Abstract
Autoantigen-specific regulatory immunity emerges in the spleen of mice recovering from experimental autoimmune uveitis (EAU), a murine model for human autoimmune uveoretinitis. This regulatory immunity provides induced tolerance to ocular autoantigen, and requires melanocortin 5 receptor (MC5r) expression on antigen presenting cells with adenosine 2 A receptor (A2Ar) expression on T cells. During EAU it is not well understood what roles MC5r and A2Ar have on promoting regulatory immunity. Cytokine profile analysis during EAU revealed MC5r and A2Ar each mediate distinct T cell responses, and are responsible for a functional regulatory immune response in the spleen. A2Ar stimulation at EAU onset did not augment this regulatory response, nor bypass the MC5r requirement to induce regulatory immunity. The importance of this pathway in human autoimmune uveitis was assayed. PBMC from uveitis patients were assayed for MC5r expression on monocytes and A2Ar on T cells, and comparison between uveitis patients and healthy controls had no significant difference. The importance for MC5r and A2Ar expression in EAU to promote the induction of protective regulatory immunity, and the expression of MC5r and A2Ar on human immune cells, suggests that it may be possible to utilize the melanocortin-adenosinergic pathways to induce protective immunity in uveitic patients.
Highlights
In the spleen of mice that have recovered from the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis[14]
In order to study an antigen-specific T cell response, the spleen cells were reactivated with human interphotoreceptor retinoid binding protein (IRBP) peptide for two days, and supernatants were assayed for IFN-γ, TGF-β,and IL-17
There was a biphasic production of IFN-γ, which was significantly higher at the start of experimental autoimmune uveitis (EAU) in Melanocortin 5 receptor (MC5r)(−/−) mice; its production decreased through the chronic phase, and significantly increased during resolution of EAU (Fig. 1C)
Summary
In the spleen of mice that have recovered from the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis[14]. The current treatment paradigm for autoimmune uveitis is to suppress the inflammation for a period of time that is long enough for the eye or the immune system to re-establish regulatory immunity to ocular autoantigen on its own[23,24] This immunosuppressive strategy places the patient at an increased susceptibility to infection. Non-steroidal anti-inflammatory drugs such as naproxen and celecoxib can cause gastrointestinal bleeding[24,25] Biologics are another class of therapies that target specific cytokines or cytokine receptors to inhibit the inflammatory response[26,27,28]. In this study we show that MC5r and A2Ar have distinct roles in the recovery from EAU, and that MC5r expression on specific subsets of monocytes and A2Ar expression on CD4 T cells is similar between uveitis patients and healthy controls
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