Inducible immune regulation following autoimmune disease in the immune-privileged eye

Abstract

The immune-privileged eye has the potential to induce regulatory immunity along with local mechanisms of immunosuppression. Rodent models of human autoimmune uveoretinitis [experimental autoimmune uveoretinitis (EAU)] recover without spontaneous recurrence of uveitis, which differs from uveitis in some humans. This raises the possibility that the mechanism of immune privilege in the rodent eye can reimpose itself during autoimmune uveoretinitis and re-establish tolerance to autoantigen. To investigate this possibility, we examined the spleens of EAU-recovered mice for regulatory immunity. We detected regulatory immunity when we adoptively transferred post-EAU spleen cells into other mice immunized for EAU. We could not detect this regulatory immunity in enucleated mice nor in naive mice. Moreover, unlike the mechanisms of anterior chamber-associated immune deviation, the suppression was only mediated by post-EAU CD4 + T cells, which required activation with autoantigen presented by post-EAU spleen antigen-presenting cells (APC). Our results demonstrate that when the immune-privileged ocular microenvironment recovers from an autoimmune response, it has influenced systemic immunity to retinal autoantigen by affecting APC and mediating induction of potential regulatory CD4 + T cells laying in wait in the post-EAU spleen for restimulation.

The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (α-MSH) therapy

“…Although all the reimmunized α-MSH-treated EAE mice succumbed to a second episode of EAE, the delay prior to the first symptoms of EAE and their subsequent EAE response after the second episode were significantly different from the untreated mice. We have seen a similar delay in mice that naturally recovered from EAU and were reimmunized with retinal autoantigen to induce a second episode of uveitis (Kitaichi et al, 2005). We found that α-MSH may have a role in this phenomena, because melanocortin 5 receptor knockout EAUconvalescing mice exhibited a rapid and sever uveitic response following reimmunization that was reminiscent of an immunological memory response to the retinal autoantigen (Taylor et al, 2006).…”

“…When we made a similar systemic injection of α-MSH in mice with EAU there was an accelerated resolution of ocular inflammation (Taylor et al, 2000). Recently we have found that α-MSH may have an important role in the natural recovery of mice from EAU by promoting induction of retinal autoantigen-specific Treg cells that we find in the post-EAU spleen, and in minimizing retinal tissue damage during an episode of uveitis (Kitaichi et al, 2005).…”

“…How such α-MSH-induced Treg cells function in vivo is unknown, and we do not know if the Treg cells are a by-product of the α-MSH-treatment or play role in the suppression of EAE. We have constantly find that their presence after the initial episode of autoimmune disease delays the onset of an induced second episode of autoimmune disease, but cannot prevent the second episode from happening (Kitaichi et al, 2005;Taylor et al, 2006). The importance of Th17 cells in autoimmunity has recently been reported in the literature (Hofstetter et al, 2005;Komiyama et al, 2006;Kroenke and Segal, 2007).…”

Autoimmune Uveitis Elicited with Antigen-Pulsed Dendritic Cells Has a Distinct Clinical Signature and Is Driven by Unique Effector Mechanisms: Initial Encounter with Autoantigen Defines Disease Phenotype

“…In the traditional EAU model, recovery is accompanied by induction of active regulatory mechanisms that help to restore homeostasis and limit reinduction of the disease (33). The milder and self-limiting nature of DC-induced inflammation compared with the active immunization model, which leaves a persistent Ag depot, raised the possibility that Ag availability might be a limiting factor and might potentially account for remission of DC-induced EAU in the absence of active resolution mechanisms.…”

A look at autoimmunity and inflammation in the eye

“…Although its relevance to autoimmunity has been contested (partly due to the fact that most studies used ovalbumin as antigen and delayed-type hypersensitivity as the only readout), ACAID or ACAID-like mechanisms might limit immune reactions to retinal antigens following ocular trauma. In addition, in animals that recovered from EAU, post-recovery CD4 + regulatory T cells have been described, and these cells appear to be distinct from ACAID-induced regulatory cells (65). Their induction is dependent on the presence of the eye (they are not induced in enucleated animals immunized as for EAU) and on expression of melanocortin-5 receptor by T cells (66).…”