Regulation of pathogen-specific and self-reactive antibodies after Salmonella infection

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King, Lloyd (2018). Regulation of pathogen-specific and self-reactive antibodies after Salmonella infection. University of Birmingham. Ph.D.

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Abstract

Systemic Salmonella Typhimurium infection induces an atypical antibody response in which the extrafollicular and germinal centre reactions develop at discordant rates. Dysregulated or atypical antibody responses represent a potential source of autoantibodies. In this thesis, we show that systemic infection induces pathogen-specific and self-reactive IgM and lgG antibodies early after infection, but with differing kinetics, suggesting that they are distinct responses. To characterize these two responses the antibody response was assessed in a range of genetically altered mice. We identified a role for TLR4 in this process, but this is dependent upon the genetic background of the murine host. There is strong reactivity of self-reactive antibodies from wild-type mice with stomach, muscle and liver. These antibodies can persist long after infection is cleared from the liver and spleen. Our investigation into the induction of these antibodies suggest that IL-6 from stromal cells may play a role in this response, but ICOSL, TNF, IFN-\(\gamma\) and Th1 responses are dispensable. Critically, CD80/CD86 are essential for the induction of the anti-self, but not the pathogen-specific response. This data suggests that pathogenspecific and self-reactive antibody responses are independently regulated and thus it may be possible to modulate anti-self-responses without compromising anti-pathogen immunity.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):