The Role of the MHC Class II Transactivator in Class II Expression and Antigen Presentation by Astrocytes and in Susceptibility to Central Nervous System Autoimmune Disease

Stüve, Olaf; Youssef, Sawsan; Slavin, Anthony; King, Chelsea; Patarroyo, Juan C.; Hirschberg, David L.; Brickey, W. June; Soos, Jeanne M.; Piskurich, Janet F.; Chapman, Harold A.; Zamvil, Scott S.

doi:10.4049/jimmunol.169.12.6720

Cited by 87 publications

(65 citation statements)

References 73 publications

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“…Clearly, APCs, and in particular the presentation of myelin peptide by MHC class II molecules expressed by APCs, are critically required to induce EAE. In mice unable to express MHC class II molecules (42), EAE is abolished. Furthermore, DCs seem to be more critical than microglia for the induction of EAE (15,43).…”

Section: Discussionmentioning

confidence: 99%

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Sosa

Murphey

Robinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Evidence has suggested both a pathogenic and a protective role for the proinflammatory cytokine IFN-γ in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying the protective role of IFN-γ in EAE have not been fully resolved, particularly in the context of CNS antigen-presenting cells (APCs). In this study we examined the role of IFN-γ in myelin antigen uptake by CNS APCs during EAE. We found that myelin antigen colocalization with APCs was decreased substantially and that EAE was significantly more severe and showed a chronic-progressive course in IFN-γ knockout (IFN-γ −/− ) or IFN-γ receptor knockout (IFN-γR −/− ) mice as compared with WT animals. IFN-γ was a critical regulator of phagocytic/activating receptors on CNS APCs. Importantly, "free" myelin debris and lipid peroxidation activity at CNS lesions was increased in mice lacking IFN-γ signaling. Treatment with N-acetyl-L-cysteine, a potent antioxidant, abolished lipid peroxidation activity and ameliorated EAE in IFN-γ-signalingdeficient mice. Taken together the data suggest a protective role for IFN-γ in EAE by regulating the removal of myelin debris by CNS APCs and thereby limiting the substrate available for the generation of neurotoxic lipid peroxidation products.

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Section: Discussionmentioning

confidence: 99%

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Sosa

Murphey

Robinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Further investigation showed that inhibition of Cat S expression in BCG-infected cells was responsible for the block of the maturation of class II molecules (20). Unlike MHC class II, IFN-␥-induced Cat S gene expression is not controlled by CIITA (47).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium bovis Bacillus Calmette-Guérin Secreting Active Cathepsin S Stimulates Expression of Mature MHC Class II Molecules and Antigen Presentation in Human Macrophages

Soualhine

Deghmane

Sun

et al. 2007

The Journal of Immunology

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A successful Th cell response to bacterial infections is induced by mature MHC class II molecules presenting specific Ag peptides on the surface of macrophages. In recent studies, we demonstrated that infection with the conventional vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) specifically blocks the surface export of mature class II molecules in human macrophages by a mechanism dependent on inhibition of cathepsin S (Cat S) expression. The present study examined class II expression in macrophages infected with a rBCG strain engineered to express and secrete biologically active human Cat S (rBCG-hcs). Cat S activity was completely restored in cells ingesting rBCG-hcs, which secreted substantial levels of Cat S intracellularly. Thus, infection with rBCG-hcs, but not parental BCG, restored surface expression of mature MHC class II molecules in response to IFN-γ, presumably as result of MHC class II invariant chain degradation dependent on active Cat S secreted by the bacterium. These events correlated with increased class II-directed presentation of mycobacterial Ag85B to a specific CD4+ T cell hybridoma by rBCG-hcs-infected macrophages. Consistent with these findings, rBCG-hcs was found to accelerate the fusion of its phagosome with lysosomes, a process that optimizes Ag processing in infected macrophages. These data demonstrated that intracellular restoration of Cat S activity improves the capacity of BCG-infected macrophages to stimulate CD4+ Th cells. Given that Th cells play a major role in protection against tuberculosis, rBCG-hcs would be a valuable tuberculosis vaccine candidate.

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“…Induction of HO-1 expression in microglia suppressed STAT-1 phosphorylation as well as CIITA expression, 2 critical events for MHC class II expression in APCs (28) (reviewed in ref. 29) as well as in the reactivation of myelin-reactive Th cells in the CNS (31). This effect is likely to contribute to the overall protective effect of HO-1 induction, as MHC class II expression in microglia is thought to be involved in EAE pathogenesis and progression (reviewed in refs.…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase–1 and carbon monoxide suppress autoimmune neuroinflammation

et al. 2007

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Heme oxygenase-1 (HO-1, encoded by HMOX1) dampens inflammatory reactions via the catabolism of heme into CO, Fe, and biliverdin. We report that expression of HO-1 dictates the pathologic outcome of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Induction of EAE in Hmox1 -/-C57BL/6 mice led to enhanced CNS demyelination, paralysis, and mortality, as compared with Hmox1 +/+ mice. Induction of HO-1 by cobalt protoporphyrin IX (CoPPIX) administration after EAE onset reversed paralysis in C57BL/6 and SJL/J mice and disease relapse in SJL/J mice. These effects were not observed using zinc protoporphyrin IX, which does not induce HO-1. CoPPIX protection was abrogated in Hmox1 -/-C57BL/6 mice, indicating that CoPPIX acts via HO-1 to suppress EAE progression. The protective effect of HO-1 was associated with inhibition of MHC class II expression by APCs and inhibition of Th and CD8 T cell accumulation, proliferation, and effector function within the CNS. Exogenous CO mimicked these effects, suggesting that CO contributes to the protective action of HO-1. In conclusion, HO-1 or exposure to its end product CO counters autoimmune neuroinflammation and thus might be used therapeutically to treat MS.

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The Role of the MHC Class II Transactivator in Class II Expression and Antigen Presentation by Astrocytes and in Susceptibility to Central Nervous System Autoimmune Disease

Cited by 87 publications

References 73 publications

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Mycobacterium bovis Bacillus Calmette-Guérin Secreting Active Cathepsin S Stimulates Expression of Mature MHC Class II Molecules and Antigen Presentation in Human Macrophages

Heme oxygenase–1 and carbon monoxide suppress autoimmune neuroinflammation

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