[Intraocular inflammation and homeostasis of the eye].
The pathogenic mechanisms of intraocular inflammation had not been well studied until Wacker and his colleagues found retinal soluble antigen (S antigen) and established experimental autoimmune uveitis (EAU), an animal model for autoimmune uveitis. Using this animal model, great progress in understanding the immunopathogenic mechanisms of uveitis was achieved not only in EAU, but also in many inflammatory disorders in humans. Intraocular inflammation is mediated by activated CD4+ T cells. However, the eye has a unique regional immune system which protects intraocular tissues from these pathogenic activated CD4+ T cells and contributes to the homeostasis of the intraocular microenvironment. In the present review article, the role of T cells in immunopathogenic mechanisms of ocular inflammatory disorders as well as in the regional defense system of the eye is highlighted. 1. Immunopathogenic mechanisms of EAU: Experiments using athymic nude rats as well as adoptive transfer of EAU by S-antigen-sensitized T lymphocytes into naive Lewis rats disclosed that T lymphocytes, particularly CD4+ T lymphocytes, play a central role in the immunopathogenic mechanisms of EAU. In addition, immunopharmacological studies showing the intense effects of cyclosporine on EAU with selective immunosuppression to T lymphocytes allowed us to use clinically the agent to treat patients with refractory uveitis of non-infectious origins, such as Behcet's disease. 2. Immunopathogenic mechanisms of uveitis in human: Two clinical uveitis entities commonly seen in Japan, i. e. Vogt-Koyanagi-Harada (VKH) disease and human T-cell leukemia virus type 1 (HTLV-1) uveitis, were studied for their pathogenic mechanisms. (1) VKH disease: We established T cell clones from infiltrating cells in the eyes of VKH patients using limiting dilution methods. CD4+ T cell clones from VKH disease, but not from other uveitis entities, responded to tyrosinase, a melanocyte-associated antigen, and produced inflammatory cytokines, and the response was specific to tyrosinase. Furthermore, DataBank analysis disclosed that tyrosinase had a structural homology with an exogenous antigen, a glycoprotein peptide of cytomegalovirus (CMV). CD4+ T lymphocytes from VKH patients, but not from other diseases, which responded to both tyrosinase and CMV peptide. This indicates that molecular mimicry between CMV peptide and tyrosinase plays an important role in the immunopathogenic mechanisms by which CD4+ T lymphocytes are sensitized to autoantigen of tyrosinase and cause inflammation in VKH disease. (2) HTLV-1 uveitis: Similar to adult T cell leukemia and HTLV-1 associated myelopathy, uveitis in asymptomatic carriers of HTLV-1, prevalent in southern Kyushu, is a distinct clinical entity associated with HTLV-1, a human retrovirus. We analyzed ocular infiltrating cells and found that (a) HTLV-1-infected CD4+ T lymphocytes were significantly accumulated in the eye, and (b) HTLV-1-infected CD4+ T lymphocytes produced a large amount of various inflammatory cytokines. Thus, CD4+ T lymphocytes play a central role in the pathogenic mechanisms of HTLV-1 uveitis. 3. Regional defense system of the eye: As described above, CD4+ T lymphocytes made active by either autoantigens or exogenous pathogens, enter the eye and cause inflammatory responses. However, the eye is known to be an immune privileged site. We focused on ocular pigment epithelial cells because they form a blood-ocular barrier, and they may protect the eye immunologically from infiltrating inflammatory cells. Our major findings by in vitro experiments in mice are (a) ocular pigment epithelial cells have the capacity to suppress activated CD4+ T lymphocytes; (b) the mode of action of iris pigment epithelial cells (IPE) and retinal pigment epithelial cells (RPE) are different: T lymphocyte suppression by IPE requires cell-to-cell contact, whereas suppression by RPE requires soluble factors, but not cell-to-cell contact; (c) both IPE and RPE have the capacity to generate regulatory T cells(Treg), thereby enhancing immune regulation in the eye. In conclusion, CD4+ T lymphocytes activated by either autoantigens or infectious agents play a central role in the pathogenic mechanisms of ocular inflammation, and ocular resident cells such as IPE and RPE suppress the pathogenic activated CD4+ T lymphocytes, thereby contributing to homeostasis of the eye.
Department of Ophthalmology & Visual Science, Tokyo Medical and Dental University Graduate School, Japan. m.manabu.oph@tmd.ac.jp
Manabu
M
Mochizuki
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005123:Eye / Q000276:immunology*; D015490:HTLV-I Infections / Q000276:immunology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D014605:Uveitis / Q000276:immunology*; D014607:Uveomeningoencephalitic Syndrome / Q000276:immunology