Mucosal Immune Ontogeny and Intestinal Microbiota in Infants

描述（由申请人提供）：大多数儿童致命感染发生在粘膜部位，全球每年有超过600万人死于腹泻和肺炎)，特别是在生命的第一年。婴儿主动粘膜免疫能力的发展，特别是T细胞和B细胞的多样性和表达，以及引发它们的刺激还没有很好的定义。我们提出，儿童获得性抗体反应的发展源于肠道细菌微生物群的连续和累积获得的进行性刺激。这些数据将增强我们了解幼儿控制粘膜感染挑战的能力和无能的能力，以及我们更有效地设计疫苗以预防它们的能力。由于新生儿肠道是无菌的，出生后的几天和几周内，其微生物生态发生了非凡的变化，新生儿免疫系统也随之发育2,3。母乳喂养限制了胃肠道微生物群的复杂性。定殖细菌（如拟杆菌和梭状芽胞杆菌）与驱动免疫球蛋白基因的发育和多样性有关，而免疫球蛋白基因决定了体液免疫库的多样性。抗原暴露与B细胞的进化、激活、功能选择和从幼稚表型到记忆表型的成熟有关。在B细胞中，免疫球蛋白基因，特别是重链（VH）的3高变互补决定区（CDR），表现出最大的多样性，对抗原结合的贡献最大5。我们将确定正常生理免疫发育与正常细菌微生物群在个体发育中的作用之间的时间关系。因此，我们假设：1)从出生到2岁，婴儿固有层中T淋巴细胞、B淋巴细胞和浆细胞的数量会增加。在浆细胞中，从产生IgM的优势向产生IgA的优势转变将伴随着活化T细胞的获得。2)从出生到9个月大，循环B细胞中T细胞和B细胞记忆细胞的进化以及免疫球蛋白基因高变区体细胞超突变的频率和多样性将增加，这与肠道细菌微生物群的类型和复杂性有关。

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.