Heat shock protein gp96 is a key downstream chaperone in the endoplasmic reticulum (ER) that mediates ER unfolded protein responses (UPR). Cell surface expression of gp96 in a transgenic mouse leads to spontaneous lupus-like autoimmune disease which is dependent on commensal bacteria and Toll-like receptor 4 (TLR4). This finding, together with the discovery that gp96 is a master chaperone for TLRs, has moved the field forward significantly: we now hypothesize that gp96 tunes the immune system by chaperoning TLRs but not by signaling through TLRs;depending on its expression level and location, gp96 can break tolerance if upregulated and can confer immunodeficiency if compromised in expression or function. The previously unappreciated roles of TLR4 in lupus have been validated by lupus in TLR4-overexpressing mice. Studies of the mechanism of autoimmunity in gp96 transgenic mice have also uncovered the potential impact of chronic TLR hyperresponsiveness to commensal flora on IL-10-producing CD4? T cells (TR1) and IL-17-secreting CD4 cells (TH17) in vivo. In this proposal, we will critically address the hypothesis that TLR4 amplification at either DNA level or post translational level significantly impact the biology (priming, maintenance and function) of both TR1 and TH17, leading to breakdown of peripheral tolerance. We will also define the hierarchy of TLRs in driving lupus with particular focus on the roles of nucleic acid-sensing TLRs in our model. Our study is of fundamental significance in understanding the roles of TLRs in immunity and tolerance via regulating TR1 and TH17, since the dysregulation of these cell types has been increasingly implicated in autoimmune diseases. Our recent findings that the surface expression of gp96 is highly regulated in vivo and that the increased expression of gp96 on the cell surface correlates with human lupus highlight the clinical relevance of our study.

Public Health Relevance

This project addresses the mechanism of lupus, which has implications in the understanding of general immunobiology, cancer immunity and other autoimmune diseases.
We aim to prove the hypothesis that the overexpression of particular cell surface stress proteins leads to heightened responses against microbes, which in turn triggers the development of autoimmunity through complex actions on two critical immune regulatory cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077283-09
Application #
8230772
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Johnson, David R
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$361,412
Indirect Cost
$116,387
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Anas, Adam A; de Vos, Alex F; Hoogendijk, Arie J et al. (2016) Endoplasmic reticulum chaperone gp96 in macrophages is essential for protective immunity during Gram-negative pneumonia. J Pathol 238:74-84
Zhou, Zejun; Ding, Miao; Huang, Lei et al. (2016) Toll-like receptor-mediated immune responses in intestinal macrophages; implications for mucosal immunity and autoimmune diseases. Clin Immunol 173:81-86
Zhang, Yongliang; Wu, Bill X; Metelli, Alessandra et al. (2015) GP96 is a GARP chaperone and controls regulatory T cell functions. J Clin Invest 125:859-69
Patel, Hardik J; Patel, Pallav D; Ochiana, Stefan O et al. (2015) Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog Grp94. J Med Chem 58:3922-43
Rachidi, Saleh; Sun, Shaoli; Wu, Bill X et al. (2015) Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis. J Hepatol 62:879-88
Zhang, Yongliang; Helke, Kristi L; Coelho, Sergio G et al. (2014) Essential role of the molecular chaperone gp96 in regulating melanogenesis. Pigment Cell Melanoma Res 27:82-9
Zhang, J; Fu, S; Sun, S et al. (2014) Inflammasome activation has an important role in the development of spontaneous colitis. Mucosal Immunol 7:1139-50
Rachidi, Saleh; Wallace, Kristin; Day, Terry A et al. (2014) Lower circulating platelet counts and antiplatelet therapy independently predict better outcomes in patients with head and neck squamous cell carcinoma. J Hematol Oncol 7:65
Thaxton, Jessica E; Liu, Bei; Zheng, Pan et al. (2014) Deletion of CD24 impairs development of heat shock protein gp96-driven autoimmune disease through expansion of myeloid-derived suppressor cells. J Immunol 192:5679-86
Jiang, Wei; Zhang, Lumin; Lang, Ren et al. (2014) Sex differences in monocyte activation in systemic lupus erythematosus (SLE). PLoS One 9:e114589

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