Fetalneonatal B cells exhibit a restricted antibody repertoire

It has been shown that the fetal/neonatal repertoire of available antibody specificities is restricted. The development of antibody specificities during ontogeny proceeds in a temporally dependent and programmed manner. BALB/c mice possess B cells capable of responding to the hapten dinitrophenyl and to the carbohydrate antigen (32,6-fructosan by day 1 after birth; however, reproducibly, those B cells bearing the T15 idiotype and responsive to the antigen phosphorylcholine are only apparent at ~1 week after birth. As a consequence of this pattern of antibody repertoire acquisition, the developing neonate has a more limited spectrum of available B cell specificities which diversifies in a predictable fashion.

Studies in both human and mouse indicate that fetal and neonatal pre-B and B cells exhibit biased recombination and expression of those immunoglobulin heavy-chain variable region (Vn) gene families located most proximal to the DH and JH gene segment loci. Early in ontogeny, the enzyme terminal deoxynucleotidyl transferase (TdT) is limited. Lack of TdT, by restricting junctional diversity, also contributes to decreased Ig repertoire complexity. Although the decreased diversity present in the emerging B cell repertoire could contribute to the failure to respond to particular antigens as discussed above, this need not be the case. For example, as discussed by Schroeder and colleagues, the V3-23 immunoglobulin heavy-chain variable region gene in humans is a major contributor to the fetal repertoire and yet encodes specificities to antigens some of which (e.g. polysaccharides) are not responded against until ~2 years of age. This suggests that the more limited capacity to respond to the spectrum of antigens early in ontogeny and the programmed readout of the functional immune repertoire is due to complex mechanisms of which V,, gene usage is only one component.

The composition of B cells within the developing neonate may also contribute to constraints on immune function. B cells are divisible into subpopul-ations based on the expression of surface antigens. In both human and mouse, a subset of B cells (B1 cells), many of which express the CD5 surface antigen, is more prominent early in ontogeny. It has been shown that the CD5 B cells represent a separate B cell lineage with precursors distinct from those which yield the conventional (CD5 ) B2 cell population which dominates the peripheral B cell compartment in the adult. Notably, precursors of CD5 B cells are present early in fetal/neonatal life, but are not derived from adult bone marrow. In both human and mouse, CD5 B cells may be biased toward recognition of self and environmental antigens and also exhibit degenerate specificity. Differences in the composition of the B cell compartment between neonates and adults may also contribute to differences in their humoral immune capabilities.

Antibodies generated from murine neonatal spleen demonstrate an unusual capacity for recognizing idiotypic determinants on each other ('connectivity'). The neonatal antibody repertoire, although restricted in diversity, is skewed toward reactivity with self molecules, including idiotypic determinants present on immunoglobulins. This has led to the hypothesis that neonatal B cell responses may be of importance in establishing an immune network.

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