Allergic responses and immediate hypersensitivity are associated with high levels of IgE antibodies. Therefore, the study of IgE regulation is important in order to understand the basis of human allergic diseases. IgE expression is regulated, at least in part, by the efficiency of heavy chain-class switching that results in expression of the epsilon constant region (C) genes. Class switching is mediated by DNA recombination between switch (S) regions that are located 5' of every isotype's CH genes (except for delta). Experiments are proposed here to investigate the mechanism of class switch recombination at the molecular level for IgE. (1) Class-switching that occurs in IgE-secreting hybridomas will be examined. The S epsilon recombination sites will be mapped, cloned and their nucleotide sequence determined. Results will define the DNA substrates used in IgE switching and will determine the type of switching that occurs: direct recombination with the S mu region or sequential recombination (e.g., S mu to S gamma to S epsilon). (2) IgE-switching will be examined in mouse cells transfected with S mu and S epsilon DNAs. The recombination substrates will be cloned into a plasmid shuttle vector and introduced into mouse cells in different stages of B cell development. The frequency of switch recombination in these cells will be measured and the specific sites of recombination determined for several recombinants. (3) The role of certain factors in the regulation of class switching for IgE will be studied. Differentiation factors that enhance the IgE response will be tested to determine if they stimulate IgE- specific switching. The analysis will be in mouse cells transfected with S mu, C mu, S epsilon and C epsilon DNAs. (4) Proteins that bind specifically to the IgE switch region will be isolated. Two questions will be answered. First, are there isotype-specific binding proteins? And second, are these binding proteins involved in switch recombination? The long-term goals of this research are: 1) to precisely define the DNA substrates and proteins involved in IgE-specific class- switch recombination; and 2) to develop methods to study regulation of IgE switching in a defined genetic system. From an understanding of the mechanim of IgE class switching, agents that regulate switching may be developed for the treatment of human allergic disorders.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Immunobiology Study Section (IMB)
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Scripps Research Institute
La Jolla
United States
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Dunnick, W; Hertz, G Z; Scappino, L et al. (1993) DNA sequences at immunoglobulin switch region recombination sites. Nucleic Acids Res 21:365-72
Gritzmacher, C A; Mehl, V S; Liu, F T (1992) Genomic cloning of the gene for an IgE-binding lectin reveals unusual utilization of 5' untranslated regions. Biochemistry 31:9533-8
Scappino, L A; Chu, C; Gritzmacher, C A (1991) Extended nucleotide sequence of the switch region of the murine gene encoding immunoglobulin E. Gene 99:295-6
Gritzmacher, C A (1989) Molecular aspects of heavy-chain class switching. Crit Rev Immunol 9:173-200