A two-signal model for regulation of immunoglobulin isotype switching.
A characteristic feature of the humoral immune response is a switch from IgM to other Ig isotypes that typically occurs subsequent to a first exposure to antigen. Ultimately, isotype switching involves a DNA rearrangement that recombines a variable region gene, initially juxtaposed to the mu constant region gene (C mu), with a constant region gene located downstream of C mu. Isotype switching is controlled by T lymphocyte-derived cytokines, such as interleukin-4 (IL-4), gamma-interferon (gamma-IFN), and TGF beta, which direct B lymphocytes to switch to specific Ig classes. For example, IL-4, directs murine B cells to produce IgG1 and IgE, and human B cells to produce IgE and IgG4. IL-4 appears to direct switching to IgE and IgG1 by inducing transcription of the epsilon and gamma 1 constant region genes before switch recombination. However, IL-4 is not a sufficient stimulus for isotype switching, and additional signals are required to complete this process. This second signal can be provided by physical contact with activated T cells, which may involve, at least in part, ligation of the CD40 molecule. For murine B cells the second signal may also be provided by IL-5. Isotype switching in B lymphocytes may provide a useful model for directed DNA recombination in higher eukaryotes.
Purkerson
J
J
Department of Immunoinflammatory Disease Research, Searle Research and Development, St. Louis, Missouri 63198.
Isakson
P
P
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens; D005786:Gene Expression Regulation; D015322:Gene Rearrangement, B-Lymphocyte; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000235:genetics*; D007371:Interferon-gamma / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D015848:Interleukin-5 / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000502:physiology
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007132:Immunoglobulin Isotypes; D015848:Interleukin-5; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma