This study is designed to assess the subclass distribution and clonal diversity of antibodies to group A streptococcal carbohydrate (GAC), phosphocholine (PC) and H. influenzae type b capsular polysaccharide (PRP) in normal children, and in children with (IgG2) deficiency, asplenia, and sickle cell anemia. Studies in mice have shown that anti-polysaccharide (anti-PS) anitbodies are restricted to a particular subclass, IgG3. Normal infant mice, and a strain of immunodeficient mice, CBA/N, lack the ability to secrete antibodies of this subclass, and are susceptible to infections caused by PS encapsulated organisms. Similarly, many human anti-PS antibodies are restricted to a subclass IgG2 which is late to develop in normal children. Further, deficiencies of IgG2 have been recognized in children and adults with recurrent bacterial infections. We propose that the increased susceptibility of normal children and certain groups of patients, including those with asplenia and SS, to infections caused by PS encapsulated bacteria is due, at least in part, to IgG2 deficiency. Studies outlined in this proposal will examine the relation of IgG2 to the magnitude and clonal diversity of anti-PS antibodies in these subjects. In addition, factors responsible for increasing diversity and changes in clonal dominance observed by isolectric focusing of human anti-GAC antibodies will be analyzed. Specifically, the contributions of subclasses, light chains and idiotype expression will be examined. Finally, human hybridoma antibodies specific for GAC and PC will be produced. These will be used to study the functional capacity of various subclasses and to develop anti-idiotype reagents. The latter will serve as probes to examine the relation of particular V regions to IEF clonotype patterns, and to determine, in young children, the relation between antibody secretion and V region expression on B cell surfaces.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI019350-04
Application #
3128719
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1982-09-01
Project End
1988-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Granoff, D M; Shackelford, P G; Holmes, S J et al. (1993) Variable region expression in the antibody responses of infants vaccinated with Haemophilus influenzae type b polysaccharide-protein conjugates. Description of a new lambda light chain-associated idiotype and the relation between idiotype expression, avid J Clin Invest 91:788-96
Adderson, E E; Azmi, F H; Wilson, P M et al. (1993) The human VH3b gene subfamily is highly polymorphic. J Immunol 151:800-9
Adderson, E E; Shackelford, P G; Insel, R A et al. (1992) Immunoglobulin light chain variable region gene sequences for human antibodies to Haemophilus influenzae type b capsular polysaccharide are dominated by a limited number of V kappa and V lambda segments and VJ combinations. J Clin Invest 89:729-38
Adderson, E E; Shackelford, P G; Quinn, A et al. (1991) Restricted Ig H chain V gene usage in the human antibody response to Haemophilus influenzae type b capsular polysaccharide. J Immunol 147:1667-74
Shackelford, P G; Granoff, D M; Madassery, J V et al. (1990) Clinical and immunologic characteristics of healthy children with subnormal serum concentrations of IgG2. Pediatr Res 27:16-21
Granoff, D M; Suarez, B K; Pandey, J P et al. (1988) Genes associated with the G2m(23) immunoglobulin allotype regulate the IgG subclass responses to Haemophilus influenzae type b polysaccharide vaccine. J Infect Dis 157:1142-9
Shackelford, P G; Granoff, D M (1988) IgG subclass composition of the antibody response of healthy adults, and normal or IgG2-deficient children to immunization with H. influenzae type b polysaccharide vaccine or Hib PS-protein conjugate vaccines. Monogr Allergy 23:269-81
Gresham, H D; McGarr, J A; Shackelford, P G et al. (1988) Studies on the molecular mechanisms of human Fc receptor-mediated phagocytosis. Amplification of ingestion is dependent on the generation of reactive oxygen metabolites and is deficient in polymorphonuclear leukocytes from patients with chronic granulomat J Clin Invest 82:1192-201

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