Questioning the dogma of immune privilege
A paper by Monash Biomedicine Discovery Institute (BDI) researcher Professor Paul McMenamin and colleagues published in Nature Reviews Neuroscience has tackled head-on the well-known theory of immune privilege.
Immune privilege (IP), a term coined by transplantation pioneer Sir Peter Medawar (later Nobel Prize winner) in the 1940s, holds that a handful of sites in the body, including the central nervous system (CNS) and the eye, do not show typical inflammatory responses to grafts, and tolerate the introduction of antigens without eliciting an inflammatory immune response. This was held to be an evolutionary adaptation to protect these important sites from potentially damaging inflammation.
Professor McMenamin and long-term colleague Professor John Forrester from the University of Aberdeen, decided to review the existing literature on the topic to put the dogma to the test.
“John and I had been developing over many years the idea that the paradigm that had been put forward may be a bit of a straw man,” Professor McMenamin said.
“It was a concept that was convenient to explain things but scientifically we were always worried that it never really made sense,” he said.
Together with then Monash BDI postdoctoral researcher Dr Samantha Dando, they analysed the findings of more than 250 papers on the subject, approaching it from their three fields; Professor Forrester, an ophthalmologist, studies immunological function in the eye; Professor McMenamin has shifted from ocular immunology into brain research, and Dr Dando, a microbiologist, studies infections of the CNS.
“Eye researchers and brain researchers considered the neural environment to be unique in terms of being immune privileged whereas I think there are a lot of lessons to be learnt in looking at the subtle differences between the eye and the brain,” Professor McMenamin said.
“The review was to get these two fields of literature together so people could see that there were distinct lessons in each,” he said.
“There are lots of homologies between the eye and the brain. The sheath that surrounds the optic nerve, for example, is made of much the same membrane layers that surround your brain.”
“A lot of ways that microorganisms affect areas in the brain and the eye are very similar. The degrees of IP are also similar.”
Toxoplasma, for example, lives in the brain and the retina, evading the immune system because the parasite is protected behind physical, physiological and immunological barriers.
The review concluded that the CNS can in fact ‘protect’ pathogens. While many pathogens that get close to the CNS are excluded by extensive barriers, some get through those barriers and find an environment conducive to survival as latent infections – they become dormant and do not proliferate. Whether a CNS infection is cleared, persists in a latent state or kills the host depends on a balance between the virulence of the organism and the tissue-dependent host immune response, the review says. Opportunistic infections have a better chance of being “protected” (becoming latent) by the CNS.
“The paper makes the point that this occurs only when the immune system is really compromised,” Professor McMenamin said.
“For example, when the AIDS epidemic came along a lot of people were immune-compromised and all of a sudden people were getting all these toxoplasmosis lesions in the brain and the retina. The immune system was breaking down so the organism got the upper hand and could actually proliferate uncontrolled,” he said.
“IP is more of a spectrum than a black and white concept. It’s just that the retina in the eye and the cortex in the brain – the white and grey matter – have more IP than other parts of the body and much more highly developed barriers.”
“I think the review points out to people that the dogma of IP, the paradigm, no longer stands up to analysis.”
About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.