The encapsulated bacteria, H. influenzae type b (Hib), pneumococci, and meningococci are important bacterial pathogens to certain high risk groups including malignancy, particularly splenectomy for staging of Hodgkin's disease, and acute leukemia, as well as children with asplenia, immunodeficiency or belonging to certain ethnic groups. Most of these underlying illnesses are associated with a defect in splenic function and/or defect in the production of antibody to polysaccharide. Purified polysaccharide vaccines result in inadequate antibody responses in the high risk children less than 18 months of age and immunocompromised patients. Thus regulation of the human response to polysaccharide is of particular importance. In mice, a late maturing B cell subset responsive to polysaccharides has been identified. We propose to focus of identifying the human analogue of the B cell subset. We will examine the activation of this B cell subset in response to polysaccharides as well as to characterize a new immunodeficiency associated with a defect in B cell activation and response. We also propose to examine the mechanism of allotype associated regulation of the antibody response to polysaccharides. We have previously shown that immunoglobulin (Ig) allotypes, are correlated with anti-polysaccharide antibody responses and risk of Hib infections in healthy Caucasians. We will extend these observations to determine if the association is mediated by B cells or T cells. Finally we will study the light chain restriction of the antibody response to polysaccharides and the relationship to ontogeny of the antibody response. We propose to examine which polysaccharides of encapsulated bacteria elicit a predominant kappa or lambda response. We will further document the slow maturation of kappa response as compared to lambda in humans. We propose to examine if slow maturation of kappa response is correlated with the occurrence of disease b a pathogen that elicits a kappa predominant response, Hib. In summary, we propose to focus on identifying the B cell subset responsive to polysaccharides, the regulation of antibody production associated with immunoglobulin allotypes expressed on the B cells and finally the regulation of the light chain those B cells display. Elucidation of regulatory mechanism may provide clues to new approaches for development of efficacious vaccines, the identification of risk factors for poor response and disease susceptibility.
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