GENETIC-REGULATION OF THE CAPACITY TO MAKE IMMUNOGLOBULIN-G TO PNEUMOCOCCAL CAPSULAR POLYSACCHARIDES

Background: Genetic regulation of immunoglobulin G(IgG) responses to p neumococcal capsular polysaccharides (PPS), has been demonstrated in m ice but not in humans. Earlier studies from this laboratory showed tha t healthy adults have a varying capacity to generate IgG antibody to P PS; this study sought to determine whether this capacity is geneticall y controlled. Methods: A 23-valent pneumococcal vaccine was administer ed to 72 unrelated White adults, 4 nuclear families, and 61 members of an extended Ashkenazic Jewish family. Selected individuals later rece ived one or more doses of the vaccine and/or a single dose of protein- conjugated PPS. Four to six weeks after each vaccination, IgG to PPS w as measured by ELISA. Immunoglobulin allotypes and HLA types were dete rmined by standard techniques. Results: After vaccination, 53% of the 72 unrelated White adults had measurable levels of IgG antibody to all of 10 PPS studied (high-level responders), 36% had IgG to 6-9 PPS, an d 11% had IgG to less than or equal to 5 of 10 PPS (low-level responde rs). Persons who did not make IgG to an individual PPS also failed to make IgM or IgA to that antigen. Low-level responders had reduced mean IgG levels to PPS to which they did make IgG; nevertheless, their tot al serum concentrations of IgG, IgG,, IgA, and IgM were normal, and ea ch made IgG, to at least one PPS, all indicating that a global defect in Ig production was not responsible. The responder status of offsprin g was highly associated with that of their parents. Segregation analys is of 61 Ashkenazic family members revealed that the capacity to gener ate anti-PPS IgG was inherited in a mixed, codominant fashion. Repeate d vaccination or administration of protein-conjugated PPS did not elic it measurable IgG in nonresponders. The HLA type was not associated wi th antibody responses. An association between IgG level and Gm(23)(+) allotype was observed in unrelated Whites but not in Ashkenazic Jews. Conclusions: Thus, humans exhibit a variable capacity to respond to PP S. This response is hereditable in a mixed, codominant fashion. The ab sence of IgG to a PPS, even after antigen is presented in a protein-co njugate form, may reflect a genetically mediated failure to recognize polysaccharide antigens. Since persons who respond to fewer PPS also h ave lower levels of IgG to PPS to which they do respond, genetically d etermined deficiencies in events that involve proliferation of committ ed B lymphocytes may also play a role.