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.

R21AI083615

2009-08-05

2011-07-31