Investigation of the role of an evolutionarily selected autoimmunity variant in the BAFF gene in response to Malaria antigens

Population genetics signatures have revealed that an autoimmunity variant (BAFF-var) overexpressing soluble BAFF (sBAFF) showed significant evidence of positive selection, possibly due to adaptations to malaria infection. Interestingly, different studies have shown that mice overexpressing BAFF are protected from lethal Malaria infections.The aim of this project is to elucidate the role of BAFF-var during the response to malaria antigens, and thus to explain the possible protective role of BAFF-var. We prepared lysates of erythrocytes infected (iRBCs) or not infected (Control, uRBCs) withPlasmodium falciparum, a malaria pathogen that was highly prevalent in Sardinia were BAFF-var was detected and has been positively selected. The lysates were used to stimulate PBMCs genotyped for BAFF-var. After stimulation, samples were analyzed for differential gene expression and cell profiles by flow cytometry. In PBMCs purified from BAFF-var donors and treated with iRBCs, differential levels of B- and T- cell subpopulations, immunoglobulins as well as several cytokines were observed. These variations were associated with differential gene expression in several immune-related pathways such as the NFkB2 pathway and cytokines as determined by changes in RNA and protein levels. Increased production of sBAFF was observed in patients carrying the BAFF-var allele, which leads to an increased risk of autoimmunity. Differential gene expression, levels of specific B and T cells and cytokines secretion, implicated in malaria response potentially enhanced protection against malaria. These findings describe a previously unknown mechanism by which BAFF-var can potentiate the immune system againstPlasmodiuminfection.