The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called ‘immune privilege’. Corneal tissue has inherent immune privilege properties with underlying three mechanisms: (1) anatomical, cellular, and molecular barriers in the cornea; (2) an immunosuppressive microenvironment; and (3) tolerance related to regulatory T cells and anterior chamber-associated immune deviation. This review describes the molecular mechanisms of the immunosuppressive microenvironment and regulatory T cells in the cornea that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, it also provides an update on immune checkpoint molecules in corneal and systemic immune regulation, and its relevance for dry eye associated with checkpoint inhibitor therapy.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside theHLAcomplex,CCL24,STYXL1-SRRM3, andC1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10⁻⁸) with sarcoidosis;CCL24andSTYXL1-SRRM3were novel. The disease-risk alleles inCCL24andIL23Rwere associated with reducedCCL24andIL23Rexpression, respectively. The disease-risk allele inSTYXL1-SRRM3was associated with elevatedPORexpression. These results suggest that genetic control ofCCL24,POR, andIL23Rexpression contribute to the pathogenesis of sarcoidosis. We speculate that theCCL24risk allele might be involved in a polarized Th1 response in sarcoidosis, and thatPORandIL23Rrisk alleles may lead to diminished host defense against sarcoidosis pathogens.

Purpose: V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel immune checkpoint receptor and ligand for regulating T cell proliferation and cytokine production. The purpose of the present study was to determine the role of VISTA in the immune privilege of corneal allografts. Methods: Expression of VISTA mRNA in mouse eyes was assessed with reverse-transcription PCR. Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of BALB/c wild-type recipients treated with anti-VISTA mAb, and graft survival was assessed. A separate set of BALB/c mice treated with anti-VISTA mAb or rat IgG received injection of C57BL/6 splenocytes into the anterior chamber, and induction of allospecific anterior chamber-associated immune deviation (ACAID) was assessed. CD4⁺ and CD8⁺ T cells in the spleen were assessed with flow cytometry. Results: VISTA mRNA was constitutively expressed in the cornea, and the expression of VISTA was localized to CD11b⁺ cells on the corneal stroma. Survival of allografts treated with anti-VISTA mAb was less than that of the control. ACAID was induced less efficiently in BALB/c mice treated with VISTA mAb. The proportions of CD8⁺ T cells and CD8⁺ CD103⁺ T cells (CD8⁺ T regulatory cells) in the spleen of BALB/c mice treated with anti-VISTA mAb were significantly lower than those of the control. Conclusions: VISTA may play an essential role in the acceptance of corneal allografts via involvement with allospecific ACAID, which suppresses T cell infiltration into the cornea.

Scleritis involves inflammation of the sclera, which constitutes 75% of the wall of the eye. This pathology is often seen as an ocular lesion associated with systemic inflammatory diseases. Severe types of scleritis such as posterior scleritis require urgent immunosuppressive treatments, including molecularly targeted therapies to avoid permanent visual impairment. Which molecules should be selected as targets has remained unclear. To clarify the pathogenesis of scleritis and propose appropriate target molecules for therapy, we have established novel animal model of scleritis by modifying the Collagen-II Induced Arthritis (CIA) model. Immunization twice with collagen II emulsified with complete Freund’s adjuvant (CFA) caused arthritis and scleritis. The clinical appearance resembled human diffuse scleritis. Histopathological analysis suggested that macrophages, plasma cells, deposition of immune complexes, and growth of blood and lymphatic vessels are involved in the pathogenesis of CIA-associated scleritis. In addition, we analysed the background diseases of posterior scleritis and responses to molecularly targeted therapies as a case series study. We inferred from both the animal model and case series study that targets should not be T cells, but factors inhibiting macrophage activity such as tumor necrosis factor (TNF) and interleukin (IL)-6, and molecules suppressing antibody-producing cells such as CD20 on B cells should be targeted by molecularly targeted therapies.