Peckham, Hannah Louise; (2024) Investigating the role of sex, hormones and puberty in classswitch recombination of B lymphocytes. Doctoral thesis (Ph.D), UCL (University College London).

Text 240205 H.Peckham - PhD Thesis - Final revised copy.pdf - Submitted Version Access restricted to UCL open access staff until 1 March 2025. Download (16MB)

Abstract

Heightened humoral immune responses in cisgender females are well-documented and have been postulated to contribute to the female bias seen in autoimmune disorders, and the male bias in infection morbidity. Here, I analyse global data to show that males are more likely to die or to require intensive care treatment following infection with SARS-CoV-2 than females. To investigate the stark sex differences in disease outcomes, my research focused on understanding the mechanisms controlling baseline differences in the immune system. I focus on B cell Class-Switch Recombination (CSR), a process implicit in both the clearance of infection and in the production of the majority of damage-causing autoantibodies seen in autoimmunity. To investigate the role of the sex hormones (oestrogen and testosterone) and the sex chromosomes (XX and XY) in CSR, a unique cohort of healthy post-pubertal cisgender-females and -males and age-matched transgender-females and -males on gender-affirming hormone treatment and/or hormone “blockers” were recruited. I demonstrate that oestrogen on an XX chromosomal background is associated with higher levels of class-switched, specifically IgG+ B cells. Post-pubertal cisgender females had higher levels of these than age-matched cisgender males and transgender males on blockers, and gender-matched pre-pubertal cisgender females. Oestradiol supplementation in transgender females (XY) however, had no impact on switched cell proportions, suggesting that interactions between oestrogens and the X chromosome are responsible for these differences. Further, unique B cell transcriptomes were established, dependant on sample donor’s gender and pubertal stage. Lastly, I show that in the context of chronic autoimmune inflammation in juvenile systemic lupus erythematosus (JSLE), the distinct female and male immune signatures in CSR are lost, suggesting that autoimmunity overrides the influences of sex. Together, these data show that hormones differentially affect CSR in a manner dependent upon chromosomal complement, and that these effects are different in the context of autoimmunity.

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