The 'ABCDEFG' of tissue groups . . .
We all know what blood groups are. They are the labels on red blood cells that mean whether a blood transfusion will be compatible or a disaster.
Less well known are tissue groups. They are the labels the other cells in the body have that determine whether an organ graft, like a kidney, a liver or a heart -- or bone marrow -- will "take" or be rejected.
These tissue groups are called HLA molecules (HLA stands for human leukocyte antigen, an "antigen" being any molecule that can elicit an immune, or antibody response; "leukocyte" being a white blood cell, which are much less compatible between people than red blood cells can be; and "human" ... well, in other animals we have to call it something else, and so the general name for this part of the genome in biology is the major histocompatibility complex, or MHC).
The MHC is dense with genes, and has a fascinating evolutionary history, having been tightly retained through the evolution of the vertebrates.
Its different genes form two main groups, the Class I genes (the first-discovered or "typical" HLA-A and HLA-B genes, and the "atypical", still poorly understood HLA-C, HLA-E, HLA-F and HLA-G genes), and the Class II genes (the HLA-D groups, comprising HLA-DR, HLA-DQ and HLA-DP), which are expressed only within the immune system, but with a more leveraged policing role. Like all genes, they come in pairs, one from your mother and one from your father.
What's their job description?
For as long as animals have consisted of more than one cell, there's been a premium on recognizing, in the melee of the pond, which cells are yours and which cells belong to someone else -- a rival, or a threat. Any cell with a different HLA "badge" belongs to a rival club and should generally be eliminated if it gets too intimate. In complex organisms, NK cells, T cells and other white blood cells can do the job ruthlessly well.
But these policing cells also have to deal with invasions of tiny organisms, such as viruses.
For viruses to properly alert the immune system, for them to work as antigens, able to elicit a specific antibody response, they need to be presented to the immune system in a special way. They need in effect to be suspended upon a background that's familiar to the police -- and that background is the HLA molecule itself. Unless the NK police recognize the HLA molecule as their own they do not trust what they are seeing and will demolish the target grossly and non-specifically. The T cell police prefer to set the antigen up for a mug-shot, parading it on an HLA background they are completely at home with, enabling it to be brought into very clear focus, then retaining an image of the antigen in immunological memory for a more rapid response next time. And then they incarcerate and digest the antigen without too much of a fuss.
At least, that's the theory. In practice once a T cells is alerted it gets impatient. Not wanting to wait for the antigen to replicate faster than it can, it swiftly recruits any other T cell or NK cell in the vicinity (and a few other warrior white cells as well), justice is summary, and collateral damage is often considerable. But trouble is contained.
So far, so good; but it gets better.
Remember that genes come in pairs, and that there can be different versions or polymorphisms of the particular gene in a population, called alleles. (If you happen to get the same allele from your two parents you are homozygous for that gene; if the alleles are different you are heterozygous.)
It so happens that different alleles display a particular virus or antigen in different ways. It depends both on the particular virus and on the particular allele, and the net effect determines how well the immune system will respond. In other words, when a particular virus hits your village or valley, you will be more or less likely to survive depending on which alleles you happen to have you. This means two things.
First, it pays to have two different alleles instead of an identical pair. There's an obvious survival advantage for you as an individual to be heterozygous not homozygous, because your immune system can choose the best of two alleles instead of the best of one.
Second, the population you belong to -- your village or your valley or your tribe -- will have a survival advantage if there is as wide a range of alleles as possible represented among you as a group. So even if certain individuals succumb to some scourge, other individuals will survive to repopulate the village, the valley or the tribe.
The net result is that evolution has produced extraordinary diversity ... and there's a huge range of HLA combinations possible. It's estimated that there are more than 10 billion different combinations of the various HLA alleles possible -- which is more than the world's population of humans! It's no wonder it can be hard to secure a perfect, or sometimes even adequate, tissue match for a kidney transplant outside your own family.
And within your family, among your children, there will be as many as four different alleles to help at least some of your children through the next dreadful epidemic, provided you have mated with someone not closely related to you (someone from the next valley or from a different tribe is ideal).
In fact, and as is well known, there are other advantages in outbreeding over inbreeding.
Here's how nature uses the HLA molecules to encourage it.
. . . the sweet smell of genetic diversity . . .
The HLA molecules, as well as providing the back-drop upon which antigens are held conspicuous, also have a special affinity for all sorts of tiny volatile compounds that smell ... that evaporate and tease the olfactory senses. These particular molecules will be as personal as your HLA genes and as individual as your environment. They will only be the same as someone else's if you share HLA groups with that person. And if you share HLA groups you will most likely share a heap of other recessive genes, mating would mean inbreeding, and a much greater risk of inheriting two dud genes and developing a serious genetic disease.
These HLA molecules can separate away from the cell surface to become soluble in your blood, able to be filtered out into the urine or through your sweat pores, and enter your environment. The HLA molecules themselves are generally too big to be volatile and smelly, but when a dog marks it territory with a pee the soluble HLA molecules break down, and then release the volatile compounds the HLA molecule has snared from you and your environment. Other dogs can tell the difference between their own smell and another dog's, and know to stay away (or sometimes to become especially interested!).
In mice, these molecules are so powerfully linked to the reproductive system that when a pregnant female loses contact with her mate and consorts with a new male, the mismatch between his volatiles and those of her earlier experience is enough to induce abortion of her embryos, so that she can go on to bear the new male's young instead.
. . . and shaking hands with HLA-GReturn to top
Not surprisingly, prudent embryos keep their heads down, and display no HLA molecules of the HLA-A, HLA-B or HLA-D kind. And the implanted gestation, gloved in HLA-free syncytiotrophoblast, does the same, remaining almost invisible on the mother's immune radar screen.
The same applies to the cells of the extravillous trophoblast (see the main text) as they venture deep into the mother's decidua and body. What they do need to do (in order to push the right buttons on potentially helpful maternal NK cells and T cells) is to show HLA-E and HLA-G badges. Without some kind of HLA badge they might be summarily expelled as total strangers.
And so, HLA-E and HLA-G have come to be two components of this amazing MHC gene group that is not polymorphic, but instead has been tightly conserved by evolution. Only a handful of different alleles are known.
What we know about them in pregnancy so far is that
And how all this relates to miscarriage is one of the most exciting areas or research in reproductive medicine today.