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Immunoglobulin Class Switching
Kathryn Kronquist, Ph.D. & Ronald A. Blum, Ph.D.
The nine classes or serological isotypes of human immunoglobulins are defined according to the sequence of their heavy chain constant region, which are encoded by one of nine individual constant-region genes (CH) clustered in tandem on human chromosome 14 in the following order: 5'-Cm, Cd, Cg3, Cg1, Ca1, Ca2, Cg4, Ce, Ca2-3'. Fusion of a functional variable region exon (VHDJH) with one of the m, d, g, a, or e CH genes leads to the production of heavy chain mRNA for IgM, IgD, IgG, IgA or IgE, respectively.1
In B-cell ontogeny, a functional VHDJH gene is first expressed with the constant region Cm and/or Cd gene. The Cm and Cd genes are adjacent to one another and are both frequently incorporated into a single primary transcript that is differentially spliced to produce mu and delta chain mRNAs.2 Translation of these messages leads to surface co-expression of IgM and IgD molecules with identical variable-region sequences on B cells.
Isotype or class switching is the process by which an IgM and/or D-expressing B-cell is activated to undergo a somatic rearrangement that associates a V/D/J exon originally linked to Cm/Cd with another CH constant-region sequence.3,4 Recombination sites containing repetitive sequences for this rearrangement (S-regions) are located at the 5' side of each CH gene except for the Cd gene.5 The class switch, which occurs through a mechanism involving looping out and deletion of intervening CH genes, results in a cell producing IgE or a subclass of IgG or IgA. The class switch process is important in humoral immune responses because it allows the effector function of an immunoglobulin to be changed without altering antigenic specificity.
Control of switch recombination is directed by B-cell interactions with T cells and soluble T-cell factors.6 The cytokine transforming growth factor b stimulates B cells to produce IgA.7 IL-4 and IL-13 induce human B cells to switch to IgG4 and IgE synthesis.8 In addition to cytokines, contact-mediated signals delivered by activated CD4+ T helper cells can also result in isotype switching, as in the interaction between the T-cell-expressed CD40-ligand protein and the B-cell surface protein CD40.9 Tracy et al., report that the selection of antibody class could be regulated by RNA-DNA hybrids that choose the sites of recombination.10,11
Some hereditary or acquired immunodeficiency disorders can result from defective immunoglobulin gene switching processes. X-linked hyper-IgM syndrome, for example, is characterized by elevated IgM concentrations and decreased concentrations of all other immunoglobulin isotypes. Point mutations or deletions in the CD40L gene which result in CD40L proteins that are incapable of binding to CD4012 are identified in a group of patients with this disorder.
IgA deficiency is a common immune defect not consistently linked to clinical illness but thought to confer increased susceptibility to certain types of infectious disease. Rare IgA-deficient individuals with chromosome 14 deletions involving portions of the Ig heavy chain locus are described but the disorder is more frequently linked to deletions in chromosome 18 (within both the long and short arms) and to chromosome 6, where uncharacterized genes that influence class switching or IgA secretion may reside.13 A study examining the severity of respiratory infections in a group of IgA deficient individuals found that the most infection-susceptible group did not demonstrate lowest levels of IgA. Rather, susceptibility was related to decreased serum IgG4 and IgG2 concentrations and non-protective concentrations of serum antibodies to one or more pneumococcal polysaccharides. The association of IgA deficiency with reduced concentrations of other immunoglobulin isotypes suggests a possible class switching defect or a disorder of the antibody affinity maturation process.14
REFERENCES
- Flanagan JG and Rabbits TH. Arrangement of human immunoglobulin heavy chain constant region genes implies evolutionary duplication of a segment containing g, e and a genes. Nature 1982;300:709-13.
- Knapp MR, Liu C-P, Newell N, et al. Simultaneous expression of immunoglobulin
m and d chains by a cloned B-cell lymphoma: a single copy of the VH gene is shared by two adjacent CH genes. Proc Natl Acad Sci USA 1982;79:2996-3000. - Esser C, Radbruch A. Immunoglobulin class switching: molecular and cellular analysis. Annu Rev Immunol 1990;8:717-35.
- Snapper CM, Mond JJ. Towards a comprehensive view of immunoglobulin class switching. Immunol Today 1993;14:15-7.
- Kataoka T, Miyata T, Honjo T. Repetitive sequences in class-switch recombination regions of immunoglobulin heavy chain genes. Cell 1981;23;357-68.
- Schultz CL and Coffman RL. Control of isotype switching by T-cells and cytokines. Curr Op Immunol 1991;3:350-4.
- Van Vlasselaer P, Punnonen J, de Vries JE. Transforming growth factor
b directs IgA switching in human B cells. J Immunol 1992;148:2062. - Punnonen J, Aversa G, Cocks BG, et al. Interleukin-13 induces interleukin-4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci USA 1993;90:3730-3.
- Aversa G, Punnonen J, Carballido JM, Cocks BG, de Vries JE. CD40 ligand-CD40 interaction in Ig isotype switching in mature and immature human B cells. Semin Immunol 1994;6:295-301.
- Tracy R, Hsieh C-L, Lieber M. Stable RNA/DNA hybrids in the mammalian genome: inducible intermediates in immunoglobulin class switch recombination. Science 2000;288:1058-61.
- Stavnezer J. A Touch of antibody class. Science 2000;288:984-5.
- Allen RC, Armitage, RJ, Conley ME, et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 1933;259:990-3.
- Cunningham-Ruddles C. Genetic aspects of immunoglobulin A deficiency. Adv Hum Genet 1990;19:235-66.
- French MAH, Dawkins DR, Peter JB. Severity of infections in IgA deficiency: correlation with decreased serum antibodies to pneumococcal polysaccharides and decreased serum IgG2 and/or IgG4. Clin Exp Immunol 1995;100:47-53.
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