19 Oct 2020
Issue #29: Surveillance of self: the major histocompatibility complex
Setting it Straight - Issue #29
Written by Nobel Laureate Professor Peter Doherty
Probing the nature of the psychological self is way beyond my professional expertise, though a good place to start is, no doubt, with what we see in the mirror and how we (or those who speak frankly to us) consider to be our personality and character, or lack thereof. Clearly, there’s plenty of scope for error, bias and subjectivity in such assessments! But, when it comes to the immunological self that we introduced into this discussion several weeks back, that definition happens below the level of consciousness and is, basically, a matter of chemistry, of molecular interactions.
Here, we are discussing phenomena discovered, and probed in, the realm of science, using methodology that depends on hypothesis, measurement, critical analysis and open publication. The whole intent is, so far as that’s possible for human beings, to avoid making conclusions influenced by bias and subjectivity. If you’re not familiar with these basic rules, I discussed them at length in The Knowledge Wars.
Despite the power of this approach that has defined science since the mid 17th century there are still, when it comes to self/non-self-discrimination and its conceptual partner immune tolerance, significant gaps in our understanding. What we do know a lot about, though, is the identity of some of the key molecules, the glycoproteins (proteins with a carbohydrate/sugar attached) of the major histocompatibility complex, the MHC. More of that later.
Histocompatibility? ‘histo’ refers to tissue – most of us have looked at stained histological sections down a microscope in biology class – and we all know what compatibility means. As initially defined, the MHC was all about tissue (skin) and organ (kidney, heart) graft (or transplant) acceptance or rejection. Though every species of higher vertebrate has its own particular version of the MHC, we’ll focus, for obvious reasons, on the HLA (human lymphocyte antigen) and H-2 (histocompatibility 2) systems that were originally defined in people and in mice. Why are mice obvious? That’s because they’ve provided a readily manipulated experimental system that allowed researchers, working over decades, to tease out the MHC story. If anyone tells you that mouse experiments have not been, or are not now, central to advances in biomedicine, walk away. They are either deliberately ignorant, or lying.
The terminology we use with the MHC is taken straight from genetics, which was a robust science long before JD Watson (a biologist) and FHC Crick (a physicist) established (in 1953) how the genes work and showed us that DNA is the basis of inheritance. In fact, much of the transplantation/MHC story was already well developed before those two heroes came on the scene. We talk about MHC haplotypes, a genetic region on the chromosome where these genes cluster; about loci, the sites where single gene variants are expressed; and about alleles, the variant genes at a particular locus.
Genetically identical mice (developed by brother sister mating and back-crossing) have only one MHC haplotype, while an F1 cross between two inbred strains (p and q) will give an pxq F1 with two haplotypes. A p mouse will reject a q skin graft and vice versa, while a pxq F1 should accept both. The human MHC loci that were defined initially by antibody tests (serology) and graft rejection are named HLA-A, HLA-B and HLA-C, while the H-2 loci are H2-K, H2-D and H-2L. Alleles mapping to the HLA ABC and the H-2 KDL loci encode what were initially called the strong transplantation antigens and are now known as the class I MHC (MHCI) glycoproteins. Also mapping to the MHC region, though not central to graft rejection are the class II MHC loci (HLA-D and HLA-DR and H-2IA) loci specifying what were initially called the immune response (Ir) genes.
Early on, from the graft rejection work, we knew that the class I antigens (cell surface glycoproteins) are recognised by the CD8+ killer, or cytotoxic T cells and later, we learned that the class II molecules are involved in CD4+ or helper T cell responses. This is the area of human knowledge that was recognised by the 1980 Nobel Prize for Medicine to France’s Jean Dausset (HLA), New Englander George Snell (H2) and Harvard’s Baruj Benaceraff (Ir genes). Because of the rule of three, Jan van Rood from the Netherlands (HLA) and Stanford’s Hugh McDevitt (Ir) were missing from that list, as was H2 pioneer, London’s Peter Gorer, who died in 1961.
Why discuss transplantation in a series focused on infection, particularly with the SARS-CoV-2 virus that causes COVID-19? The reason is that the MHC is central to T cell-mediated immunity, the other half (additional to B cells and antibody) of the adaptive, or virus specific, host response. Graft rejection is not, it seems, what the MHC is basically about.
Why, for instance, would placental mammals, where about half the inherited genome comes from the father, want to take the risk that the mother could react immunologically against the foetus? The answer rests in the summary statement: that if the MHC was discovered for the first time today, it would likely be termed the ‘self-surveillance complex’, the SSC. More to come on this story of immune ‘surveillance of self’.