Recovery of an Antiviral Antibody Response following Attrition Caused by Unrelated Infection

The homeostatic mechanisms that regulate the maintenance of immunological memory to the multiple pathogen encounters over time are unknown. We found that a single malaria episode caused significant dysregulation of pre-established Influenza A virus-specific long-lived plasma cells (LLPCs) resulting in the loss of Influenza A virus-specific Abs and increased susceptibility to Influenza A virus re-infection. This loss of LLPCs involved an FcγRIIB-dependent mechanism, leading to their apoptosis. However, given enough time following malaria, the LLPC pool and humoral immunity to Influenza A virus were eventually restored. Supporting a role for continuous conversion of Influenza A virus-specific B into LLPCs in the restoration of Influenza A virus immunity, B cell depletion experiments also demonstrated a similar requirement for the long-term maintenance of serum Influenza A virus-specific Abs in an intact LLPC compartment. These findings show that, in addition to their established role in the anamnestic response to reinfection, the B cell pool continues to be a major contributor to the maintenance of long-term humoral immunity following primary Influenza A virus infection, and to the recovery from attrition following heterologous infection. These data have implications for understanding the longevity of protective efficacy of vaccinations in countries where continuous infections are endemic.长期以来，调控机体针对随时间推移发生的多次病原体感染所建立的免疫记忆维持过程的稳态机制仍未明确。本研究发现，单次疟疾感染会显著失调预先建立的甲型流感病毒（Influenza A virus）特异性长寿命浆细胞（long-lived plasma cells, LLPCs），进而造成甲型流感病毒特异性抗体（Abs）丢失，并使机体对甲型流感病毒再感染的易感性升高。此类长寿命浆细胞的丢失依赖于FcγRIIB介导的机制，最终引发其细胞凋亡。不过，在疟疾感染后经过足够长的时间，甲型流感病毒特异性长寿命浆细胞库与体液免疫功能最终可恢复至正常水平。为验证甲型流感病毒特异性B细胞（B cell）持续转化为长寿命浆细胞在甲型流感病毒免疫恢复中的作用，本研究开展的B细胞耗竭实验也证实，该转化过程是在完整的长寿命浆细胞库中长期维持血清甲型流感病毒特异性抗体水平的必要条件。上述研究结果表明，除了在再感染的回忆应答（anamnestic response）中发挥既定作用外，B细胞库在原发性甲型流感病毒感染后仍持续作为维持长期体液免疫的核心参与者，并可促进异种感染（heterologous infection）后免疫损耗的恢复。本研究数据有助于理解在持续存在病原体地方性流行的国家中，疫苗保护效力的持久性机制。