Abstract/Details

Chemistry and biology of antigen presentation in celiac sprue


2006 2006

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Abstract (summary)

Built on the previous discovery of the 33-mer gluten peptide and the revelation of the crystal structure of HLA-DQ2, this dissertation aims to explore the new avenue of blocking HLA-DQ2 mediated presentation of antigenic gluten peptides as a therapeutic option in celiac spure. First we conducted equilibrium and kinetic analysis of the binding interaction between this 33-mer peptide and recombinant DQ2, and concluded that the remarkable antigenicity of the deamidated 33-mer peptide is primarily due to its unusually efficient ability to displace existing ligands in the HLA-DQ2 binding pocket. Secondly, an N-methylation scan in conjunction with proline-to-norvaline displacement scan allowed us to explore the unusual main chain hydrogen bonding interactions in the binding of gluten peptides to HLA-DQ2. Thirdly , a systematical investigation of the structure-activity-relationship of the binding of the 33-mer peptide to DQ2 led to the discovery of a 20-mer peptide as the core binding sequence. Chemical modifications of this lead peptide yielded blocking agents which were able to attenuate the proliferation of disease-specific T cell lines in response to gluten antigens using fixed antigen presenting B cells. Next, in an attempt to optimize the effect of the blockers, we systematically synthesized a series of cyclic peptides and dimeric peptides and explored their binding affinities to HLA-DQ2 as well as their capacities to block DQ2-mediated antigen presentation. Furthermore, by quantifying the amount of DQ2 proteins expressed on the surface of DQ2+ B cells and the amount of antigen presented per cell at saturation by chemical methods, we observed a very low occupancy percentage of DQ2 on the surface of B cells even by high affinity antigens. Lastly, we explored the possibility of synthesizing reversible covalent antigen/antagonist to DQ2 in order to gain increased surface presentation hence the better inhibitory effect. Some aldehyde-containing peptide analogues can form covalent linkage with Lysβ71 of DQ2. Given the promising effect of some DQ2 blocking agents, our research provides a foundation for further research toward a therapeutic option to celiac sprue.

Indexing (details)


Subject
Organic chemistry;
Pathology;
Immunology
Classification
0490: Organic chemistry
0571: Pathology
0982: Immunology
Identifier / keyword
Health and environmental sciences; Pure sciences; Antigen presentation; Celiac sprue
Title
Chemistry and biology of antigen presentation in celiac sprue
Author
Xia, Jiang
Number of pages
140
Publication year
2006
Degree date
2006
School code
0212
Source
DAI-B 67/11, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780542984648
Advisor
Khosla, Chaitan
University/institution
Stanford University
University location
United States -- California
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3242640
ProQuest document ID
304978408
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304978408
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