Experimental autoimmune uveoretinitis (EAU)<i>versus</i>experimental allergic encephalomyelitis (EAE): a comparison of T cell-mediated mechanisms

Calder, Virginia L.; Lightman, Susan

doi:10.1111/j.1365-2249.1992.tb06926.x

Cited by 23 publications

(11 citation statements)

References 43 publications

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“…The retina was long thought to be entirely devoid of MHC class II, as part of the immune privilege. However, in line with our data, some studies have highlighted faint MHC class II expression in the naive retina, as well as an increased expression of MHC class II during uveitis [ 21 ]. Despite years of research, great controversies remain on the role of MHC class II expression by different cell types in uveitis development.…”

Section: Discussionsupporting

confidence: 92%

MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis

Lipski

Dewispelaere

Foucart

et al. 2017

J Neuroinflammation

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BackgroundControversy exists regarding which cell types are responsible for autoantigen presentation in the retina during experimental autoimmune uveitis (EAU) development. In this study, we aimed to identify and characterize the retinal resident and infiltrating cells susceptible to express major histocompatibility complex (MHC) class II during EAU.MethodsEAU was induced in C57BL/6 mice by adoptive transfer of autoreactive lymphocytes from IRBP1-20-immunized animals. MHC class II expression was studied by immunostainings on eye cryosections. For flow cytometry (FC) analysis, retinas were dissected and enzymatically digested into single-cell suspensions. Three MHC class II+ retinal cell populations were sorted by FC, and their RNA processed for RNA-Seq.ResultsImmunostainings demonstrate strong induction of MHC class II expression in EAU, especially in the inner retina at the level of inflamed vessels, extending to the outer retinal layers and the subretinal space in severely inflamed eyes. Most MHC class II+ cells express the hematopoietic marker IBA1. FC quantitative analyses demonstrate that MHC class II induction significantly correlates with disease severity and is associated with upregulation of co-stimulatory molecule expression. In particular, most MHC class IIhi cells express co-stimulatory molecules during EAU. Further phenotyping identified three MHC class II+ retinal cell populations: CD45−CD11b− non-hematopoietic cells with low MHC class II expression and CD45+CD11b+ hematopoietic cells with higher MHC class II expression, which can be further separated into Ly6C+ and Ly6C− cells, possibly corresponding to infiltrating macrophages and resident microglia. Transcriptome analysis of the three sorted populations leads to a clear sample clustering with some enrichment in macrophage markers and microglial cell markers in Ly6C+ and Ly6C− cells, respectively. Functional annotation analysis reveals that both hematopoietic cell populations are more competent in MHC class II-associated antigen presentation and in T cell activation than non-hematopoietic cells.ConclusionOur results highlight the potential of cells of hematopoietic origin in local antigen presentation, whatever their Ly6C expression. Our work further provides a first transcriptomic study of MHC class II-expressing retinal cells during EAU and delivers a series of new candidate genes possibly implicated in the pathogenesis of retinal autoimmunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0915-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis

Lipski

Dewispelaere

Foucart

et al. 2017

J Neuroinflammation

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“…For example, EAU and EAE are two well-characterized models of the human CNS autoimmune diseases, uveitis and multiple sclerosis, respectively, and both diseases share essential immunopathological mechanisms in terms of critical roles of Th17 cells in their etiology (35, 43). It is therefore surprising that loss of IRF8 in CD4 + T cells exacerbates EAU but does not have a significant role in EAE (17).…”

Section: Discussionmentioning

confidence: 99%

Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection

Kim

Burton

et al. 2015

The Journal of Immunology

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Interferon regulatory factor 8 (IRF8) is constitutively expressed in monocytes and B cells and plays critical role in the functional maturation of microglia cells. It is induced in T-cells following antigen stimulation but its functions are less well understood. However, recent studies in mice with T cell-specific Irf8 disruption under direction of the Lck promoter (LCK-IRF8KO) suggest that IRF8 directs a silencing program for Th17 differentiation and IL-17 production is markedly increased in IRF8 deficient T-cells. Paradoxically, loss of IRF8 in T-cells has no effect on the development or severity of experimental autoimmune encephalomyelitis (EAE) while exacerbating colitis in a mouse colitis model. On the other hand, mice with a macrophage/microglia-specific Irf8 disruption are resistant to EAE, further confounding our understanding of the roles of IRF8 in host immunity and autoimmunity. To clarify the role of IRF8 in autoimmune diseases, we have generated two mouse strains with targeted deletion of Irf8 in retinal cells including microglial cells and a third mouse strain with targeted Irf8 deletion in T-cells under direction of the non-promiscuous, CD4 promoter (CD4-IRF8KO). In contrast to the report that IRF8 deletion in T-cells has no effect on EAE, experimental autoimmune uveitis is exacerbated in CD4-IRF8KO mice and disease enhancement correlates with significant expansion of Th17 cells and a reduction in Tregs. In contrast to CD4-IRF8KO mice, Irf8 deletion in retinal cells confers protection from uveitis, underscoring divergent and tissue-specific roles of IRF8 in host immunity. These results raise cautionary note in context of therapeutic targeting of IRF8.

