Tolerance Induction in Relation to the Eye

Abstract

Inflammatory intraocular eye diseases, grouped under the term uveitis are blinding conditions, believed to be mediated by pathogenic autoimmune processes that overcome the protective mechanisms of the immune privilege status of the eye. An animal model for these diseases, named experimental autoimmune uveitis (EAU), is induced by initiation of immunity against ocular-specific antigens, or it develops spontaneously in mice with T-cells that transgenically express TCR specific to the target eye antigen(s). T-Cells specific to ocular antigens are generated in the thymus and their majority are eliminated by exposure to their target antigen expressed in this organ. T-cells that escape this negative selection acquire pathogenicity by their activation with the target antigen. In spontaneous EAU, the microbiota play crucial roles in the acquisition of pathogenicity by providing both antigenic stimulation, by molecules that mimic the target ocular antigen, and an additional stimulation that allows invasion of tissues that harbor the target antigen. The pathogenic process is physiologically inhibited by the peripheral tolerance, composed of antigen-specific T-regulatory (Treg) lymphocytes. Deleting the Tregs enhances the ocular inflammation, whereas adoptively transferring them suppresses the pathogenic response. Potential usage of Treg cells for suppression of autoimmune diseases in humans is under intensive investigation.

Keywords: T-helper (Th) cells; T-regulatory cells (Treg); experimental autoimmune uveitis (EAU); microbiota; ocular inflammation (uveitis); tolerance process.

Figure 1

Peripheral tolerance is inefficient in the case of retina-specific T cells. Schematic representation of the process of self-tolerance to retinal antigens. Adapted from Horai and Caspi (48). No copyright permissions are required for the reuse of this image.

Figure 2

Persisting retina-specific T cells can be activated by peripheral stimuli. Schematic representation of EAU induction after activation of retina-specific T cells in the gut. Green cells in left panel are nurllgfP-positive T cells that are signaling through their T cell receptor [Horai et al. (45)]. Red cell in the middle top panel is a retina-specific T cell extravasating from a retinal vessel. The cell is stained by the PKH26 tracking dye and this photo was previously published in Prendergast et al. (50). No copyright permissions are required for the reuse of this image.