Issue #26: Self and non-self: autoimmunity and immunological tolerance

Setting it Straight - Issue #26

Written by Nobel Laureate Professor Peter Doherty

Self and non-self, self and other? That may sound more like a theme for a deep philosophical discussion between psychologists rather than a topic that is of direct relevance to COVID-19 and infectious disease. But telling the difference between the ‘self’ proteins, cells, tissues and organs of our own bodies versus those of some ‘non-self’ invading pathogen, then reacting accordingly is exactly what immunity is about. When self/non-self discrimination goes wrong and our very own immune system starts to see something of us as ‘foreign’, the consequence can be autoimmune diseases like type 1 diabetes (in children), rheumatoid arthritis, multiple sclerosis, lupus, and Grave’s Disease.

Autoimmunity is an enormous subject and, as we’re basically focused on understanding COVID-19, I won’t go into it in depth here. Still, there are suspicions that some virus infections do, at times, trigger our own immune systems into ‘self-attack’ mode. While we know that there can be a lot of ‘background noise’ immunoglobulin (Ig) production concurrent with virus-specific immune responses, establishing any direct link between that ‘irrelevant Ig’ and later autoimmunity has proven to be largely elusive. The likely problem is that the two disease events are too remote in time. Still, there can be some more obvious links. The flaccid paralysis of Guillain Barre Syndrome (GBS) can follow influenza virus infection (less than 1:15,000 cases) or vaccination (1-2 cases per million people). In general, the over-50’s are at greatest risk of developing GBS and a very few may die, though most recover fully within weeks.

The idea of autoimmunity was first raised when 1908 Nobel Medicine Laureate Paul Ehrlich (We met him briefly in the Horses essay) coined the term ‘Horror Autotoxicus’. Much later, Australian Sir Mcfarlane Burnet and Britain’s Sir Peter Medawar shared the 1960 Medicine Nobel for the ‘discovery of acquired Immunological tolerance”, the idea that we are ‘tolerant’ of self but react aggressively to destroy and eliminate the ‘non-self’ of some invading pathogen. Building on earlier (1945) work by Ray Owen at the California Institute of Technology (Caltech, Pasdena) that identified shared (chimeric) red blood cell populations in non-identical (fathered by different sires) cattle twins developing together in utero, their insights and experiments led us to the understanding that immunological tolerance (of self) has to be ‘learned afresh’ during the development of every individual. Most agree that Owen, who outlived both Burnet and Medawar, should have shared in the Nobel, but it’s not uncommon for a key person to be missed.

Mac Burnet, the long-time Director of Melbourne’s Walter and Eliza Hall Institute (WEHI) was a medical doctor and a brilliant infectious disease investigator, who focused earlier in his career on understanding viruses, then switched to the study of immunity. Researching the Nobel archives that are opened after 50 years (you have to be able to read Swedish) eminent Stockholm-based virologist Erling Norrby discovered that Burnet was nominated many times for his virus work, especially on influenza.  But he was finally recognized for his essentially theoretical (and somewhat brief) statement on tolerance in a book that he co-authored with his later to be eminent trainee, Frank Fenner.

Oxford-trained, Birmingham, then London-based (from 1951) zoologist Peter Medawar became very involved in research on transplantation during World War 2 when, because of burns and other damage, there was great interest from the aspect of tissue repair.  In 1953, the team of Rupert Billingham, Leslie Brent and Peter Medawar published (Nature 172: 603) a research paper titled ‘Actively Acquired Tolerance of Foreign Cells’ where they showed that injecting the cells of inbred mouse strain A into newborns, or embryos in utero, of strain B would allow a later A skin graft that would normally be rejected by a B mouse to survive and be treated as ‘B self’. In effect, the recipient B mouse had ‘learned’, as a consequence of being exposed to A cells during development, to be tolerant of the different spectrum of ‘strong transplantation antigens’ expressed on the skin graft from the A donor. We will be hearing much more in subsequent essays about how the recognition of those transplantation molecule, which are now called the class I Major Histocompatibility Complex (MHCI) glycoproteins, defines our biologically unique ‘self’ and is central to T cell-mediated immunity. This is the science that I’ve now been involved in for 46 years and led to my Swiss colleague, Rolf Zinkernagel, and I being awarded the 1996 Nobel Prize for Medicine.

With the exception of Ray Owen, who lived until 2014 but wasn’t on the immunology circuit (his 1945 publication made me think he was long gone) I met and talked with all the men mentioned above. Leslie Brent, who had come to Britain as a young Jewish boy fleeing Nazi Germany, was the last to leave us when he died in January of this year. All science builds on what went before, and the ‘what’ came out of the efforts and minds of human beings. As we go on, you may find it intriguing to see at least some of the science I’m writing about developed from a more personal and people-oriented perspective.