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“…Recent reports indicating requirement of STAT3 for commitment of naive T cells toward the Th17 developmental pathway (9, 10) suggest a potential involvement of STAT3 pathway in mediating CNS inflammatory diseases. In this study, we have generated mice with targeted deletion of Stat3 in the CD4 ϩ T cell compartment (CD4 Stat3Ϫ/Ϫ ) and used them to examine whether STAT3 pathways are required for development of EAU, as well as, experimental autoimmune encephalomyelitis (EAE), another CNS disease that shares essential immunopathologic features as EAU (11). In this study, we have shown that unlike the partial protection conferred by IL-17 blockage with IL-17 Abs (5), CD4 stat3Ϫ/Ϫ mice are completely resistant to EAU or EAE, and this dramatic outcome derives from combinatory mechanisms that include: IL-17 blockade; altered T cell homeostasis that favor expansion of anti-inflammatory responses; and inhibition of T cell entry to CNS tissues.…”

Section: Loss Of Stat3 In Cd4 ؉ T Cells Prevents Development Of Expermentioning

confidence: 99%

“…Mice were immunized with 150 g interphotoreceptor retinoid-binding protein (IRBP) and 300 g of human IRBP peptide (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) in 0.2 ml emulsion 1:1 v/v with CFA containing Mycobacterium tuberculosis strain H37RA (2.5 mg/ml). The mice also received Bordetella pertussis toxin (0.2 g/mouse) concurrent with immunization, and clinical disease was established by fundoscopy as described previously (12).…”

Section: Induction Of Eau By Active Immunizationmentioning

confidence: 99%

Loss of STAT3 in CD4+ T Cells Prevents Development of Experimental Autoimmune Diseases

Liu

Lee

et al. 2008

The Journal of Immunology

256

222

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Th17 cells are implicated in CNS autoimmune diseases. We show that mice with targeted-deletion of Stat3 in CD4+ T cells (CD4Stat3−/−) do not develop experimental autoimmune uveoretinitis (EAU) or experimental autoimmune encephalomyelitis. Defective Th17 differentiation noted in CD4Stat3−/− mice is compensated by exaggerated increases in Foxp3-, IL-10-, IL-4-, and IFN-γ-expressing T cells, suggesting critical roles of STAT3 in shaping Ag-specific CD4+ T cell repertoire. In mice with EAU, a high percentage of IL-17-expressing T cells in their peripheral lymphoid organs also secrete IFN-γ while these double-expressors are absent in CD4Stat3−/− and wild-type mice without EAU, raising the intriguing possibility that uveitis maybe mediated by Th17 and IL-17-expressing Th1 cells. Resistance of Stat3-deficient mice to EAU derives in part from an inability of uveitogenic Th17 and Th1 cells to enter eyes or brain of the CD4Stat3−/− mouse because of the reduction in the expression of activated α4/β1 integrins on CD4Stat3−/− T cells. Adoptive transfer of activated interphotoreceptor retinoid-binding protein-specific uveitogenic T cells induced in CD4Stat3−/− mice a severe EAU characterized by development of retinal folds, infiltration of inflammatory cells into the retina, and destruction of retinal architecture, underscoring our contention that the loss of STAT3 in CD4+ T cells results in an intrinsic developmental defect that renders CD4Stat3−/− resistant to CNS inflammatory diseases. STAT3 requirement for IL-17 production by Th17, generation of double positive T cells expressing IL-17 and IFN-γ, and for T cell trafficking into CNS tissues suggests that STAT3 may be a therapeutic target for modulating uveitis, sceritis, or multiple sclerosis.

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Experimental autoimmune uveoretinitis (EAU)versusexperimental allergic encephalomyelitis (EAE): a comparison of T cell-mediated mechanisms

Cited by 23 publications

References 43 publications

MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis

MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis

Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection

Loss of STAT3 in CD4+ T Cells Prevents Development of Experimental Autoimmune Diseases

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