Thymic plasma cells as a source of protective natural antibodies in human neonates

胸腺浆细胞作为人类新生儿保护性天然抗体的来源

• 批准号: 10605000
• 负责人: Emmanuel Zorn
• 金额: $ 24.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-10 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605000
• 关键词: Anti-Bacterial Agents; Antibodies; Antibody Response; Antibody-Producing Cells; Apoptotic; Area; B-Lymphocytes; B-cell receptor repertoire sequencing; Bacteria; Birth; Blood; Bone Marrow; Cell Ontogeny; Cells; Cessation of life; Clonal Expansion; Clone Cells; Developed Countries; Fetus; Gut associated lymphoid tissue; Haemophilus influenzae; Human; Humoral Immunities; Immune; Immunity; Immunoglobulin D; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Individual; Infant; Infection; Life; Liver; Lower Respiratory Tract Infection; Masks; Modeling; Monoclonal Antibodies; Mus; Natural Source; Neonatal; Newborn Infant; Organ; Placenta; Plasma Cells; Population; Pregnancy; Reaction; Recombinant Antibody; Recombinants; Reporting; Research; Rest; Sepsis; Serology; Site; Source; Spleen; Testing; Thymus Gland; Umbilical Cord Blood; Uncertainty; Work; combat; commensal bacteria; design; experimental study; exposed human population; expression cloning; fetal; in utero; in vivo; natural antibodies; neonatal death; neonatal infection; neonatal period; neonate; pathogen; pathogenic bacteria; plasma cell development; plasma cell differentiation; reconstitution; single-cell RNA sequencing; transcriptome; unborn child

PROJECT SUMMARY Infection is among the leading causes of neonatal deaths worldwide. Serological immunity is considered to be the most effective first line of defense against endemic pathogens. Understanding how this protective immunity develops in early life is essential to identify areas of vulnerability and design strategies to combat neonatal infections worldwide. This area of research however is underexplored. Several recent studies indicate that B cell immunity starts to develop during fetal life. For instance, cord blood IgM present in the cord blood originate exclusively from the fetus. Along the same line, IgG from fetal origin is also present in newborns blood although its exact concentration is masked by the abundance of maternal IgG. Overall, very little is known about the composition and repertoire of innate humoral immunity developed by the unborn child. The source of these natural antibodies in the fetus is also unclear. Liver and spleen are important sites of B cell ontogeny in utero but the differentiation of antibody-producing cells in these two organs during fetal life has not been reported. Our recent work revealed an alternate and rather unexpected source of natural antibodies in newborns. We uncovered that the human thymus at birth contains a significant contingent of antibody-producing PC. This subset is surprisingly heterogenous and includes clones producing all classes and subclasses of immunoglobulin with the exception of IgD. Furthermore, converging lines of evidence support the view that these PC differentiate intrathymically through a mechanism that remains to be fully elucidated. Remarkably, ~7% of neonatal PC reacted to at least 1 of 7 pathogenic and commensal bacteria tested. Neonatal thymic PC were also enriched in clones reactive to apoptotic cells, a hallmark of natural antibodies. Collectively, these findings exposed the human thymus as an unsuspected source of natural antibodies in human newborns. Investigating these thymic PC will therefore provide a rare opportunity to examine how innate humoral immunity develops in humans. Here, we further characterize the composition of neonatal thymic PC populations and more specifically identify predominant clones which were more likely to have contributed to innate serological immunity. Studies will also assess their reactivity profile toward bacteria as well as their protective capabilities. We anticipate these studies will shed new light on this essential component of natural immune defenses against infections in early life. Experiments will be carried out in two specific aims: Aim 1. To characterize Nabs produced by dominant neonatal thymic plasma cells Aim 2. To assess antibacterial activity of Nabs produced by neonatal thymic plasma cells

项目摘要 感染是全世界新生儿死亡的主要原因之一。血清免疫被认为是 是抵御地方病病原体最有效的第一道防线。了解这种保护性免疫力 对于确定脆弱领域和制定战略， 感染全球。然而，这一领域的研究还不够深入。最近的几项研究表明，B细胞 免疫力在胎儿时期就开始形成例如，脐带血中存在的脐带血IgM来源于 完全来自胎儿。沿着相同的路线，来自胎儿来源的IgG也存在于新生儿血液中，尽管 其确切浓度被母体IgG的丰度掩盖。总的来说，人们对它知之甚少。 未出生的孩子发展的先天性体液免疫的组成和全部功能。这些的来源 胎儿体内的天然抗体也不清楚。肝脏和脾脏是子宫内B细胞个体发育的重要部位， 在胎儿期这两个器官中抗体产生细胞的分化还没有报道。我们 最近的研究揭示了新生儿中天然抗体的另一种意想不到的来源。我们 发现人类出生时的胸腺含有大量产生抗体的PC。这 亚群是令人惊讶的异源性的，包括产生免疫球蛋白的所有类别和亚类的克隆 除了IgD。此外，汇聚的证据支持这样的观点，即这些PC区分 胸腺内通过一个机制，仍然是完全阐明。值得注意的是，约7%的新生儿PC 对7种致病菌和寄生菌中的至少1种有反应。新生儿胸腺PC也富含 对凋亡细胞有反应的克隆，这是天然抗体的标志。总的来说，这些发现揭示了 人类胸腺作为人类新生儿天然抗体的未知来源。研究这些胸腺 因此，PC将提供一个难得的机会来研究先天体液免疫在人类中是如何发展的。在这里， 我们进一步描述了新生儿胸腺PC群体的组成，并更具体地鉴定了 占优势的克隆，更有可能有助于先天性血清免疫。研究还将 评估它们对细菌的反应特性以及它们的保护能力。我们预计这些研究 将为这种在生命早期对抗感染的天然免疫防御的重要组成部分提供新的线索。 将在两个具体目标下进行实验： 目标1.鉴定优势新生儿胸腺浆细胞产生的Nab 目标2.评价新生儿胸腺浆细胞产生的Nabs的抗菌活性