Roles of igh intronic enhancer Emu in clonal selection at the pre-B to immature B cell transition and in the elimination of autoreactive B cells
Item
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Title
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Roles of igh intronic enhancer Emu in clonal selection at the pre-B to immature B cell transition and in the elimination of autoreactive B cells
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Identifier
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d_2009_2013:57595fbf46ff:12069
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Creator
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Peng, Cheng,
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Contributor
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Laurel A. Eckhardt
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Date
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2013
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Language
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English
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Publisher
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City University of New York.
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Subject
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Immunology | Cellular biology
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Abstract
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The immunoglobulin heavy chain locus (Igh) intronic enhancer, Emu, enhances transcription of recombined Igh genes. We have previously shown that in mice with an Emu-deficient Igh allele (V Hdeltaa), Igmu is expressed at half of the wild-type levels in pre-B cells. We also described an Emu-dependent "check-point", operating at the pre-B to immature B cell transition, for heavy chain allelic exclusion. We now show that deletion of Emu results in a smaller immature B cell compartment, and the pre-BCR/BCR signaling is diminished in pre-B cells as a result of the reduced Igmu levels, making it difficult for emerging BCRs to reach the signaling threshold required for positive selection of pre-B cells to the immature B cell stage. Our hypothesis is that, to circumvent the problem of inadequate signaling, E-mudeficient B cells either 1) expand the rare precursor B cells seemingly breaking the rules of allelic exclusion to express a second IgH allele as "double-producers", to achieve higher levels of Ig mu-chain and hence higher pre-BCR and BCR levels, or 2) undergo heightened light-chain editing to create an IgH/IgL combination with superior signaling properties to make up for the lower Ig mu-chain (lower BCR) levels and signaling. To test these hypotheses and to determine whether escape from the developmental defects in Emu-deficient B cells is dependent upon light chain, we provided the Emu-deficient mice with a pre-assembled VL gene (3-83Vkappa). This led to not only a larger immature B cell compartment, but also a decrease in "double-producers". We suggest that an IgH/IgL combination with superior signaling properties may compensate for the reduced BCR levels and eliminate the selective advantage of "double-producers". We also find that "double-producers" in Emu-deficient heterozygous mice (VHdeltaa/WT b), include a subpopulation with autoreactive BCRs. We infer that the BCRs with IgH from the VHdeltaa allele are ignored during negative selection at the pre-B to immature B cell transition, due to their low density. Instead, the double-producers are both positively and negatively selected on the basis of BCRs with IgH from the alternate allele (with Emu intact). Taken together, these results suggest that Emu functions to ensure sufficient Igmu(IgH) levels at the pre-B to immature B transition, which has an important impact on the maintenance of heavy chain allelic exclusion, the breadth of the BCR repertoire, and the elimination of autoreactive B cells.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
