Recovery of an antiviral antibody response following attrition caused by unrelated infection.
Recovery of an antiviral antibody response following attrition caused by unrelated infection.
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DOI：
10.1371/journal.ppat.1003843
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发表时间：
2014-01
期刊：
影响因子：
6.7
通讯作者：
Langhorne J
中科院分区：
文献类型：
--
作者：
Ng DH;Skehel JJ;Kassiotis G;Langhorne J
随着时间的推移，调节对多种病原体遇到的免疫记忆的维持的动态平衡机制尚不清楚。我们发现，单个疟疾发作引起预先建立的甲型流感病毒特异性长寿浆细胞(LLPC)的显著失调，导致甲型流感病毒特异性抗体的丢失，并增加了甲型流感病毒再次感染的易感性。LLPC的这种丢失涉及FcγRIIB依赖的机制，导致它们的凋亡。然而，在疟疾后给予足够的时间，LLPC池和对甲型流感病毒的体液免疫最终恢复。B细胞耗竭实验表明，在恢复甲型流感病毒免疫的过程中，持续将甲型流感病毒特异性B细胞转化为低密度脂蛋白前体的作用，也证明了在完整的低密度脂蛋白库中长期维持血清甲型流感病毒特异性抗体的类似要求。这些发现表明，除了在对再次感染的记忆反应中已确立的作用外，B细胞池仍然是在甲型流感病毒初次感染后维持长期体液免疫以及在异种感染后从磨损中恢复的主要贡献者。这些数据对了解在持续感染流行的国家接种疫苗的保护效力的持久性具有重要意义。对感染性病原体的抗体反应对宿主的生存、康复和防止再次感染至关重要；它们也与疫苗接种的成功相关。目前认为，抗体血清效价在很长一段时间内由专门的长期分泌抗体的浆细胞维持在保护性水平。事实上，在90多年前1918年西班牙流感的幸存者中，仍然可以找到针对原始病毒的抗体。然而，后来感染异源病原体可能会导致先前建立的免疫记忆的磨损，以便在宿主的有限空间中适应新的淋巴细胞特异性，这一点也变得越来越明显。这一现象似乎与免疫记忆的长期维持不符。我们还表明，由查鲍迪疟原虫感染引起的一次疟疾发作，会导致原有浆细胞、血清抗体和对甲型流感病毒的保护性免疫丧失。然而，随着B细胞在几周的过程中补充浆细胞，这些动物的甲型流感病毒特异性免疫最终确实恢复了。因此，已报道的机制协调了异源感染和长期稳定性对免疫记忆的磨损，并将B细胞而不是其后代浆细胞置于体液记忆的中心。
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. Antibody responses to infectious pathogens are critical in host survival, recovery and protection from reinfection; they also correlate with the success of vaccination. It is currently thought that antibody serum titers are maintained at protective levels over long periods of time by specialized long-lived antibody-secreting plasma cells residing in the bone marrow. Indeed, antibodies against the original virus can still be found in survivors of the 1918 Spanish Flu, more than 90 years ago. However, it is also becoming clear that subsequent infection with heterologous pathogens may cause attrition of previously established immunological memory, in order to accommodate new lymphocyte specificities in the finite space of the host. This phenomenon is seemingly at odds with long-term maintenance of immunological memory. We also show that a single episode of malaria, caused by infection by Plasmodium chabaudi, leads to the loss of preexisting plasma cells, serum antibodies and protective immunity against Influenza A virus. However, Influenza A virus-specific immunity does eventually recover in these animals with the replenishment of plasma cells by B cells over the course of several weeks. Thus, the reported mechanism reconciles attrition of immunological memory by heterologous infection and long-term stability, and places B cells, instead of their descendant plasma cells, at the center of humoral memory.
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