Antibody Diversity

Citation

Schilling, James Walter, Jr. (1981) Antibody Diversity. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/npny-et15. https://resolver.caltech.edu/CaltechTHESIS:03292017-102353875

Abstract

Vertebrate organisms possess a large and diverse repertoire of antibody variable regions. A number of different genetic mechanisms have been proposed to account for immunoglobulin variable (V) region diversity, including multiple germline genes, somatic mutation, somatic recombination, and multiple small gene segments which are joined to form a complete variable region gene segment. Analyses of variable region amino acid sequences demonstrate the relative contribution of each of these mechanisms to antibody diversity.

Twenty-four V_K21 chains have been examined. They suggest that the kappa chain variable region is encoded in two separate gene segments: V_K and J_K which are rearranged and joined during B cell differentiation. Diversification of the N terminus of the J_K segment occurs as a consequence of V_K-J_K joining and has been explained by a site-specific recombination model. The amino acid sequence data are consistent with the existence of a minimum of six V_K and five J_K germline gene segments. Possible cases of somatic mutation are also observed. These conclusions are supported by nucleic acid sequence analyses performed by others.

Complete variable region amino acid sequences have been determined for twenty-one heavy chains from dextran binding antibodies. These sequences suggest that the heavy chain variable region is encoded by three gene segments: V_H, D, and J_H. Nucleic acid sequence analyses are consistent with this conclusion. The existence of a minimum of two V_H and four J_H germline gene segments is suggested by these sequences. Possible examples of somatic mutation of V_H and J_H gene segments have also been found. Diversification of the N-terminal residue of the J_H segment may occur as a consequence of D-J_H joining by a mechanism analogous to that observed in kappa chains. Although comprised of only two residues, the D segment is the most diverse portion of dextran binding heavy chains.

Combinatorial joining of V_K and J_K gene segments and V_H, D, and J_H gene segments contributes significantly to antibody diversity.

Precise molecular locations of idiotypic determinants can be established in the dextran heavy chains. A cross-reactive idiotypic determinant (IdX) is located in the second hypervariable region of the V_H segment. Individual idiotypic determinants (IdIs) correspond to particular D segments.

Thesis Files