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Investigating the roles of HLA-DO in the immune response in humans and mice

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TitleInfo
Title
Investigating the roles of HLA-DO in the immune response in humans and mice
Name (type = personal)
NamePart (type = family)
Graves
NamePart (type = given)
Austin M.
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Austin M. Graves
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author
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Covey
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Lori
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Lori Covey
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Advisory Committee
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chair
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Denzin
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Lisa
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Lisa Denzin
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Advisory Committee
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internal member
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Daniels
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Brian
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Brian Daniels
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Advisory Committee
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internal member
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Haimovich
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Beatrice
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Beatrice Haimovich
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Advisory Committee
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internal member
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Rutgers University
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degree grantor
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School of Graduate Studies
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theses
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ETD doctoral
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2021
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2021-01
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2021
Language
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English
Abstract (type = abstract)
The MHC class II antigen presentation pathway acts as a bridge between the innate and adaptive immune responses. HLA molecules of the MHC class II (MHCII) bind and present pathogen-derived peptides for CD4 T cell activation. Peptide loading of MHCII in the endosomes of cells is controlled by the interplay of the nonclassical MHCII molecules, HLA-DM (DM) and HLA-DO (DO). DM catalyzes peptide loading, whereas DO, an MHCII substrate mimic, prevents DM from interacting with MHCII, resulting in an altered MHCII-peptide repertoire and increased MHCII-CLIP. Previous studies from our lab revealed that the mouse homolog of DO, H2-O, blocks a neutralizing antibody response to a retrovirus. We investigated the effect of H2-O deficiency on immune function in mice. Interestingly, we found an increase in immune cell activation in the small intestines of H2-O deficient mice. These changes appeared to dissipate as the mice aged. Our previous study also found naturally occurring variants of the gene that encodes the beta chain of DO, DOB, that altered DO function. A more functional variant of DOB was linked to individuals who struggle to neutralize Hepatitis C virus. We have now analyzed naturally occurring variants of the gene that encodes the alpha chain of DO, DOA, and found several with altered function. In fact, 52% of the variants analyzed altered DO function, two of which were linked to Hepatitis B viral immune responses. A more functional variant, DOA*0102, was linked to Hepatitis B viral persistence. A functionally null variant, DOalpha F114L, was conversely linked to Hepatitis B viral clearance. Further characterization of the gain-of-function variants identified in this study suggests that the mechanism of DO’s inhibitory function of DM is more complex than previously understood. DO binding to DM may permanently alter DM’s functional capability, even if DO is no longer bound to DM.
Subject (authority = local)
Topic
Immunology
Subject (authority = local)
Topic
HLA-DO
Subject (authority = LCSH)
Topic
Immunogenetics
Subject (authority = RUETD)
Topic
Microbiology and Molecular Genetics
RelatedItem (type = host)
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Rutgers University Electronic Theses and Dissertations
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ETD_11460
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application/pdf
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text/xml
Extent
1 online resource (xii, 120 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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Identifier (type = doi)
doi:10.7282/t3-yvj6-9286
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The author owns the copyright to this work.
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Name
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Graves
GivenName
Austin
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Permission or license
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2021-01-06 17:36:02
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Name
Austin Graves
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Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
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Copyright protected
Availability
Status
Open
Reason
Permission or license
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2021-01-11T10:40:49
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2021-01-11T10:40:49
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