The broad, long-term objective of the proposed research is to characterize the biochemical processes and immunological importance of a novel antigen processing and loading pathway recently shown to utilize empty or """"""""peptide-receptive"""""""" cell-surface MHC class II proteins in certain professional antigen cells. The proposed research is intended to determine the relationship between MHC class II stability and expression of empty molecules on the surface of dendritic cells, to investigate the expression and functional capacity of empty class II MHC molecules on central nervous system microglia cells, to identify the protease(s) involved in extracellular antigen processing in immature dendritic cells, and to evaluate the importance of extracellular versus intracellular antigen loading pathways in dendritic cells and microglia. These goals will be achieved through biochemical characterization of empty and peptide-loaded MHC molecules using antibody and peptide binding assays, purification and characterization of secreted protease activity, and the use of specific inhibitors of intracellular and extracellular processing pathways. The proposed research is part of an interactive research project group. The overall objective of the IRPG is to characterize a novel pathway for antigen processing and presentation involving extracellular proteases and empty class II MHC proteins that has been identified initially in immature dendritic cells. This project supports that goal by focusing on biochemical aspects of antigen processing and peptide loading in dendritic cells and microglia. The companion project focuses on MHC trafficking and antigen presentation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI048833-03
Application #
6626406
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2001-01-29
Project End
2005-12-31
Budget Start
2002-10-01
Budget End
2002-12-31
Support Year
3
Fiscal Year
2002
Total Cost
$128,644
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Clement, Cristina C; Wang, Wei; Dzieciatkowska, Monika et al. (2018) Quantitative Profiling of the Lymph Node Clearance Capacity. Sci Rep 8:11253
Clement, Cristina C; Becerra, Aniuska; Yin, Liusong et al. (2016) The Dendritic Cell Major Histocompatibility Complex II (MHC II) Peptidome Derives from a Variety of Processing Pathways and Includes Peptides with a Broad Spectrum of HLA-DM Sensitivity. J Biol Chem 291:5576-95
Clement, Cristina C; Moncrieffe, Halima; Lele, Aditi et al. (2016) Autoimmune response to transthyretin in juvenile idiopathic arthritis. JCI Insight 1:
Yin, Liusong; Stern, Lawrence J (2014) Measurement of Peptide Binding to MHC Class II Molecules by Fluorescence Polarization. Curr Protoc Immunol 106:5.10.1-12
Mellins, Elizabeth D; Stern, Lawrence J (2014) HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation. Curr Opin Immunol 26:115-22
Yin, Liusong; Stern, Lawrence J (2014) A novel method to measure HLA-DM-susceptibility of peptides bound to MHC class II molecules based on peptide binding competition assay and differential IC(50) determination. J Immunol Methods 406:21-33
Yin, Liusong; Trenh, Peter; Guce, Abigail et al. (2014) Susceptibility to HLA-DM protein is determined by a dynamic conformation of major histocompatibility complex class II molecule bound with peptide. J Biol Chem 289:23449-64
Santambrogio, Laura; Stern, Lawrence J (2013) Carrying yourself: self antigen composition of the lymphatic fluid. Lymphat Res Biol 11:149-54
Yin, Liusong; Stern, Lawrence J (2013) HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange. Front Immunol 4:336
Guce, Abigail I; Mortimer, Sarah E; Yoon, Taejin et al. (2013) HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism. Nat Struct Mol Biol 20:90-8

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