Isotype Switching

The genes for Ig and TcR protein chains are located on different chromosomes. The genes for k chains are 

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Class (Isotype) Switching Occurs During Immune Responses... 

IMMUNODEFICIENCY WITH HYPER-IGM (HIGMl), AN IMMUNOGLOBULIN ISOTYPE SWITCH DEFECT CHARACTERIZED BY ELEVATED CONCENTRATIONS OF SERUM IGM AND DECREASED AMOUNTS OF ALL OTHER ISOTYPES. AFFECTED MALES PRESENT AT AN EARLY AGE (USUALLY WITHIN THE FIRST YEAR OF LIFE) RECURRENT BACTERIAL AND OPPORTUNISTIC INFECTIONS, INCLUDING PNEUMOCYSTIS CARINII PNEUMONIA AND INTRACTABLE DIARRHEA DUE TO CRYPTOSPORIDIUM INFECTION. DESPITE SUBSTITUTION TREATMENT WITH INTRAVENOUS IMMUNOGLOBULIN, THE OVERALL PROGNOSIS IS RATHER POOR, WITH A DEATH RATE OF ABOUT 10% BEFORE ADOLESCENCE. 

Antibody isotypes can change upon B-cell activation. Upon maturity, both IgM and IgD become expressed as membrane-bound forms on the B cell surface. Activation results in the production of antibody in secreted forms. Isotype switching takes place with some daughter cells to pro-... 

CD4+ ] Provides help to b cells, including TFI2 ) Ig isotype switching... 

CD40 48 monomer B lineage cells, follicular dendritic cells, endothelial cells, macrophages B-ceh growth, differentiation, isotype switching. Induction of cytokine release and adhesion molecules... 

IL-4 TH2 cells, mast cells, NK cells B cells, T cells, mast cells, macrophages Proliferation, isotype switching, induction of MHC class II expression... 

IFN-y THi,Tc, NK Various cells including macrophages Inhibitor of viral replication. Inhibitor of cell proliferation. Inhibitor of IL-4-induced isotype switching... 

Durdik, J., Gerstein, R.M., Rath, S., Robbins, P.F., Nisonoff, A., Seising, E. (1989). Isotype switching by a microinjected p immunoglobulin heavy chain gene in transgenic mice. Proc. Natl. Acad. Sci. USA 86,2346-2350. 

Kipps, T.J. Herzenberg, L.A. (1986). Homologous chromosome recombination generating immunoglobulin allotype and isotype switch variants. EMBO J. 5, 263-268. 

Liu, Y.J., Malisan, F., de Bouteiller, O., Guret, C., Lebecque, S., Banchereau, J., Mills, F.C., Max, E.E., Martinez-Valdez, H. (1996). Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 4,241-250. 

Anti-dsDNA Antibodies Are Antigen-Driven. There is evidence that variable regions of both heavy and light chains of both murine and human monoclonal anti-dsDNA antibodies are produced after an affinity maturation process via isotype switching, clonal selection, and somatic mutation (D5, D9, Wll, C16, V3). These findings suggest that anti-dsDNA antibodies are produced by an... 

In summary, structural analyses of anti-DNA antibodies support the hypothesis that autoimmunity to DNA is both initiated and sustained as a clonally selected, antigen-specific immune response to DNA. The initial autoimmune response to DNA is dominated by lower affinity IgM antibody primarily specific for single-stranded, denatured mammalian DNA. As the autoimmune response progresses, the antibody isotype switches to IgG, and the antibody acquires increasing affinity for native, double-stranded DNA. 

Stem, D. A., Riedler, J., Nowak, D. et al. 2007. Exposure to a farming environment has allergen-specific protective effects on TH-2 dependent isotype switching in response to common inhalants. J Allergy Clin Immunol 119 351-358. 

B.B., Crit. Rev. Immunol. 24, 297-320, 2004 Fiset, P.O., Cameron, L., and Hamid, Q., Local isotype switching to IgE in airway mucosa, J. Allergy Clin. Immunol. 116, 233-236, 2005 Min, I.M. and Seising, E., Antibody class switch recombination roles for switch seqences and mismatch repair proteins, Adv. Immunol. 87, 297-328, 2005 Apian, P.D., Causes of oncogenic chromosomal translocation. Trends Genet. 22, 46-55, 2006. 

Antibodies of the IgG, IgA and IgE classes are made later than IgM during a primary immune response, but account for most of the antibody that is made during a memory response. Although isotype switching and affinity maturation are independent processes, they usually occur simultaneously (Fish et al., 1989), so that the increased affinity of bivalent antibodies of isotypes other than IgM is rapidly enhanced. IgG antibody is the predominant isotype in plasma and lymph, while IgA antibody predominates at mucosal surfaces and in secretions from these surfaces. 

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