Following EAU recovery there is an associated MC5r-dependent APC induction of regulatory immunity in the spleen.

The eye is an immune-privileged tissue that has multiple mechanisms of immunomodulation to suppress the induction of inflammation.1–4 These mechanisms also manipulate immunity to regulate itself. For most, the mechanisms of immune privilege are highly effective in contributing to a lifetime of vision free from inflammation; however, uveitis (intraocular inflammation) does occur and threatens vision. Uveitis is the third leading cause of blindness among Americans; its prevalence is 204 per 100,000 persons per year.5 However, the rate of uveitis may be increasing in our aging population.6 Each year 17.6% of patients with active uveitis experience a transient or permanent loss of vision, and 12.5% of patients with active uveitis will develop glaucoma.7 After an initial episode of uveitis, 11.3% of the patients will within 5 years have at least one recurrence, and 2.5% of the patients will experience two recurrences.8 The mechanisms contributing to the relapsing and remitting nature of chronic autoimmune uveitis are not understood, nor is it well understood how prolonged remission of this disease can be achieved. Rodent models of experimental autoimmune uveoretinitis (EAU) have greatly helped in exploring the pathology of uveitis.9 Mice immunized with the ocular autoantigen interphotoreceptor retinoid binding-protein (IRBP) show retinal inflammation within 1 to 2 weeks of immunization; untreated B10.RIII mice recover within 30 to 45 days, and untreated C57BL/6 mice recover in 75 to 90 days. The mechanisms of recovery are unclear; however, it must involve the ocular microenvironment reestablishing the mechanisms of immune privilege.10,11 During the resolution of EAU, IRBP-specific CD4+CD25+ Treg cells emerge in the spleens of EAU mice.12 These Treg cells prevent the induction and the expression of memory immunity to IRBP.13 Induction of these Treg cells requires recovery from EAU because naive mice and enucleated mice immunized for EAU do not have this regulatory immunity in their spleens.12 Interestingly, induction of these Treg cells in the spleen is not required for the ocular microenvironment to recover from EAU because melanocortin 5 receptor (MC5r) knockout mice at the resolution of EAU do not express IRBP-specific regulatory immunity in their spleens, but display a tempo and severity of EAU similar to those of wild-type mice.12,13 Moreover, when the MC5r−/− mice are reimmunized with IRBP, they show clinical signs of uveitis within a couple of days and a severity far exceeding levels observed in the first episode.13 In contrast, IRBP-reimmunized wild-type mice have a second episode of EAU with a severity and tempo of a naive mouse. This includes the 9- to 10-day delay in seeing the first symptoms of uveoretinitis. The adoptive transfer of post-EAU spleen Treg cells from wild-type mice suppresses the memory immunity in the IRBP-reimmunized MC5r−/− mice. However, wild-type Treg cells after EAU have to be reactivated by post-EAU spleen APCs before they can adoptively transfer their regulatory activity. Therefore, this suggests that the induction of IRBP-specific Treg cells that reside in the spleens of post-EAU mice is dependent on the expression of MC5r and the activity of an APC that mediates tolerogenic activity. What is not known is whether the expression of MC5r is necessary for the emergence of the Treg cells or for the tolerance-mediating APCs in the spleens of mice recovered from EAU. Greater understanding of the melanocortin pathway in EAU recovery has the potential to lead to more effective therapies with long-term benefits not only for uveitis but also for other immunologic diseases needing the induction of immune tolerance.14 This article reports that the dependence on MC5r expression occurs with an APC that mediates regulatory activity in CD4+ effector T cells found in the post-EAU spleen.