title: Mycoplasma superantigen initiates a TLR4-dependent Th17 cascade that enhances arthritis after blocking B7-1 in Mycoplasma arthritidis-infected mice.
abstract: Mycoplasma arthritidis is a natural pathogen of rodents causing arthritis, toxic shock and necrotizing fasciitis. It secretes a potent superantigen (SAg), MAM, that differentially affects the immune system depending upon presence or absence of TLR4, thus potentially influencing disease outcomes. Here, we establish that antibody to co-stimulatory molecule B7-1(CD80) enhances arthritis in wild-type C3H/HeSnJ (TLR2+4+) mice but suppresses arthritis in TLR4-defect C3H/HeJ (TLR2+4-) mice. Also, blockade of the B7-1/CD28 co-stimulatory pathway in C3H/HeSnJ mice resulted in a marked increase in an alternative co-stimulatory pathway ICOS/ICOSL that was associated with elevation of the IL-17/Th17cascade with enhanced IL-23, IL-6, and the RORγt and STAT3 transcriptional factors on CD4+ T cells. Anti- B7-1 also increased inflammatory chemokines and the stress protein HMGB1 that promotes cellular infiltration to joints. Using a MAM-deficient strain of M. arthritidis, a monoclonal antibody to TLR4 and a TLR4-defective mouse strain, we established that both MAM and TLR4 are required for the systemic and local joint triggering of the Th17/IL-17 cascade in mice treated with anti-B7-1 antibody. Importantly, blocking of IL-17 with anti-IL-17 antibody suppressed the elevated arthritis in M. arthritidis-infected mice treated with anti-B7-1 antibody. Thus, this unique model of arthritis illustrates how microbial agonists can bridgeinnate and adaptive immune responses to redirect signalling pathways, thus promoting chronic inflammatory and autoimmune disease.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT, 84132, USA.
authors.forename: Hong-Hua
authors.initials: HH
authors.lastname: Mu
authors.forename: Maziar M
authors.initials: MM
authors.lastname: Nourian
authors.forename: Hua Hui
authors.initials: HH
authors.lastname: Jiang
authors.forename: Justin W
authors.initials: JW
authors.lastname: Tran
authors.forename: Barry C
authors.initials: BC
authors.lastname: Cole
mesh_terms: D000818:Animals; D001170:Arthritis, Infectious / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D018122:B7-1 Antigen / Q000037:antagonists & inhibitors*; D051379:Mice; D045645:Mycoplasma arthritidis / Q000276:immunology*; D015398:Signal Transduction; D018089:Superantigens / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D018089:Superantigens; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4