The immune response to the natural hapten, phosphocholine (PC), is derived from three different VL which pair with a single VH. Extensive diversity is found in the expressed antibodies of each VH/VL pair and is due to usage of different DH, junctional diversity and somatic point mutations. We have recently found that different PC-containing microbes stimulate preferential expression of one or two of the three VH/VL gene pairs. The most dramatic occurs in the PC-specific response to Proteus morganii in which only a single idiotype is expressed. Analysis of anti-PC mRNA isolated from hybridomas reveals that the mature response is confined to a single VH/VL gene pair and diversity is dependent on somatic mutation. The most striking finding is that the response in individual mice seems to originate from as few as one precursor B lymphocyte. Our main goal is to use this example of an immune response to evaluate the somatic evolution of antibody diversity. Using hybridoma methodology and molecular biological technics, we propose to investigate the clonality of the anti-PC response to P. morganii in order to gain an understanding of the origins of clonal diversity; the time of commitment of B cell precursors and the influence of environment on acquisition of commitment; the impact of antigen and somatic mutation on selection and clonal expansion; and the nature of regulatory cells that might contribute to clonal expansion and clonal dominance. We expect that new and significant information will also be forthcoming about the nature of B cell memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI012533-15
Application #
3125217
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1978-04-01
Project End
1992-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
15
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Weber, J S; Berry, J; Manser, T et al. (1994) Mutations in Ig V(D)J genes are distributed asymmetrically and independently of the position of V(D)J. J Immunol 153:3594-602
George, J; Penner, S J; Weber, J et al. (1993) Influence of membrane Ig receptor density and affinity on B cell signaling by antigen. Implications for affinity maturation. J Immunol 151:5955-65
Kenny, J J; Moratz, C M; Guelde, G et al. (1992) Antigen binding and idiotype analysis of antibodies obtained after electroporation of heavy and light chain genes encoding phosphocholine-specific antibodies: a model for T15-idiotype dominance. J Exp Med 176:1637-43
Weber, J S; Berry, J; Litwin, S et al. (1991) Somatic hypermutation of the JC intron is markedly reduced in unrearranged kappa and H alleles and is unevenly distributed in rearranged alleles. J Immunol 146:3218-26
Weber, J S; Berry, J; Manser, T et al. (1991) Position of the rearranged V kappa and its 5' flanking sequences determines the location of somatic mutations in the J kappa locus. J Immunol 146:3652-5
Schultz, C; Petrini, J; Collins, J et al. (1990) Patterns and extent of isotype-specificity in the murine H chain switch DNA rearrangement. J Immunol 144:363-70
Claflin, J L; George, J; Dell, C et al. (1989) Patterns of mutations and selection in antibodies to the phosphocholine-specific determinant in Proteus morganii. J Immunol 143:3054-63
Dell, C L; Lu, Y X; Claflin, J L (1989) Molecular analysis of clonal stability and longevity in B cell memory. J Immunol 143:3364-70
Claflin, J L; Berry, J (1988) Genetics of the phosphocholine-specific antibody response to Streptococcus pneumoniae. Germ-line but not mutated T15 antibodies are dominantly selected. J Immunol 141:4012-9
Claflin, J L; Berry, J; Flaherty, D et al. (1987) Somatic evolution of diversity among anti-phosphocholine antibodies induced with Proteus morganii. J Immunol 138:3060-8

Showing the most recent 10 out of 11 publications