Kochayoo Piyawan, Moriyama Saya, Kotaki Ryutaro, Thawornpan Pongsakorn, Malee Chayapat, Leepiyasakulchai Chaniya, Ntumngia Francis Babila, Adams John H, Takahashi Yoshimasa, Chootong Patchanee
Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan.
PLoS Pathog. 2025 Jan 23;21(1):e1012866. doi: 10.1371/journal.ppat.1012866. eCollection 2025 Jan.
Expansion of atypical memory B cells (aMBCs) was demonstrated in malaria-exposed individuals. To date, the generation of P. vivax-specific aMBCs and their function in protective humoral immune responses is unknown. Here, P. vivax Duffy Binding Protein II (PvDBPII) probes were generated to detect the development and durability of specific aMBCs, and to demonstrate the capacity of these cells to produce neutralizing antibodies following natural infections. PvDBPII-specific aMBCs were elicited during malaria illness, and they persisted through the recovery phase of infections. To address biology and function of P. vivax-specific aMBCs in producing protective antibodies, a single MBC was cultured, and the secreted IgG was tested for binding and inhibition activity. The aMBC-derived clones produced antibodies with variable levels of anti-PvDBPII IgG in cultures, and some produced high antibody levels comparable to classical MBC clones. Thus, we focused our attention on the function of aMBCs in producing neutralizing antibodies. Among the aMBC clones, A1F12 and B4E11 produced broadly neutralizing antibodies against a panel of PvDBPII variants. Notably, B cell receptors (BCRs) of PvDBPII-specific aMBCs expressed unique IGHV genes, with similar usage of IGHV1-3, comparable to classical MBCs. The somatic hypermutation (SHM) rate and CDR3 length of VH and Vκ in these two MBC subsets were not significantly different. Together, our findings revealed that P. vivax infections elicited the development and persistence of P. vivax-specific aMBCs. The accumulation of aMBCs during and following infections might play an important role in producing protective antibodies against malaria.
在暴露于疟疾的个体中证实了非典型记忆B细胞（aMBCs）的扩增。迄今为止，间日疟原虫特异性aMBCs的产生及其在保护性体液免疫反应中的功能尚不清楚。在此，生成了间日疟原虫达菲结合蛋白II（PvDBPII）探针，以检测特异性aMBCs的发育和持久性，并证明这些细胞在自然感染后产生中和抗体的能力。PvDBPII特异性aMBCs在疟疾发病期间被诱导产生，并在感染的恢复阶段持续存在。为了研究间日疟原虫特异性aMBCs在产生保护性抗体方面的生物学特性和功能，培养了单个MBC，并检测分泌的IgG的结合和抑制活性。aMBC衍生的克隆在培养物中产生了具有不同水平抗PvDBPII IgG的抗体，一些克隆产生的抗体水平与经典MBC克隆相当。因此，我们将注意力集中在aMBCs产生中和抗体的功能上。在aMBC克隆中，A1F12和B4E11产生了针对一组PvDBPII变体的广泛中和抗体。值得注意的是，PvDBPII特异性aMBCs的B细胞受体（BCRs）表达独特的IGHV基因，IGHV1-3的使用情况与经典MBCs相似。这两个MBC亚群中VH和Vκ的体细胞超突变（SHM）率和CDR3长度没有显著差异。总之，我们的研究结果表明，间日疟原虫感染引发了间日疟原虫特异性aMBCs的发育和持续存在。感染期间和感染后aMBCs的积累可能在产生抗疟疾保护性抗体中起重要作用。
