Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antoniogrid.267309.9, San Antonio, Texas, USA.
Infectious Disease Research Collaboration, Kampala, Uganda.
mSphere. 2021 Oct 27;6(5):e0072621. doi: 10.1128/mSphere.00726-21. Epub 2021 Sep 15.
Malaria, caused by parasites of the 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 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 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 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 -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. Malaria, caused by parasites, still contributes to a high global burden of disease, mainly in children under 5 years of age. Chronic and recurrent 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 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.
疟疾是由疟原虫属寄生虫引起的，在全球范围内导致了大量的发病率和死亡率。慢性恶性疟原虫暴露会影响 B 细胞群，导致非典型记忆 B 细胞（atMBC）的积累。在疟疾背景下，IgM 阳性（IgM）和 IgG atMBC 尚未进行深入比较，也不知道疟疾患者的 atMBC 是否与无已知暴露史个体中表型相似的 B 细胞不同。为了解决这些问题，我们从 13 名疟疾无经验的美国成年人和 7 名疟疾有经验的乌干达成年人中，对幼稚 B 细胞（NBC）、IgM 和 IgG 经典记忆 B 细胞（cMBC）和 IgM 和 IgG atMBC 的 B 细胞受体（BCR）库进行了特征描述。我们的结果表明，恶性疟原虫暴露主要导致 atMBC 的变化。与疟疾无经验的成年人相比，暴露成年人的 BCR 重链 V 区的体细胞超突变水平在 IgM 和 IgG atMBC 中增加，IgG atMBC 中的重链互补决定区 3（HCDR3）变短，IGHV3-73 在 IgG cMBC 和 IgM 和 IgG atMBC 中的使用增加。无论暴露与否，IgM atMBC 都与 NBC 非常相似，而 IgG atMBC 与 IgG cMBC 相似。HCDR3 的理化性质似乎是细胞类型固有的，与疟疾经验无关。无暴露的 atMBC 与幼稚成年人之间的相似性表明，无论慢性抗原暴露如何，分化途径相似。此外，这些数据表明，IgM 和 IgG atMBC 是不同的群体，在未来的分析中应分别考虑。
疟原虫引起的疟疾仍然是全球疾病负担的主要原因，主要发生在 5 岁以下儿童中。慢性和复发性感染会影响针对寄生虫的 B 细胞记忆的发展，并促进非典型记忆 B 细胞（atMBC）的积累，其在免疫反应中的功能尚不清楚。了解这些细胞的来源以及它们在恶性疟原虫免疫反应中是否有益，将有助于为疫苗开发工作提供信息。我们发现，疟疾无经验和有经验成年人之间的 atMBCs 的 B 细胞受体（BCR）特性存在差异，提示存在不同的选择过程，导致更多的体细胞超突变和不同的免疫球蛋白重链 V（IGHV）基因使用。尽管存在这些差异，但来自疟疾无经验和有经验成年人的 atMBCs 在 BCR 特征方面也存在许多相似之处，例如 HCDR3 区域的理化性质，这表明 atMBCs 在应对不同病原体时经历了相似的分化途径。我们的研究为疟疾经验对 B 细胞群的影响以及 atMBCs 与其他 B 细胞群之间的关系提供了新的见解。
