Author ORCID Identifier

https://orcid.org/0000-0002-2108-2733

Semester

Spring

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Jennifer Franko

Committee Member

Michael Hu

Committee Member

Ivan Martinez

Committee Member

Edwin Wan

Committee Member

Michael Schaller

Committee Member

Roberta Leonardi

Abstract

Sex dimorphisms in immunity are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones have been extensively documented, recent recognition of the nuanced contributions of the sex chromosome complement (XX vs. XY) and the gut microbiome to immune sex dimorphisms underscores the need for a more comprehensive understanding. Within this context, the work herein focuses on unraveling the individual and collaborative impacts of the sex chromosome complement and gut microbiota on humoral immune activation. We assessed humoral immune responses to immunization with heat-killed Streptococcus pneumoniae (HKSP) in Four Core Genotype (FCG) mice and found elevated IgM-secreting B cells and plasma cells in XX vs. XY mice, regardless of gonadal sex. RNA-Sequencing was used to identify X-linked, immune-related genes that may be biallelically expressed in XX mice, potentially contributing to the XX-specific phenotype. Kdm6a, an X-linked epigenetic regulatory gene, was shown to be upregulated in XX mice and expressed from the inactive X chromosome in some B cell subsets. However, inhibition of its enzymatic activity did not impact mitogen-induced plasma cell differentiation or antibody production in a sex chromosome-dependent manner in ex vivo studies, suggesting its biallelic expression is not directly causing the observed XX vs. XY phenotype. Additionally, we examined whether gut microbiota differentially influence immune cell activation in a sex chromosome-dependent manner. The study involved antibiotic depletion of endogenous gut microbiome, followed by HKSP immunization and subsequent assessment of immune responses. The enhancement of humoral responses in XX mice observed post-immunization was lost upon antibiotic depletion of the microbiota, while XY responses were not affected. Reconstitution of microbiota-depleted mice with select short-chain fatty acid (SCFA)-producing bacteria restored humoral responses specifically in XX FCG mice. However, exposure to the SCFA propionate alone did not enhance responses to mitogenic B cell stimulation in ex vivo studies, suggesting another microbiota-specific element may be contributing. This dissertation, by navigating the complex interplay between sex hormones, the sex chromosome complement, and the gut microbiome in shaping immune responses, sheds light on the interdependent and collaborative influence of the sex chromosome complement and gut microbiota and also underscores the critical importance of deciphering sexual dimorphisms in immunity for the development of targeted therapeutic strategies.

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