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Chapter 3 : Mycoplasma arthritidis-Derived Superantigen (MAM), a Unique Class of Superantigen That Bridges Innate and Adaptive Immunity
Category: Bacterial Pathogenesis; Immunology
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This chapter begins with an outline of the original observations that led to the discovery of Mycoplasma arthritidis-derived superantigen (MAM) and discusses the structural basis of its interaction with class II major histocompatibility complex (MHC) molecules and T-cell receptors (TCRs). It reviews recent work on the interaction of MAM with Toll-like receptors and their importance in control of innate and adaptive immunity and in disease expression. The chapter discusses the potential role of MAM-like superantigens (SAgs) in autoimmune disease and how this might relate to recent findings on Toll-like receptor (TLR) control of adaptive immunity. Antigen-induced activation of T cells leading to cytokine production and proliferation requires signals delivered by antigen-presenting cells (APC), i.e., macrophages or dendritic cells (DCs), through costimulatory molecules such as B7-1 (CD80) and B7-2 (CD86) that are related membrane-bound molecules. In view of the demonstrated allelic specificity of MAM for MHC molecules it is also tempting to project that these polymorphisms may influence the outcome of the MAM/TLR interactions. A recent observation that has relevance to the potential role of MAM-like SAgs in human rheumatoid arthritis (RA) is that in preliminary studies transgenic mice bearing the HLA-DR and HLA-DQ alleles that predispose to RA develop a type 1 adaptive cytokine profile in response to MAM, whereas cells from MAM-injected mice bearing those alleles that protect against RA develop a type 2 cytokine profile.
Arthritis induced by M. arthritidis in BALB/c and C3H/HeJ mice. Mice were injected i.v. with 1 X 108 CFU M. arthritidis and scored for arthritis as described for 28 days. Mean scores for BALB/c ( ) and C3H/HeJ ( ) mice ±SEM are shown. C3H/HeJ mice were significantly more susceptible at all time periods (P < 0.002). Reprinted from Infection and Immunity ( 62 ) with permission of the publisher.
Inducible cytokines in cells from MAM-injected mice 3 days postinjection. Splenocytes (107 cells/ml) from C3H/HeJ and C3H/HeSnJ mice injected 72 hours previously with MAM (0.1 to 100 ng/mouse) were rechal-lenged in vitro with a second dose of MAM (1 ng/ml) for an additional 24 h. Inducible cytokines (IL-2, IFN-γ, TNF-α, IL-4, -6 and -10) were analyzed by ELISA. Splenocytes from three to five mice were included in each experiment for each specific dose point; the data shown are representative of three different experiments. Reprinted from Infection and Immunity ( 63 ) with permission of the publisher.
Early serum cytokines induced by MAM in C3H/HeSnJ and C3H/HeJ mice. Mice were injected i.v. with diluent PBS and MAM at doses of 0.1, 1, or 10 ng/mouse. After 90 minutes, mice were exsanguinated under anesthesia and the sera were collected for cytokine assays for IL-2, IL-6, IFN-γ, IL-10, TNF-α, and IL-12p40. Sera from three to five mice were assayed in each experiment for each specific dose point. Similar results were seen in three repeat experiments. Reprinted from Infection and Immunity ( 63 ) with permission of the publisher.
Expression of TLR2 and TLR4 by macrophages in response to MAM. Peritoneal macrophages from C3H/HeSnJ (TLR2+/+/TLR4+/+) and C3H/HeJ (TLR2+/+/TLR4-/-) were treated with MAM (100 ng/ml) or NS for 18 h and then stained and analyzed for expression of TLR2 and TLR4. Flow cytometry was conducted, as before, for the expression of both TLR2 and TLR4. Insertions are the mean results of mean fluorescence intensity (MFI) ± SEM of three experiments. Reprinted from Cellular Microbiology ( 61 ) with permission of the publisher.
Regulation of TLR2 and IL-12p40 by MAM/TLR4 interaction. Resident peritoneal macrophages from C3H/HeN mice were pretreated with anti-mouse TLR4 (20 ng/ml) for 2 h. MAM (1 and 10 ng/ml, final concentration) was then added, followed by incubation for a further 18 h. Surface expression of TLR2 by macrophages was analyzed by flow cyto-metric analysis and the culture supernatants were assessed for IL-12p40. The data are the mean ±SEM for three experiments (*P < 0.05; **P < 0.01). Each experiment contained cells pooled from three to five mice. Reprinted from Cellular Microbiology ( 61 ) with permission of the publisher.
Effect of in vivo treatment with anti-B7-1 antibody on inducible cytokine profiles induced in cells from MAM-injected mice. Mice were injected with varying doses of MAM after treatment with anti-B7-1 or isotype-matched anti-mouse antibody (250 μg of each mAb per mouse, respectively) on two separate occasions. Twenty-four hours after MAM injection, splenocytes (107 cells/ml) were isolated and rechallenged in vitro with MAM (2.5 ng/ml) and culture supernatants were assayed for cytokines IL-2, IFN-γ, TNF-α, IL-4, and IL-10. The data shown are pooled from three different experiments (*P < 0.05; **P < 0.01). Reprinted from Cellular Microbiology ( 60 ) with permission of the publisher.
Proposed models for MAM selection of cytokine profiles triggered through different TLRs.
Disease caused by M. arthritidis