Human plasma IgG1 repertoires are simple, unique, and dynamic.
Human plasma IgG1 repertoires are simple, unique, and dynamic.
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人血浆免疫球蛋白1谱系简单、独特、动态。
DOI：
10.1016/j.cels.2021.08.008
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发表时间：
2021-12-15
期刊：
影响因子：
9.3
通讯作者：
Heck AJR
中科院分区：
文献类型：
--
作者：
Bondt A;Hoek M;Tamara S;de Graaf B;Peng W;Schulte D;van Rijswijck DMH;den Boer MA;Greisch JF;Varkila MRJ;Snijder J;Cremer OL;Bonten MJM;Heck AJR
虽然人类可以通过重组和超突变产生数十亿个IgG1变体，但在人类血浆中循环的IgG1克隆的多样性在很大程度上无法直接表征。在这里，我们结合了几种基于质谱学的方法，揭示了健康献血者和脓毒症患者血浆中循环的IgG1谱系由有限数量的克隆主导。我们观察到，每个个体捐赠者都表现出独特的血清IgG1谱系，该谱系随着时间的推移保持稳定，但可以快速适应生理变化。我们介绍了一种以蛋白质和多肽为中心的整合方法，以获得和验证单个血浆IgG1克隆从头开始的全序列。这个IgG1克隆出现在脓毒症发作时，与最匹配的生殖系DNA序列相比，显示出高突变率(13%)，突显了蛋白质水平上从头测序的重要性。补充资料中包括了本文件透明的同行审查过程的记录。新的基于LC-MS的方法可以在血浆中进行个性化的IgG1分析每个捐赠者都展示了一个简单但独特的血清IgG1图谱这个图谱可以适应生理上的变化，例如败血症，单个血浆IgG1克隆可以通过结合自上而下和自下而上的蛋白质组学来识别人体产生免疫球蛋白(IG)来帮助对抗病原体。我们的身体可以产生的不同的免疫球蛋白分子的数量超过数十亿。与这个近乎无限的理论数字相反，我们在这里揭示，正如LC-MS直接监测的那样，只有几十个不同的克隆丰富地支配着健康和疾病捐赠者的血浆IgG1的总光谱。我们的数据表明，每个捐赠者的IgG1谱系都是独特的。我们纵向描述个人的免疫球蛋白1谱系，并观察特定免疫球蛋白随着时间的变化而发生或消失，以响应生理变化，例如，在败血症发作期间。作为概念的证明，我们展示了使用自上而下和自下而上的蛋白质组学相结合的方法，可以对单个血浆IgG1克隆进行量化、完全测序和鉴定。
Although humans can produce billions of IgG1 variants through recombination and hypermutation, the diversity of IgG1 clones circulating in human blood plasma has largely eluded direct characterization. Here, we combined several mass-spectrometry-based approaches to reveal that the circulating IgG1 repertoire in human plasma is dominated by a limited number of clones in healthy donors and septic patients. We observe that each individual donor exhibits a unique serological IgG1 repertoire, which remains stable over time but can adapt rapidly to changes in physiology. We introduce an integrative protein- and peptide-centric approach to obtain and validate a full sequence of an individual plasma IgG1 clone de novo. This IgG1 clone emerged at the onset of a septic episode and exhibited a high mutation rate (13%) compared with the closest matching germline DNA sequence, highlighting the importance of de novo sequencing at the protein level. A record of this paper’s transparent peer review process is included in the supplemental information. Novel LC-MS-based methods enable personalized IgG1 profiling in plasma Each donor exhibits a simple but unique serological IgG1 repertoire This repertoire adapts to changes in physiology, e.g., sepsis Individual plasma IgG1 clones can be identified by combining top-down and bottom-up proteomics The human body produces immunoglobulins (Igs) to help combat pathogens. The number of distinct IgG molecules our body can produce exceeds several billions. In contrast to this near-infinite theoretical number, we reveal here, as monitored directly by LC-MS, that only a few dozen distinct clones dominate in abundance the total spectrum of plasma IgG1s of both healthy and diseased donors. Our data indicate that each donor’s IgG1 repertoire is distinctively unique. We longitudinally profile an individual’s IgG1 repertoire and observe the occurrence or disappearance of specific IgGs over time in response to changes in physiology, e.g., during a septic episode. As a proof of concept, we show that individual plasma IgG1 clones can be quantified and fully sequenced and identified by using a combination of top-down and bottom-up proteomics.
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