roles, an issue that will be directly addressed by this proposal. Intriguingly, new preliminary data suggests ABCs are themselves present in the kidney and other lupus target tissues of diseased mice, and a recent paper suggests the same is true in human lupus. We hypothesize that ABCs are important drivers of lupus pathogenesis, and that they function in part by presenting self-Ags to autoreactive T cells in the spleen and locally in target organs. Here we propose to define and investigate the pathogenic functions of tissue-infiltrating B cells, including ABCs and other memory B cells, in murine lupus models via two specific aims: 1) Characterize tissue-infiltrating B cells and evaluate their roles in lupus pathogenesis by identifying organ-specific and cross- tissue B cell clonotypes and gene regulatory networks; 2) Genetically test the roles of ABCs in lupus pathogenesis using novel mouse models to inducibly deplete ABCs or specific genes within them. Project Number: 1R01AI189529-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: MARK SHLOMCHIK (+1 co-PI) | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $499,175 | Activity Code: R01 | Study Section: Mechanisms of Autoimmunity Study Section[MAI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18952901A1