Transgenic expression of an immunologically privileged retinal antigen extraocularly enhances self tolerance and abrogates susceptibility to autoimmune uveitis

Abstract

Interphotoreceptor retinoid-binding protein (IRBP) is an immunologically privileged retinal antigen that can elicit experimental autoimmune uveitis (EAU). The nature and extent of tolerance to immunologically privileged self antigens is poorly understood. To investigate whether transgenic expression of IRBP extraocularly enhances tolerance and protects from EAU we prepared mice that express half of the mouse IRBP gene, containing a potent uvei-togenic epitope (residues 161-180), under control of MHC class II promoter. Transgene mRNA was detectable in many tissues. Transgenic protein was undetectable by conventional assays, but was detected in thymic tissue by lymphocyte proliferation assay after induction of the promoter. Transgenic mice challenged with p161-180 did not develop EAU and had reduced immunological responses, but remained susceptible to EAU induced by whole IRBP, that contains additional uveitogenic epitopes. Disease was also induced by wild type T cells specific to p161-180. Thus, extraocular expression of a privileged retinal antigen enhances self tolerance, supporting the notion that sequestration contributes to immune privilege. Exceedingly low levels of transgene expression result in tolerance that is both profound and epitope specific, implying anergy or deletion of the endogenous uveitogenic repertoire. The same level of expression is, however, insufficient to tolerize wild-type effector T cells in the periphery.

A look at autoimmunity and inflammation in the eye

“…Thus, circulating retinal antigen-specific T cells are likely to be "ignorant" of their cognate antigen rather than tolerant and can be activated by a chance encounter with antigen, possibly in the form of a microbial component that structurally mimics their cognate tissue antigen (19). Indeed, it has been demonstrated that forced expression of a retinal antigen in the periphery (as a transgene, by retroviral delivery, or by vaccination with naked DNA) results in tolerance and in resistance to the subsequent induction of autoimmunity (20)(21)(22)(23). Therefore, by sequestering retinal antigens within the eye and hindering peripheral tolerance, immune privilege may actually predispose to ocular autoimmunity (24).…”

Limited Peripheral T Cell Anergy Predisposes to Retinal Autoimmunity

“…However, this mechanism may be deficient for retinal proteins that are sequestered from circulating lymphocytes behind the blood-retinal barrier. Resting ␤-galactosidase-specific CD4 ϩ T cell clones transferred into transgenic mice expressing retinal ␤-galactosidase appear to be immunologically ignorant (19,20) while the systemic expression of retinal Ags reduces susceptibility to EAU, presumably by converting a state of immunological ignorance to one of active tolerance (21,22). However, the exact contribution, if any, of peripheral tolerance, Ag sequestration, and local forms of tolerance, such as anterior chamber-associated immune deviation (20,(23)(24)(25)(26) vs central tolerance, remains to be determined.…”

Retroviral gene therapy with an immunoglobulin-antigen fusion construct protects from experimental autoimmune uveitis

“…In this context it is interesting to point out a similarity to IRBP-transgenic mice, which express a portion of IRBP containing the 161-180 epitope extraocularly under control of a class II promoter. These mice, which are highly refractory to induction of EAU, also show a 20-fold dose-response shift in antigen-specific proliferation, rather than complete unresponsiveness (30). A thorough dissection of the relative contributions of various possible mechanisms will be made feasible by the development of transgenic mice expressing uveitogenic T-cell receptors.…”