Germline-encoded specificities and the predictability of the B cell response.

IF 6.7 1区 医学 Q1 Immunology and Microbiology PLoS Pathogens Pub Date : 2023-08-25 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011603
Marcos C Vieira, Anna-Karin E Palm, Christopher T Stamper, Micah E Tepora, Khoa D Nguyen, Tho D Pham, Scott D Boyd, Patrick C Wilson, Sarah Cobey
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Abstract

Antibodies result from the competition of B cell lineages evolving under selection for improved antigen recognition, a process known as affinity maturation. High-affinity antibodies to pathogens such as HIV, influenza, and SARS-CoV-2 are frequently reported to arise from B cells whose receptors, the precursors to antibodies, are encoded by particular immunoglobulin alleles. This raises the possibility that the presence of particular germline alleles in the B cell repertoire is a major determinant of the quality of the antibody response. Alternatively, initial differences in germline alleles' propensities to form high-affinity receptors might be overcome by chance events during affinity maturation. We first investigate these scenarios in simulations: when germline-encoded fitness differences are large relative to the rate and effect size variation of somatic mutations, the same germline alleles persistently dominate the response of different individuals. In contrast, if germline-encoded advantages can be easily overcome by subsequent mutations, allele usage becomes increasingly divergent over time, a pattern we then observe in mice experimentally infected with influenza virus. We investigated whether affinity maturation might nonetheless strongly select for particular amino acid motifs across diverse genetic backgrounds, but we found no evidence of convergence to similar CDR3 sequences or amino acid substitutions. These results suggest that although germline-encoded specificities can lead to similar immune responses between individuals, diverse evolutionary routes to high affinity limit the genetic predictability of responses to infection and vaccination.

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种系编码的特异性和B细胞反应的可预测性。
抗体来自B细胞谱系的竞争,在选择下进化以提高抗原识别能力,这一过程被称为亲和力成熟。据报道,针对HIV、流感和严重急性呼吸系统综合征冠状病毒2型等病原体的高亲和力抗体经常来自B细胞,其受体是抗体的前体,由特定的免疫球蛋白等位基因编码。这增加了B细胞库中特定种系等位基因的存在是抗体反应质量的主要决定因素的可能性。或者,种系等位基因形成高亲和力受体倾向的最初差异可能会通过亲和力成熟过程中的偶然事件来克服。我们首先在模拟中研究了这些场景:当种系编码的适应度差异相对于体细胞突变的速率和效应大小变化较大时,相同的种系等位基因持续主导不同个体的反应。相反,如果种系编码的优势可以很容易地被随后的突变所克服,那么随着时间的推移,等位基因的使用会变得越来越不同,我们随后在实验感染流感病毒的小鼠中观察到了这种模式。我们研究了亲和力成熟是否可能在不同的遗传背景下强烈选择特定的氨基酸基序,但我们没有发现与类似CDR3序列或氨基酸取代趋同的证据。这些结果表明,尽管种系编码的特异性可以导致个体之间类似的免疫反应,但高亲和力的不同进化途径限制了对感染和疫苗接种反应的遗传可预测性。
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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