Our results uncover a previously unknown mechanism by which BAFF-var increases the circulating sBAFF levels in Sardinian donors, enhancing the expression of numerous mRNAs and proteins, modulating immune cell populations and immunoglobulin representation, thereby potentiating the immune system against Plasmodium infection while also increasing the risk of autoimmune diseases such as multiple sclerosis. Here, TNFSF13B is linked to multiple sclerosis.