title: Investigating the associations between plasmodium infections and autoimmunity in sub-Saharan Africa
Creators: name: Kimathi, Rinter Karimi
Publisher: name: University of Glasgow
Year: 2025

description: Autoimmune diseases affect 5- 8% of the global population and are known to occur due to a misguided immune response towards the host, consequently affecting several organs. Importantly, infections are considered key environmental triggers of autoimmunity and contribute to the onset of autoimmune diseases, though this idea remains controversial. In this research, I focus on malaria, a disease caused by Plasmodium species, which has been linked to autoimmunity through the induction of anti-self-antibodies, with higher levels of autoantibodies associated with disease severity. By contrast, there is evidence suggesting that autoantibodies play a crucial role in anti-malarial protection, with increased autoantibodies shown to inhibit parasite growth. Thus, autoantibodies play a dual role in protection and pathology. However, this raises a crucial question on whether the induction of autoimmune antibodies during malaria increases predisposition to autoimmune disease later in life.

Herein, anti-citrullinated protein autoantibodies (ACPA) commonly associated with clinical diagnosis of rheumatoid arthritis and their corresponding native peptides were first screened using ELISA in mice infected with the model pathogen Plasmodium chabaudi. This approach was chosen to investigate whether Plasmodium triggers ACPA production, providing insights into the potential link between Plasmodium infections and autoimmunity. Subsequently, the impact of heightened antibody responses to both the native and citrullinated peptides on the development of a model of experimental arthritis in mice was assessed. Extending the findings to humans, serum samples obtained from individuals residing in areas with varying levels of malaria exposure were examined for the presence of autoimmune markers using ELISA and protein microarray assays. This was followed by assessing differential cellular immune phenotypes using flow cytometry.

Interestingly, increased levels of antibody responses to both the native and citrullinated peptides were observed in the P. chabaudi-infected mice with levels comparable to those observed in a chronic experimental arthritis model. However, despite the elevated autoantibodies, under the experimental conditions used in our study, infection-induced autoantibodies did not appear to influence the outcome of either acute or chronic experimental arthritis in mice.

Furthermore, expanding our findings to adults and children residing in malariaendemic areas, I observed that individuals living in high malaria transmission areas exhibited elevated antibody responses to both the native and citrullinated peptides compared to those in low transmission areas. Interestingly, a similar trend was observed in children, particularly children with uncomplicated and severe malaria who had increased levels of autoantibodies compared to healthy children. In addition, protein microarray data suggested that individuals from a high malaria transmission area had an overall increase in autoimmune reactivity. Notably, higher levels of antibodies against both the native and citrullinated peptides were also associated with increased frequency of atypical B cells (CD27⁻ CD21⁻CD11c⁺T-bet⁺) and a reduction in the levels of FOXP3 regulatory T cells.

My research indicates that Plasmodium infection leads to a broad spectrum of autoantibodies, including responses to both the native and citrullinated peptides as well as extracellular antigens, mirroring a profile of increased autoantibodies typically observed in autoimmune diseases. Moreover, in this study, I report the presence of elevated antibody responses to these peptides in both Plasmodium infected mice and humans residing in areas of high Plasmodium falciparum transmission. Notably, the pre-existing autoantibody response to these peptides from a single Plasmodium infection episode did not modulate susceptibility to experimental autoimmune arthritis. Thus, the effect and role of chronic exposures to P. falciparum infections on the risk of developing autoimmune diseases in people living in endemic areas cannot be ruled out and should be determined.