Autoimmune diseases such as rheumatoid arthritis (RA) are currently considered to be due to a complex interplay of host genetics with environmental triggering agents, which include infectious agents bacteria, viruses or mycoplasms. The overall goals of this project are to determine how microbial products such as superantigens (SAgs) might interact with RA MHC-susceptibility alleles to drive a type 1 inflammatory cytokine profile that might trigger active disease in the human host. As a model we will use the newly developed murine class II knockout mice that display various human MHC molecules that predispose to development of collagen arthritis in mice. Mice expressing these molecules will be tested for their cytokine profiles in response to in vivo exposure to the mycoplasma SAg, MAM and other bacterial SAgs using RT PCR and ELISA methodologies. We shall also investigate the mechanisms of any differences seen including the potential role of MHC binding, cell type, role of co-stimulatory molecules, and region of the SAg molecule responsible. Also we will investigate the pathogenetic effects of M. arthritidis in these """"""""humanized"""""""" mice and determine strategies to overcome the effect of the superantigen MAM in initiating disease pathogenesis by modification of the cytokine milieu.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR002255-38A1
Application #
6478547
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Gretz, Elizabeth
Project Start
1978-03-01
Project End
2007-03-31
Budget Start
2002-04-22
Budget End
2003-03-31
Support Year
38
Fiscal Year
2002
Total Cost
$334,640
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Mu, Hong-Hua; Hasebe, Akira; Van Schelt, Adam et al. (2011) Novel interactions of a microbial superantigen with TLR2 and TLR4 differentially regulate IL-17 and Th17-associated cytokines. Cell Microbiol 13:374-87
Hasebe, Akira; Mu, Hong-Hua; Washburn, Leigh R et al. (2007) Inflammatory lipoproteins purified from a toxigenic and arthritogenic strain of Mycoplasma arthritidis are dependent on Toll-like receptor 2 and CD14. Infect Immun 75:1820-6
Mu, Hong-Hua; Humphreys, Jennifer; Chan, Fok Vun et al. (2006) TLR2 and TLR4 differentially regulate B7-1 resulting in distinct cytokine responses to the mycoplasma superantigen MAM as well as to disease induced by Mycoplasma arthritidis. Cell Microbiol 8:414-26
Hasebe, Akira; Pennock, Nathan D; Mu, Hong-Hua et al. (2006) A microbial TLR2 agonist imparts macrophage-activating ability to apolipoprotein A-1. J Immunol 177:4826-32
Cole, Barry C; Mu, Hong-Hua; Pennock, Nathan D et al. (2005) Isolation and partial purification of macrophage- and dendritic cell-activating components from Mycoplasma arthritidis: association with organism virulence and involvement with Toll-like receptor 2. Infect Immun 73:6039-47
Mu, H-H; Pennock, N D; Humphreys, J et al. (2005) Engagement of Toll-like receptors by mycoplasmal superantigen: downregulation of TLR2 by MAM/TLR4 interaction. Cell Microbiol 7:789-97
Mu, H H; Sawitzke, A D; Cole, B C (2001) Presence of Lps(d) mutation influences cytokine regulation in vivo by the Mycoplasma arthritidis mitogen superantigen and lethal toxicity in mice infected with M. arthritidis. Infect Immun 69:3837-44
Sawitzke, A; Joyner, D; Knudtson, K et al. (2000) Anti-MAM antibodies in rheumatic disease: evidence for a MAM-like superantigen in rheumatoid arthritis? J Rheumatol 27:358-64
Mu, H H; Sawitzke, A D; Cole, B C (2000) Modulation of cytokine profiles by the Mycoplasma superantigen Mycoplasma arthritidis mitogen parallels susceptibility to arthritis induced by M. arthritidis. Infect Immun 68:1142-9
Cole, B C (1999) Mycoplasma-induced arthritis in animals: relevance to understanding the etiologies of the human rheumatic diseases. Rev Rhum Engl Ed 66:45S-49S

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