Mycoplasma superantigen initiates a TLR4-dependent Th17 cascade that enhances arthritis after blocking B7-1 inMycoplasma arthritidis-infected mice

    loading  Checking for direct PDF access through Ovid


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.

Related Topics

    loading  Loading Related Articles