Evolutionarily Selected Overexpression of the Cytokine BAFF Enhances Mucosal Immune Response AgainstP. falciparum

We have previously shown that a variant of theTNFSF13Bgene that we calledBAFF-varincreases the production of the cytokine BAFF, upregulating humoral immunity and increasing the risk for certain autoimmune diseases. In addition, genetic population signatures revealed thatBAFF-varwas evolutionarily advantageous, most likely by increasing resistance to malaria infection, which is a prime candidate for selective pressure. To evaluate whether the increased soluble BAFF (sBAFF) production confers protection, we experimentally assessed the role ofBAFF-varin response to malaria antigens. Lysates of erythrocytes infected withPlasmodium falciparum(iRBCs) or left uninfected (uRBCs, control) were used to treat peripheral blood mononuclear cells (PBMCs) with distinct BAFF genotypes. The PBMCs purified fromBAFF-vardonors and treated with iRBCs showed different levels of specific cells, immunoglobulins, and cytokines as compared withBAFF-WT.In particular, a relevant differential effect on mucosal immunity B subpopulations have been observed. These findings point to specific immune cells and molecules through which the evolutionary selectedBAFF-varmay have improved fitness duringP. falciparuminfection.