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The eye and the immune system

Insights on mechanisms and benefits of ocular immune privilege and its loss

Cheryl Guttman Krader

Posted: Sunday, September 1, 2019


Jerry Y Niederkorn PhD

US president John F Kennedy once said: “When written in Chinese, the word ‘crisis’ is composed of two characters – one represents danger and the other represents opportunity.”

Jerry Y Niederkorn PhD referenced the famous quote in his delivery of the Proctor Lecture at the 2019 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Vancouver, Canada, drawing an analogy with the eye and the immune system.

He provided a detailed review of research showing how the same concept describes the consequences of sympathetic loss of immune privilege (SLIP), a phenomenon in which perturbation of the ocular surface in one eye leads to termination of immune privilege in the opposite eye.

Dr Niederkorn is Professor and Vice Chair of Research, University of Texas Southwestern Medical School, Dallas, USA. In his talk, “The eye sees eye to eye with the immune system”, Dr Niederkorn explained that ocular immune privilege is a beneficial adaptation for preserving vision. He went on to describe how its termination can also be beneficial because it serves to protect the host from potentially life-threatening infections, albeit at the risk of blindness.

UNDERSTANDING IMMUNE PRIVILEGE
Providing a contemporary definition of immune privilege, Dr Niederkorn said that it describes a compromise between the eye and the immune apparatus to minimise immune-mediated inflammation and injury to ocular tissues that have limited or no regenerative capacity.

“Immune privilege of the ocular surface allows the ocular surface to tolerate daily exposure to nominal non-infectious agents. It is an adaptation to silence an immune-mediated inflammatory response and protect the ocular tissues from irreparable injury in order to preserve vision.”

Ocular immune privilege also explains the extremely low rejection rate (~10%) of first corneal transplants that occurs in the absence of histocompatibility matching or use of systemic immunosuppressive medications.

“I know of no other type of transplant that can survive at that rate under those conditions. Subsequent corneal allografts in the second eye in humans have a two- to three-fold increased incidence of rejection. Mouse studies suggest that this increased risk for rejection in humans is due to SLIP,” noted Dr Niederkorn.

RESPONDING TO CRISIS – MECHANISMS EXPLAINED
The dichotomous effects of loss of ocular immune privilege were demonstrated by the findings of an animal experiment that investigated the inflammatory response to herpes simplex virus (HSV) corneal inoculation. The research showed that while T-cell-deficient animals developed infection and died, their corneas remained clear. In contrast, the normal mice that were able to generate an immune response developed necrotising keratitis, but the animals survived because their intact immune response protected against virus dissemination.

“This experiment tells us that the immune response to HSV infection, not the virus, is responsible for damaging the cornea, and that the outcome of being unable to mount an immune response is death as opposed to blindness,” Dr Niederkorn said.

He explained that the mechanism for immune privilege involves anterior chamber-associated immune deviation (ACAID), a phenomenon in which antigens introduced into the eye reach the spleen where they induce formation of T regulatory cells that suppress the immune response in the eye. SLIP occurs when the T regulatory cells become disabled through a pathway that is regulated by corneal nerves and mediated by release of the neuropeptide, substance P.

Research conducted by Dr Niederkorn and colleagues provided understanding of these mechanisms and showed that in the setting of a first corneal transplant, the severing of corneal nerves by trephination is responsible for inducing secretion of substance P. Similarly, the release of substance P explains SLIP in HSV keratitis.

Substance P is released in response to infection as the dense network of corneal sensory nerves acts to alert the immune system of infectious agents that produce tissue damage but that are also a threat to host survival, Dr Niederkorn explained.

“In its wisdom, the immune system anticipates that an ocular infection in one eye will be followed by infection in the fellow eye. The eye has a dialogue with the immune system, and in an adaptation to preserve life, the dialogue leads to termination of immune privilege, even if it means blinding the eyes, because some of those infections can take the life of the host.”

Jerry Y Niederkorn: Jerry.Niederkorn@utsouthwestern.edu