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

项目概要 感染是全球新生儿死亡的主要原因之一。血清学免疫被认为是 对抗地方性病原体最有效的第一道防线。了解这种保护性免疫力是如何产生的 生命早期发展对于确定脆弱领域和设计应对新生儿的战略至关重要 世界范围内的感染。然而，这一研究领域尚未得到充分探索。最近的几项研究表明 B 细胞 免疫力在胎儿时期就开始发展。例如，脐带血中存在的脐带血 IgM 源自 完全来自胎儿。同样，新生儿血液中也存在来自胎儿的 IgG，尽管 它的确切浓度被母体 IgG 的丰度所掩盖。总体而言，人们对它知之甚少 未出生的孩子发育的先天体液免疫的组成和全部。这些的来源 胎儿中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场所，但 胎儿时期这两个器官中产生抗体的细胞的分化尚未见报道。我们的 最近的工作揭示了新生儿天然抗体的另一种且相当意想不到的来源。我们 发现人类出生时的胸腺含有大量产生抗体的 PC。这 子集具有令人惊讶的异质性，包括产生免疫球蛋白所有类别和亚类的克隆 IgD 除外。此外，汇聚的证据支持这样的观点：这些电脑区分 胸腺内通过一种仍有待充分阐明的机制。值得注意的是，约 7% 的新生儿 PC 对所测试的 7 种致病菌和共生菌中的至少 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，这些发现暴露了 人类胸腺是人类新生儿天然抗体的一个未被怀疑的来源。研究这些胸腺 因此，PC 将为研究人类先天体液免疫如何发展提供难得的机会。这里， 我们进一步表征了新生儿胸腺 PC 群体的组成，并更具体地确定了 主要克隆更有可能有助于先天血清学免疫。研究还将 评估它们对细菌的反应特性及其保护能力。我们预计这些研究 将对生命早期感染的自然免疫防御的这一重要组成部分提供新的认识。 实验将针对两个具体目标进行： 目标 1. 鉴定新生儿显性胸腺浆细胞产生的 Nab 的特征 目标 2. 评估新生儿胸腺浆细胞产生的 Nab 的抗菌活性