- Francisco A Bonilla, MD, PhD
Francisco A Bonilla, MD, PhD
- Section Editor — Immunology and Immunodeficiency
- Associate Professor of Pediatrics
- Harvard Medical School
The genetics of immunoglobulin (Ig) during both B cell development in the bone marrow and the induction of the humoral immune response are presented here. Discussions concerning B cell development and the humoral immune response are reviewed separately (see "Normal B and T lymphocyte development" and "The humoral immune response"). A website devoted to immunoglobulin genetics is available .
IMMUNOGLOBULIN GENE ORGANIZATION
There are several classes of immunoglobulin (Ig) that are categorized by a unique heavy chain structure: IgG, IgM, IgA, IgD, and IgE. There are also subclasses of IgG (IgG1 to 4) and of IgA (IgA1,2) (see "Structure of immunoglobulins"). In addition, there are two different types of antibody light chains, kappa and lambda. Ig heavy chains and each type of light chain are encoded by genes in different loci. The table shows the locations of these gene complexes on human chromosomes (table 1).
Genes capable of encoding a complete antibody heavy or light chain do not exist, as such, within the DNA of most cells. The complete genes are assembled by the union of separate gene segments. These segments are widely separated in germ cells and in all somatic cells, except for B lymphocytes. Within B cells, these genes rearrange their relative positions to create a "mature" Ig gene that can encode a functional protein. This rearrangement process is the core of the immune system's ability to generate antibodies capable of recognizing the tremendous variety of antigenic structures in nature.
An Ig light chain gene is assembled from three types of gene segments. These are the light chain variable region (VL), joining region (JL), and constant region (CL) gene segments (figure 1). Similarly, heavy chain gene segments are VH, JH and CH, and another type of gene segment called D (diversity) (figure 2).
The nomenclature of the gene segments derives from names assigned to portions of antibody heavy or light chains based upon an analysis of their amino acid sequences (see "Structure of immunoglobulins"). Thus, the variable region shows great variation from one antibody chain to another. The constant region, as its name implies, is invariant within an Ig class or subclass. The joining and diversity regions were the names given to areas between V and C, each having its own characteristic sequence pattern. The variable regions of the heavy and light chains together form the antibody combining site. This is the portion of the Ig molecule that makes contact with antigen. (See "Function and clinical applications of immunoglobulins".)
- The International Immunogenetics Information System www.imgt.org (Accessed on October 27, 2010).
- Barbié V, Lefranc MP. The human immunoglobulin kappa variable (IGKV) genes and joining (IGKJ) segments. Exp Clin Immunogenet 1998; 15:171.
- Pallarès N, Frippiat JP, Giudicelli V, Lefranc MP. The human immunoglobulin lambda variable (IGLV) genes and joining (IGLJ) segments. Exp Clin Immunogenet 1998; 15:8.
- Matsuda F, Ishii K, Bourvagnet P, et al. The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus. J Exp Med 1998; 188:2151.
- Nagaoka H, Ozawa K, Matsuda F, et al. Recent translocation of variable and diversity segments of the human immunoglobulin heavy chain from chromosome 14 to chromosomes 15 and 16. Genomics 1994; 22:189.
- Weichhold GM, Lautner-Rieske A, Zachau HG. Human immunoglobulin genes of the kappa type. The long-range map of an orphon V kappa gene region. Biol Chem Hoppe Seyler 1992; 373:1159.
- Cobb RM, Oestreich KJ, Osipovich OA, Oltz EM. Accessibility control of V(D)J recombination. Adv Immunol 2006; 91:45.
- Azulay-Debby H, Melamed D. B cell receptor editing in tolerance and autoimmunity. Front Biosci 2007; 12:2136.
- van Zelm MC, Szczepanski T, van der Burg M, van Dongen JJ. Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion. J Exp Med 2007; 204:645.
- Kamae C, Nakagawa N, Sato H, et al. Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin κ-deleting recombination excision circles. J Allergy Clin Immunol 2013; 131:1437.
- Nakagawa N, Imai K, Kanegane H, et al. Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects. J Allergy Clin Immunol 2011; 128:223.
- Serana F, Chiarini M, Zanotti C, et al. Use of V(D)J recombination excision circles to identify T- and B-cell defects and to monitor the treatment in primary and acquired immunodeficiencies. J Transl Med 2013; 11:119.
- Maizels N. Immunoglobulin gene diversification. Annu Rev Genet 2005; 39:23.
- Rao SP, Riggs JM, Friedman DF, et al. Biased VH gene usage in early lineage human B cells: evidence for preferential Ig gene rearrangement in the absence of selection. J Immunol 1999; 163:2732.
- Grey HM, Mannik M. Specificity of recombination of H and L chains from human gamma-G-myeloma proteins. J Exp Med 1965; 122:619.
- William J, Euler C, Christensen S, Shlomchik MJ. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 2002; 297:2066.
- Rajewsky K. Clonal selection and learning in the antibody system. Nature 1996; 381:751.
- Cedar H, Bergman Y. Choreography of Ig allelic exclusion. Curr Opin Immunol 2008; 20:308.
- Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol 2008; 26:261.
- Borghesi L, Milcarek C. From B cell to plasma cell: regulation of V(D)J recombination and antibody secretion. Immunol Res 2006; 36:27.
- IMMUNOGLOBULIN GENE ORGANIZATION
- IMMUNOGLOBULIN GENE REARRANGEMENT
- ANTIBODY DIVERSITY
- Germline-encoded diversity
- Rearrangement diversity
- Nongermline encoded nucleotides
- Combinatorial diversity
- Somatic mutation
- Gene fusion
- Gene replacements
- ALLELIC EXCLUSION
- IMMUNOGLOBULIN CLASS-SWITCHING
- MEMBRANE VERSUS SECRETED IMMUNOGLOBULIN
- CLONAL DISTRIBUTION OF B CELLS