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The role of endoplasmic reticulum in...
~
Wheeler, Matthew Clay.
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The role of endoplasmic reticulum in major histocompatibility class II restricted antigen presentation and immune response.
Record Type:
Language materials, printed : Monograph/item
Title/Author:
The role of endoplasmic reticulum in major histocompatibility class II restricted antigen presentation and immune response./
Author:
Wheeler, Matthew Clay.
Description:
136 p.
Notes:
Adviser: Maurizio Zanetti.
Contained By:
Dissertation Abstracts International67-04B.
Subject:
Biology, Cell. -
Online resource:
http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3216427
ISBN:
9780542660191
The role of endoplasmic reticulum in major histocompatibility class II restricted antigen presentation and immune response.
Wheeler, Matthew Clay.
The role of endoplasmic reticulum in major histocompatibility class II restricted antigen presentation and immune response.
- 136 p.
Adviser: Maurizio Zanetti.
Thesis (Ph.D.)--University of California, San Diego, 2006.
The generation of adaptive immune responses requires presentation of major histocompatibility (MHC) class II restricted immunogenic peptides to CD4 T cells by antigen presenting cells (APCs). These peptides are derived from the processing of protein antigens in acidic endosomal compartments. Classically, the generation of such peptides has been thought to have occurred through an exogenous pathway that involves internalization of antigens from the extracellular milieu. Recently, it has been demonstrated that peptides can also be generated from endogenously synthesized and retained antigen. While research in this field is burgeoning the physiological consequences of the processing of intracellular antigen are unknown.
ISBN: 9780542660191Subjects--Topical Terms:
1017686
Biology, Cell.
The role of endoplasmic reticulum in major histocompatibility class II restricted antigen presentation and immune response.
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136 p.
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Adviser: Maurizio Zanetti.
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Source: Dissertation Abstracts International, Volume: 67-04, Section: B, page: 1908.
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Thesis (Ph.D.)--University of California, San Diego, 2006.
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The generation of adaptive immune responses requires presentation of major histocompatibility (MHC) class II restricted immunogenic peptides to CD4 T cells by antigen presenting cells (APCs). These peptides are derived from the processing of protein antigens in acidic endosomal compartments. Classically, the generation of such peptides has been thought to have occurred through an exogenous pathway that involves internalization of antigens from the extracellular milieu. Recently, it has been demonstrated that peptides can also be generated from endogenously synthesized and retained antigen. While research in this field is burgeoning the physiological consequences of the processing of intracellular antigen are unknown.
520
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This dissertation examines the in vivo consequences and in vitro pathways relevant to the processing and presentation of antigen that is endogenously synthesized and retained in different intracellular compartments by B lymphocytes. I show that peptides derived from the processing of intracellular antigen are able to prime a CD4 T cell response irrespective of intracellular targeting. Furthermore, I show that T cells primed by peptides derived from antigen retained in the endoplasmic reticulum (ER) induce higher secretion of IFN-gamma and TNFalpha in responding cells. This increase is associated with upregulation of the ER stress responsive genes GADD34, Grp78 and CHOP, and down regulation of the costimulatory molecule OX40L in B lymphocytes. An OX40L reduced phenotype was recapitulated in CpG activated B lymphocytes by treatment with the ER stress inducing compounds tunicamycin and thapsigargin.
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I also show that presentation of ER retained antigen is linked to the ER associated degradation (ERAD) pathway. Presentation of the model antigen Ealpha from an ER targeted IgH requires mannose processing, cytosolic translocation and degradation by the resident cytosolic protease tripeptidyl peptidase II. Additionally, ER stress inducing compounds are able to initiate presentation of a secretory IgH that traffics through the ER but is not normally presented.
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Ultimately, the research presented here has far reaching implications for immune responses generated under states of cellular stress, such as viral infection oncogenic transformation and anti-idiotype responses at the levels of antigen processing and immune priming. These results reveal important considerations for vaccine design, as ER stress may serve an important adjuvant effect in the induction of cellular immunity.
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School code: 0033.
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http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3216427
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