Mechanisms of immune privilege in the anterior segment of the eye: what we learn from corneal transplantation

Abstract

The eye, like the brain and reproductive organs, possesses inherent immune privilege, and inflammation is self-regulated so as to preserve the organ functions. Studies over the past 30 years have provided insights of the multiple mechanisms of immune privilege. At present, three major lines of thought prevail regarding the molecular mechanisms of immune privilege in the eye: there are (1) anatomical, cellular, and molecular barriers in the eye; (2) eye-derived immunological tolerance, the so-called anterior chamber-associated immune deviation; and (3) immune suppressive intraocular microenvironment. In this review, the mechanisms of immune privilege that have been learned from ocular inflammation animal models, especially corneal transplantation, are described. Roles of new B7 family molecules on local immune regulation within the cornea are also introduced.

Keywords: ACAID; Corneal transplantation; Costimulatory molecules; Immune privilege; Immune suppression.

Fig. 1

Induction of ACAID. In the anterior chamber, which contains transforming growth factor (TGF)-β2 and thrombospondin (TSP)-1, the eye-derived antigen-presenting cells have captured antigens. The eye-derived APCs enter the bloodstream, reach the marginal zone of spleen, and produce TGF-β, macrophage inflammatory protein 2 (MIP-2), and CXC-chemokine ligand 2 (CXCL2). These cells attract and bind, via CD1d molecules, to NKT cells. The NKT cells produce TGF-β, IL-10, CC-chemokine ligand 5 (CCL5) and TSP-1; attract marginal zone B cells; and then form clusters comprised of these three cell types. T cells, which have presented the antigens in clusters, then differentiate into ACAID-inducing regulatory T cells (ACAID-Treg). CD4+ ACAID-Treg inhibit the differentiation of Th1 cells in the lymph nodes, while CD8+ ACAID-Treg inhibit the function of effector Th1 and Th2 cells in the local site

Fig. 2

T-cell apoptosis medicated by B7-H1 expressed in corneal endothelial cells. B7-H1, which is constitutively expressed in corneal endothelial cells, induces apoptosis of PD-1+T cells. Corneal endothelial cells also constitutively express Fas L, which is involved in immune regulation in the eye by inducing T-cell apoptosis via Fas

Fig. 3

Induction of B7-H1 expression in the corneal epithelium and up-regulation of T-cell surface PD-1. B7-H1 is constitutively expressed in the endothelial cells and stromal cells of the normal cornea but not in the epithelial cells. PD-1 expression on the surface of T cells is up-regulated by contact with corneal cells. In the presence of IFN-γ, B7-H1 expression on epithelial cells is induced, and T-cell apoptosis mediated by B7-H1 and PD-1 is induced in each of the epithelium, stroma, and endothelium of the cornea