The molecular level modeling of MHC II-peptide systems to obtain a solid theory of the origins of autoimmune systems, particularly rheumatoid arthritis (RA) is proposed. The first modeling efforts will be directed toward a systematic search of the structure of a """"""""kinetic"""""""" isomer of an MHC-peptide system where a long and a short lived isomer have been observed (MHC II I-E/kPiggeon Cyt c peptide). Then, a hypothesis has been laid out in the proposal where a specific kinetic isomer of a collagen peptide in HLA-DR4 (DRB1 0401 allele) is not recognized as """"""""self"""""""" by the immune system. The T-cells recognizing the """"""""kinetic"""""""" isomer may not have been eliminated during the early maturation stage. Modeling of the proposed isomer will be done and may be eventually confirmed through experimental techniques at the McConnell lab. Specifically, it is proposed that water molecules solvating the two carboxylates in the P6 pocket of HLA-DR4 may interfere with the deep burial of the P6 Ala of the collagen peptide observed in the MHC-peptide crystal structure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI010298-02
Application #
6328654
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Prograis, Lawrence J
Project Start
2000-11-30
Project End
Budget Start
2000-11-30
Budget End
2001-11-29
Support Year
2
Fiscal Year
2001
Total Cost
$40,196
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Rinderknecht, Cornelia H; Roh, Sujin; Pashine, Achal et al. (2010) DM influences the abundance of major histocompatibility complex class II alleles with low affinity for class II-associated invariant chain peptides via multiple mechanisms. Immunology 131:18-32
Belmares, Michael P; Busch, Robert; Mellins, Elizabeth D et al. (2003) Formation of two peptide/MHC II isomers is catalyzed differentially by HLA-DM. Biochemistry 42:838-47
Belmares, Michael P; Busch, Robert; Wucherpfennig, Kai W et al. (2002) Structural factors contributing to DM susceptibility of MHC class II/peptide complexes. J Immunol 169:5109-17
Belmares, M P; McConnell, H M (2001) Kinetics of registry selection of chimeric peptides binding to MHC II. Biochemistry 40:10284-92
Belmares, M P; Rabinowitz, J D; Liu, W et al. (2000) pH stability of HLA-DR4 complexes with antigenic peptides. Biochemistry 39:14558-66