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We have previously shown that a variant of the  TNFSF13B  gene that we called  BAFF-var  increases the production of the cytokine BAFF, upregulating humoral immunity and increasing the risk for certain autoimmune diseases. In addition, genetic population signatures revealed that  BAFF-var  was 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 of  BAFF-var  in response to malaria antigens. Lysates of erythrocytes infected with  Plasmodium falciparum  (iRBCs) or left uninfected (uRBCs, control) were used to treat peripheral blood mononuclear cells (PBMCs) with distinct BAFF genotypes. The PBMCs purified from  BAFF-var  donors and treated with iRBCs showed different levels of specific cells, immunoglobulins, and cytokines as compared with  BAFF-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 selected  BAFF-var  may have improved fitness during  P. falciparum  infection.

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