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Malaria, caused by parasites of the  Plasmodium  genus, is responsible for significant morbidity and mortality globally. Chronic  Plasmodium falciparum  exposure affects the B cell compartment, leading to the accumulation of atypical memory B cells (atMBCs). IgM-positive (IgM + ) and IgG +  atMBCs have not been compared in-depth in the context of malaria, nor is it known if atMBCs in malaria-experienced individuals are different from phenotypically similar B cells in individuals with no known history of  Plasmodium  exposure. To address these questions, we characterized the B cell receptor (BCR) repertoire of naive B cells (NBCs), IgM +  and IgG +  classical MBCs (cMBCs), and IgM +  and IgG +  atMBCs from 13 malaria-naive American adults and 7 malaria-experienced Ugandan adults. Our results demonstrate that  P. falciparum  exposure mainly drives changes in atMBCs. In comparison to malaria-naive adults, the BCR repertoire of  Plasmodium- exposed adults showed increased levels of somatic hypermutation in the heavy chain V region in IgM +  and IgG +  atMBCs, shorter heavy chain complementarity-determining region 3 (HCDR3) in IgG +  atMBCs, and increased usage of IGHV3-73 in IgG +  cMBCs and both IgM +  and IgG +  atMBCs. Irrespective of  Plasmodium  exposure, IgM +  atMBCs closely resembled NBCs, while IgG +  atMBCs resembled IgG +  cMBCs. Physicochemical properties of the HCDR3 seemed to be intrinsic to cell type and independent of malaria experience. The resemblance between atMBCs from  Plasmodium -exposed and naive adults suggests similar differentiation pathways regardless of chronic antigen exposure. Moreover, these data demonstrate that IgM +  and IgG +  atMBCs are distinct populations that should be considered separately in future analyses.   IMPORTANCE  Malaria, caused by  Plasmodium  parasites, still contributes to a high global burden of disease, mainly in children under 5 years of age. Chronic and recurrent  Plasmodium  infections affect the development of B cell memory against the parasite and promote the accumulation of atypical memory B cells (atMBCs), which have an unclear function in the immune response. Understanding where these cells originate from and whether they are beneficial in the immune response to  Plasmodium  will help inform vaccination development efforts. We found differences in B cell receptor (BCR) properties of atMBCs between malaria-naive and malaria-experienced adults that are suggestive of divergent selection processes, resulting in more somatic hypermutation and differential immunoglobulin heavy chain V (IGHV) gene usage. Despite these differences, atMBCs from malaria-naive and malaria-experienced adults also showed many similarities in BCR characteristics, such as physicochemical properties of the HCDR3 region, suggesting that atMBCs undergo similar differentiation pathways in response to different pathogens. Our study provides new insights into the effects of malaria experience on the B cell compartment and the relationships between atMBCs and other B cell populations.

B Cell Receptor Repertoire Analysis in Malaria-Naive and Malaria-Experienced Individuals Reveals Unique Characteristics of Atypical Memory B Cells