Atypical memory B-cells and autoantibodies correlate with anemia during Plasmodium vivax complicated infections

Malaria caused byPlasmodium vivaxis a highly prevalent infection world-wide, that was previously considered mild, but complications such as anemia have been highly reported in the past years. In mice models of malaria, anti-phosphatidylserine (anti-PS) autoantibodies, produced by atypical B-cells, bind to uninfected erythrocytes and contribute to anemia. In human patients withP.falciparummalaria, the levels of anti-PS, atypical B-cells and anemia are strongly correlated to each other. In this study, we focused on assessing the relationship between autoantibodies, different B-cell populations and hemoglobin levels in two different cohorts ofP.vivaxpatients from Colombia, South America. In a first longitudinal cohort, our results show a strong inverse correlation between different IgG autoantibodies tested (anti-PS, anti-DNA and anti-erythrocyte) and atypical memory B-cells (atMBCs) with hemoglobin in bothP.vivaxandP.falciparumpatients over time. In a second cross-sectional cohort, we observed a stronger relation between hemoglobin levels, atMBCs and autoantibodies in complicatedP.vivaxpatients compared to uncomplicated ones. Altogether, these data constitute the first evidence of autoimmunity associating with anemia and complicatedP.vivaxinfections, suggesting a role for its etiology through the expansion of autoantibody-secreting atMBCs. Author summary Malaria is one of the top global infections causing high mortality and morbidity every year.Plasmodium vivaxis the most prevalent malarial infection, particularly in the region of the Americas. Complications associated withP.vivax, such as anemia, are a growing reported phenomenon, but the mechanisms leading to them are poorly understood. Here, we report the first evidence of autoantibodies and Atypical Memory B-cells correlating with anemia in two different cohorts ofP.vivaxpatients, particularly during complicated infections. These findings point to Atypical Memory B-cells as key pathological players, possibly through the secretion of autoantibodies, and attributes a role for autoimmunity in mediating complications duringP.vivaxinfections.