Advisory Committee Chair
Hui-Chen Hsu
Advisory Committee Members
Chander Raman
Jeffery Edberg
John Mountz
Xu Feng
Document Type
Dissertation
Date of Award
1-1-2025
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Cardinal features of lupus include elevated B cell activation and autoantibody production with a female sex preponderance. Development of T-bet+ B cells, driven by aberrant TLR7 and interferon (IFN) signaling, is a key pathogenic feature of systemic lupus erythematosus (SLE). In the present study, we developed two novel approaches to elucidate the mechanisms of female sex predisposition to lupus. We (i) quantified interactions of sex and genetic variation on the development of autoimmune B-cell phenotypes and autoantibodies in the BXD2 murine model of lupus using a cohort of backcrossed progeny (BXD2 x C57BL/6J) x BXD2; (ii) used a combination approach analyzing the transcriptomic profiles of naïve B cells female and male donors and analysis of in vitro TLR7 and IFN-ß stimulation experiments using the BXD2 mouse model of lupus to evaluate if B cell intrinsic signaling independent or downstream of hormonal and genetic influence may promote the development of T-bet+ B cells in females. In (BXD2 x C57BL/6J) x BXD2 mice (N2 mice), we found sex was the key factor leading to increased total IgG, IgG2b, and autoantibodies. The percentage of T-bet+CD11c+ IgD+ activated naive B cells (aNAV) was higher in females and was associated with increased T-bet+CD11c+ IgD− age-related B cells (ABCs), Fas+GL7+ germinal center B cells (GC), Cxcr5−Icos+ peripheral T-helper cells (Tph), and T-and Cxcr5+Icos+ follicular T-helper cells (Tfh). Interferon-beta (IFN-β) was elevated in females. Variation in aNAV cells was mapped to Chromosome (Chr) 7 in a locus that showed significant interactions between the female sex and heterozygous B/D variant. Analysis of transcriptomic profiles of naïve B cells (IGHM+IGHD+IGHG-) from 11 female (5 SLE, 6 healthy) and 11 male donors revealed upregulation of mitochondrial complex genes as a common signature of naive B cells from females. In vitro stimulation of B cells from lupus prone BXD2 mice with TLR7 and IFNβ showed comparable early CD69 induction, downregulation of IgD, expression of T-bet, and GL7+ activated subsets in B cells from females and males. However, B cells from females showed significantly higher expression of mitochondrial complex I genes, mitochondrial biogenesis, and mitochondrial respiration. This was associated with greater T-bet expression in B cells from females. Inhibiting complex I reduced development of T-bet+GL7+ B cells from females Our results suggest that activation of naive B cells forms the basis for the female-predominant development of autoantibodies in lupus-susceptible BXD2 mice, and that female-biased mitochondrial activity, albeit independent of IFN responses, supports the energy demands to promote T-bet+ B cell development.
Recommended Citation
Sullivan, Kathryn A., "Sex Differences In The Development Of T-Bet+ B Cells In Lupus" (2025). All ETDs from UAB. 6893.
https://digitalcommons.library.uab.edu/etd-collection/6893
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