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。血清学免疫被认为是 针对流行病原体的最有效的第一道防线。了解这种保护性免疫 早期发展对于确定脆弱性和设计策略以对抗新生儿至关重要 全球感染。然而，这一研究领域尚未得到充实。最近的一些研究表明B细胞 在胎儿生活中，免疫力开始发展。例如，脐带血中存在的脐带血IgM起源 仅来自胎儿。沿着同一条线，胎儿起源的IgG也存在于新生儿血液中 它的精确浓度被丰富的母体IgG掩盖。总体而言，关于 未出生的孩子开发的先天体液免疫的组成和曲目。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部位，但 尚未报道这两个器官在胎儿寿命期间的抗体产生细胞的分化。我们的 最近的工作表明，新生儿中天然抗体的另一种替代来源。我们 发现人的胸腺出生时包含产生抗体的PC的重要组成部分。这 子集令人惊讶地异源，包括产生所有类和子类的克隆 除了IGD。此外，融合的证据线支持这些PC分化的观点 胸前通过尚待完全阐​​明的机制。值得注意的是，新生儿PC的7％ 对测试的7种致病和共生细菌中的至少1个反应。新生儿胸腺也富含 克隆对凋亡细胞的反应，这是天然抗体的标志。总的来说，这些发现暴露了 人胸腺是人类新生儿中自然抗体的一种未受关注的来源。研究这些胸腺 因此，PC将提供一个难得的机会来检查人类先天的幽默免疫力。这里， 我们进一步表征了新生儿胸腺PC种群的组成，并更具体地识别 主要的克隆更有可能导致先天血清学免疫。研究也将 评估其对细菌的反应性概况及其保护能力。我们预计这些研究 威尔对早期感染的天然免疫防御措施的这一重要组成部分进行了新的启示。 实验将以两个具体的目的进行： 目的1。表征由主要的新生儿胸腺浆细胞产生的NABS 目标2。评估新生儿胸腺血浆细胞产生的NAB的抗菌活性