Generation of antibody d i v e r s i t y

1. Generation of antibodydiversity

3. Genetic Model Compatible with Ig Structure • The vast diversity of antibody specificities • The presence in Ig heavy and light chains of a variable region at the amino-terminal end and a constant region at the carboxyl-terminal end • The existence of isotypes with the same antigenic specificity, which result from the association of a given variable region with different heavy-chain constant regions Germ-Line and Somatic-Variation Models Contended To Explain Antibody Diversity The germ-line theories maintained that the genome contributed by the germ cells, egg and sperm, contains a large repertoire of immunoglobulin genes; thus, these theories invoked no special genetic mechanisms to account for antibody diversity.

4. In contrast, the somatic-variation theories maintained that the genome contains a relatively small number of immunoglobulin genes, from which a large number of antibody specificities are generated in the somatic cells by mutation or recombination. Dreyer and Bennett Proposed the Two-Gene Model In an attempt to develop a genetic model consistent with the known findings about the structure of immunoglobulins,W. Dreyer and J. Bennett suggested, in their classic theoretical paper of 1965, that two separate genes encode a single immunoglobulin heavy or light chain, one gene for the V region (variable region) and the other for the C region (constant region). They suggested that these two genes must somehow come together at the DNA level to form a continuous message that can be transcribed and translated into a single Ig heavy or light chain.

5. Tonegawa’s Bombshell—Immunoglobulin Genes Rearrange In 1976, S. Tonegawa and N. Hozumi found the first direct evidence that separate genes encode the V and C regions of immunoglobulins and that the genes are rearranged in the course of B-cell differentiation. This work changed the field of immunology. In 1987, Tonegawa was awarded the Nobel Prize for this work.

6. Multigene Organization of Ig Genes Each Multigene Family Has Distinct Features The and light-chain families contain V, J, and C gene segments; the rearranged VJ segments encode the variable region of the light chains. The heavy-chain family contains V, D, J, and C gene segments; the rearranged VDJ gene segments encode the variable region of the heavy chain. In each gene family, C gene segments encode the constant regions. Each V gene segment is preceded at its 5 end by a small exon that encodes a short signal or leader (L) peptide that guides the heavy or light chain through the endoplasmic reticulum.

10. Ig-Gene Rearrangements May Be Productive or Nonproductive Allelic Exclusion Ensures a Single Antigenic Specificity

11. Generation of Antibody Diversity • To date, seven means of antibody diversification have been identified in mice and humans: • Multiple germ-line gene segments • Combinatorial V-(D)-J joining • Junctional flexibility • P-region nucleotide addition (P-addition) • N-region nucleotide addition (N-addition) • Somatic hypermutation • Combinatorial association of light and heavy chains

13. Class Switching among Constant-Region Genes

16. Synthesis, Assembly, and Secretion of Immunoglobulins

18. References 1.Immunology by Janis Kuby 2. Cell and molecular Immunology by Abbas and Litchman