Organization and Expression of Immunoglobulin Genes
One of the most remarkable features of the vertebrate immune system is its ability to respond to an apparently limitless array of foreign antigens. As immunoglobulin (Ig) sequence data accumulated, virtually every antibody molecule studied was found to contain a unique amino acid sequence in its variable region but only one of a limited number of invariant sequences in its constant region. The genetic basis for this combination of constancy and tremendous variation in a single protein molecule lies in the organization of the im-munoglobulin genes.
In germ-line DNA, multiple gene segments encode portions of a single immunoglobulin heavy or light chain. These gene segments are carried in the germ cells but cannot be transcribed and translated into complete chains until they are rearranged into functional genes. During B-cell maturation in the bone marrow, certain of these gene segments are randomly shuffled by a dynamic genetic system capable of generating more than 106 combinations. Subsequent processes increase the diversity of the repertoire of antibody binding sites to a very large number that exceeds 106 by at least two or three orders of magnitude. The processes of B-cell development are carefully regulated: the maturation of a progenitor B cell progresses through an ordered sequence of Ig-gene rearrangements, coupled with modifications to the gene that contribute to the diversity of the final product. By the end of this process, a mature, immunocompetent B cell will contain coding sequences for one functional heavy-chain variable-region and one light-chain variable-region. The individual B cell is thus antigenically committed to a specific epitope. After antigenic stimulation of a mature B cell in peripheral lymphoid organs, further rearrangement of constant-region gene segments can generate changes in the isotype expressed, which produce changes in the biological effector functions of the immunoglobulin molecule without changing its specificity. Thus, mature B cells contain chromosomal DNA that is no longer identical to germ-line l vk jk jk ck l vk jk jk ck
Kappa Light-Chain Gene Rearrangement
■ Genetic Model Compatible with Ig Structure
■ Multigene Organization of Ig Genes
■ Variable-Region Gene Rearrangements
■ Mechanism of Variable-Region DNA Rearrangements
■ Generation of Antibody Diversity
■ Class Switching among Constant-Region Genes
■ Expression of Ig Genes
■ Synthesis, Assembly, and Secretion of Immunoglobulins
■ Regulation of Ig-Gene Transcription
■ Antibody Genes and Antibody Engineering
DNA. While we think of genomic DNA as a stable genetic blueprint, the lymphocyte cell lineage does not retain an intact copy of this blueprint. Genomic rearrangement is an essential feature of lymphocyte differentiation, and no other vertebrate cell type has been shown to undergo this process.
This chapter first describes the detailed organization of the immunoglobulin genes, the process of Ig-gene rearrangement, and the mechanisms by which the dynamic im-munoglobulin genetic system generates more than 108 different antigenic specificities. Then it describes the mechanism of class switching, the role of differential RNA processing in the expression of immunoglobulin genes, and the regulation of Ig-gene transcription. The chapter concludes with the application of our knowledge of the molecular
— Hematopoietic stem cell
Lymphoid cell None
Partial heavy-chain gene rearrangement Pro-B cell (Q) None
Complete heavy-chain gene rearrangement
Light-chain gene rearrangement
Immature B cell ^^^ Change in RNA processing
¡= Mature B cell ^Z^^ Antigen stimulation
Activated B cell
Heavy chain + surrogate light chain mIgM
mIgM + mIgD
^—> IgM-secreting plasma cells Class switching
OT Ot^ OIP Ot^ Plasma cells secreting various Memory I I I isotypes
B cells of various y y y isotypes IgG IgA IgE
Overview of B-cell development. The events that ripheral lymphoid organs require antigen. The labels mIgM and occur during maturation in the bone marrow do not require anti- mIgD refer to membrane-associated Igs. IgG, IgA, and IgE are segen, whereas activation and differentiation of mature B cells in pe- creted immunoglobulins.
biology of immunoglobulin genes to the engineering of antibody molecules for therapeutic and research applications. Chapter 11 covers in detail the entire process of B-cell development from the first gene rearrangements in progenitor B cells to final differentiation into memory B cells and antibody-secreting plasma cells. Figure 5-1 outlines the sequential stages in B-cell development, many of which result from critical rearrangements.
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