Susceptibility to and severity of many autoimmune diseases, including arthritis, are known to be closely linked with particular class II MHC alleles, but the mechanism of these associations remains unknown. We have found that class II alleles that form unusually low-stability complexes with class II-associated invariant chain peptides (CLIP) are disproportionately represented among alleles that confer susceptibility to autoimmunity. Our recent work indicates that variations in class II/CLIP affinity affect the stability, longevity, and abundance of class II molecules in model antigen presenting cells (APC) and can modulate antigen presentation. Mechanisms by which variations in class II/CLIP affinity could influence susceptibility to autoimmunity include alterations in central selection events or peripheral tolerance or activation events, all of which are controlled by antigen presentation. Here, we propose to study whether varying class II/CLIP affinity can influence autoimmune disease pathogenesis in a whole animal. We will: 1) Establish 2 short-term mouse models in which the affinity of CLIP for class II has been modulated, using two arthritis-prone haplotypes. This will be achieved by re-constituting irradiated mice with HSC expressing invariant chains with wild type CLIP (with low affinity for MHC II) or mutated CLIP (with high affinity for MHC II); 2) Measure the effects of class II/CLIP affinity on class II stability, longevity, and abundance in primary APC types from these mice, including in the context of inflammatory stimuli; 3) Determine whether modulation of class II/CLIP affinity in BM-derived APC modulates disease in the KRN model and key immunologic features in this model. The results of these experiments will shape future studies, in which we will extend this work to the second mouse model of arthritis, as well as develop a long-term model to investigate arthritis pathogenesis using mice that stably express high-affinity CLIP/Ii. If expression of high affinity CLIP in hematopoietic cells is sufficient for disease protection, it may provide new therapeutic options for individuals at risk for arthritis.

Public Health Relevance

Although it has been known for a number of years that certain proteins, the HLA proteins, are a critical genetic risk factor for arthritis and other debilitating autoimmune diseases, the explanation for this genetic link has remained unknown. We will perform experiments in a mouse model of arthritis to test a novel hypothesis for the mechanism of this association. If successful, our experiments will shed new light on the mechanism(s) of disease initiation and pathogenesis in arthritis, and may suggest new treatment approaches for people who are at high risk for arthritis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI075253-01A2
Application #
7477618
Study Section
Special Emphasis Panel (ZRG1-IMM-E (02))
Program Officer
Peyman, John A
Project Start
2008-03-15
Project End
2010-02-28
Budget Start
2008-03-15
Budget End
2009-02-28
Support Year
1
Fiscal Year
2008
Total Cost
$199,018
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Wang, Nan; Rajasekaran, Narendiran; Hou, Tieying et al. (2015) Immunological Basis for Rapid Progression of Diabetes in Older NOD Mouse Recipients Post BM-HSC Transplantation. PLoS One 10:e0128494
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Wang, Nan; Rajasekaran, Narendiran; Hou, Tieying et al. (2013) Comparison of transduction efficiency among various lentiviruses containing GFP reporter in bone marrow hematopoietic stem cell transplantation. Exp Hematol 41:934-43
Hou, Tieying; Rinderknecht, Cornelia H; Hadjinicolaou, Andreas V et al. (2013) Pulse-chase analysis for studies of MHC class II biosynthesis, maturation, and peptide loading. Methods Mol Biol 960:411-432
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
Rajasekaran, Narendiran; Wang, Nan; Truong, Phi et al. (2013) Host-derived CD4+ T cells attenuate stem cell-mediated transfer of autoimmune arthritis in lethally irradiated C57BL/6.g7 mice. Arthritis Rheum 65:681-92

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