Ocular autoimmunity: the price of privilege?

Summary:  The eye is the prototypic immune‐privileged organ. Its antigens were once believed to be expressed exclusively in the eye, which resides behind an efficient blood–organ barrier, and were believed to be unknown to the immune system. Self‐tolerance to ocular components was therefore believed to be based not on immune tolerance but on immune ignorance. It is now known that the relationship between the immune system and the eye is much more complex. On the one hand, immune privilege is now known to involve not only sequestration but also active mechanisms that (i) inhibit innate and adaptive immune processes within the eye and (ii) shape the response that develops systemically to antigens released from the eye. On the other hand, retinal antigens are found in the thymus and have been shown to shape the eye‐specific T‐cell repertoire. However, thymic elimination of self‐reactive T cells is incomplete, and such ‘escapee’ T cells are tolerized in the periphery as they recirculate through the body by encounter with self‐antigen in healthy tissues. Due to the relative inaccessibility of the healthy eye to the immune system, peripheral tolerance mechanisms may not operate efficiently for ocular antigens, leaving a weak link in the homeostasis of tolerance. The case shall be made that although immune privilege protects vision by keeping the immune system at bay, a potential for developing destructive anti‐retinal autoimmunity may be the price for the day‐to‐day protection afforded by immune privilege against inflammatory insults.