Mucosal Immune Ontogeny and Intestinal Microbiota in Infants

描述(申请人提供)：大多数儿童的致命感染发生在粘膜部位，全世界每年有600多万人死于腹泻和肺炎(由申请人提供)，特别是在出生的第一年。婴儿主动粘膜免疫功能的发展，特别是T和B细胞库的多样性和表达，以及诱导它们的刺激因素还没有很好的定义。我们认为，儿童获得性抗体反应的发展是通过一系列和累积的肠道细菌微生物区系的渐进性刺激而产生的。这些数据将增强我们了解幼儿控制黏膜感染挑战的能力和能力，以及我们更有效地设计疫苗预防挑战的能力。由于新生儿的肠道是无菌的，出生后的几天和几周，其微生物生态发生了非凡的变化，随之而来的是新生儿免疫系统的发展2.母乳喂养限制了GI微生物区系的复杂性。定植细菌(如类杆菌和梭状芽孢杆菌)与免疫球蛋白基因的发展和多样性有关，免疫球蛋白基因决定了体液免疫谱系的多样性。抗原暴露与B细胞的进化、激活、功能选择以及从幼稚表型到记忆性表型的成熟有关。在B细胞中，免疫球蛋白基因，特别是重链(VH)的3个高变量互补决定区(CDR)，表现出最大的多样性，对抗原结合的贡献最大。我们将确定正常的生理免疫发育和正常的细菌微生物区系在个体发育中的作用之间的时间关系。因此，我们推测：1)从出生到2岁，婴儿固有层中T、B淋巴细胞和浆细胞的数量会增加。在浆细胞中，从产生IgM的优势细胞向产生IgA的优势细胞的转变将伴随着激活的T细胞的获得；2)T和B细胞记忆细胞的进化以及循环B细胞中免疫球蛋白基因高变区的体细胞高突变的频率和多样性将随着肠道细菌微生物区系的类型和复杂性而从出生到9月龄增加。 相关性：粘膜组织是大多数原发感染的来源。儿童特别容易受到粘膜感染。到目前为止，我们还不知道保护我们免受感染的免疫反应在儿童中是如何发展的。这项建议解决了这个问题。

DESCRIPTION (provided by applicant): The majority of fatal infections in children occur at mucosal sites, with over 6 million deaths from diarrhea and pneumonia yearly worldwide), particularly in the first year of life. The development of active mucosal immune competence in the infant, particularly the diversity and expression of the T and B cell repertoires, and the stimuli that elicit them are not well defined. We propose that the development of acquired antibody responses in children is derived from progressive stimulation by the serial and cumulative acquisition of intestinal bacterial microbiota. These data will enhance our capacity to understand the ability and the inability of young children to control mucosal infectious challenges and our ability to more effectively design vaccines to prevent them. Because the newborn intestine is sterile, the days and weeks following birth convey extraordinary transformation in its microbial ecology, and concomitantly, development of the neonatal immune system2,3. Breastfeeding limits the complexity of the GI microbiota. Colonizing bacteria (e.g., Bacteroides and Clostridium species) are implicated in driving the development and diversity of the immunoglobulin genes that determine the diversity of the humoral immune repertoire. Antigen exposure is associated with B cell evolution, with activation, selection by function and maturation from naive to memory phenotypes. In B cells, immunoglobulin genes, particularly the 3 hypervariable complementarity determining regions (CDR) of heavy chains (VH), show the greatest diversity and contribute most to antigen binding5. We will determine the temporal relationship between normal physiologic immune development and the role of normal bacterial microbiota in that ontogeny. Therefore, we hypothesize that: 1) The number of T and B lymphocytes and plasma cells will increase in number in the lamina propria of infants from birth to 2 years of age. Among plasma cells, the switch from a predominance of those producing IgM to IgA will accompany the acquisition of activated T cells, and 2) The evolution of T and B cell memory cells and the frequency and diversity of somatic hypermutation in the hypervariable regions of immunoglobulin genes in circulating B cells will increase from birth to 9 months of age in association with the types and complexity of bacterial microbiota in their intestine. RELEVANCE: Mucosal tissues are the source of most primary infections. Children are particularly susceptible to mucosal infections. We do not as yet know how the immune response, which protects us against infections, develops in children. This proposal addresses this issue.