Mutans streptococci (MS) are considered to be major etiological agents in caries development. In spite of the opportunities for contact with other members of the population, there is a high correlation between the genotype of S. mutans strains that colonize the infant with those present in the mother. We hypothesize that both genetic factors and maternal imprinting of the immune response may contribute to the development of immunologic tolerance for different S. mutans strains. It is likely that this tolerance is accompanied, in part, by a shaping of the IgA and IgG antibody repertoires, the isotypes most common in the mouth. The human antibody repertoire is developmentally controlled, individuals reaching adult serum levels of IgG and IgA by age 6 and 12, respectively. We have previously shown that early fetal B cell populations preferentially utilize a small subset of H chain gene segments, and further restrict the potential diversity of the CDR3 region of the H chain variable domain by limiting the extent of N region addition. By the time of birth, these restrictions are not longer apparent in immunoglobulin mu transcripts. However, our preliminary data suggests that gamma H chain transcripts continue to show a fetal pattern of CDR3 diversity, whereas the alpha transcript pattern appears more mature. While the endogenous repertoire is restricted, transmission of IgG across the placental barrier and IgA in breast milk transfers a portion of the maternal repertoire directly to the infant. We propose that placental transfer of maternal IgG is a proximate cause of the delay in the maturation of the IgG repertoire, and this maternally derived repertoire contributes, in part, to the maternal inheritance of tolerance to the oral biota. We also propose that this process is influenced by genes within the major histocompatibility complex (MHC) on chromosome 6. In order to test this hypothesis, we will: 1) analyze globally the development of natural antibodies in the serum and secretions of pre-term where possible and term neonates through childhood and their mothers. 2) use a PCR based assay to establish the ontogeny of IgG and IgA CDR3 diversity in the same populations. 3) molecularly type our study cohort for alleles within the MHC DR, DQ and DP loci. Our study cohort will be focused on the Birmingham African- American population in order to reduce the confounding complexity of ethnic variation. In particular, we will study the relationship between the development of natural antibodies, the ontogeny of CDR3 diversity, and the MHC in relation to antibody reactivity towards auto-antigens and to the bacterial components of interest which colonize the oral cavity at discrete windows during development. These studies will also correlate the infection history of the mother and child, the bacterial colonization of the oral cavity, the development of the antibody response in the saliva and other mucous membrane, and the onset of dental caries as assessed by Projects 1, 2 and 3. This comprehensive examination of the normal development of systemic immunity is likely to yield fundamental knowledge of significance for the study of susceptibility to infectious diseases in general, autoimmunity, and the ability to respond to vaccines.
Showing the most recent 10 out of 21 publications
