Blood group II - Rhesus

As I mentioned recently rather less than half of adults know what is their blood group and only a tiny fraction of them really have a grasp of how blood groups work. It turns out that there is a lot more to the subject than ABO and +/-. For starters there are at least two varieties of A: A₁ and A₂. When I was last here with my teachers hat on [R - so you can imagine what it's like having me teach young people at The Institute], I explained that ABO hinges on the presence or absence of a couple of antigens [= proteins] stuck in the membrane of our red blood cells. In Human Physiology class last week, I said that a typical membrane bound protein is about 7 nm (billionths of a metre) across while each RBC is 1000x larger: 8-10 μm. About half the surface area of a cell membrane is a sea of water-repellent lipids and the rest is proteins. The maths says that there are 500,000 'seats' for proteins on this cell surface; surely they cannot all be either A or B?  And they're not: there are dozens of types of antigens [= membrane proteins] which were identified because they are variable among people. They are often named for the family or location where they first turned up: Kell, Duffy, Lewis, MNS, Lutheran, Kidd. Each has a normal function and many of them, like ABO, are associated with susceptibility to disease. the Duffy Fy antigen, for example is used as a dock by the malarial parasite Plasmodium vivax to gain entry to the RBC in which it propagates. That is not the function of the Duffy antigen; we'd much rather not have malarial parasites reproducing in our RBCs. The genetic variant Fy(a-b-), which is a null allele like the O of ABO, is very common in areas of tropical West Africa where malaria is endemic. It is another rather desperate response to malaria like sickle-cell anaemia and thalassaemia.

Kell, Duffy, Lewis, MNS, Lutheran, Kidd . . . but the greatest of them all, after ABO, is Rhesus, named after the Rhesus macaque Macaca mulatta [R looking surprised to be here]. This family of antigens is what people are talking about when they say O-positive. It's short for Rhesus⁺. Like A₁ and A₂ above, it's more complex than Rh⁺ vs Rh^-: there are at least 50 known variants DCe/dce, DcE/DCE, Dce/DcE etc. etc. But the key element is whether you carry, and express on your RBC surface, the D antigen, which is a protein that looks like, and may even be, an ion-channel [shunts Na⁺, K⁺, Cl^- or whatever in or out of the cell].

Most - 85% - European people are D aka Rhesus positive. If you are a woman and Rh -ve, the chances are, unless you're big into incest, that the bloke you hook up with is Rh+ve - it's the maths:  85% of potential partners are the opposite to your Rh-ve. Uncle Jim is more likely to be Rh-ve like yourself. That's no problem until you fall pregnant and you approach term 9 months later. Towards the end of pregnancy, the placenta gets restless and during delivery there can be nicks and tears down there and some fetal blood mixes into mother's circulation. The mother has an immune system, which recognises the incommming RBCs with Rh+ve antigens as foreign and makes anti-D antibodies against them. It's only a little blood and they are soon mopped up by these maternal antibodies. Fast forward a couple of years, the parents love each other very much and another child is on the way. The mother's immune system is primed against Rh+ve and reacts much quicker second time round.  This is related to the fact that children are beset with minor ailments and have the sniffles all the time but teenagers and adults much less so. Older people have been exposed to every common virus and bacteria and their primed antibodies put a swift cap on any attempted replay.

Furthermore these anti-D antibodies can cross the placental barrier - usually the placenta keeps maternal and fetal circulation separate and just exchanges nutrients, oxygen and waste-products - and start to wreak havoc on the baby's red blood cells, causing an anaemia, which can seriously deplete oxygen carrying capacity and can result in death. This is called haemolytic disease of the newborn HDN or erythroblastosis fetalis if you want to impress people with Latin. The reaction is even stronger with the third and any subsequent children who are incompatible with the Rh-ve mother. It's a European thing, though, the frequency of Rh-ve falls off to near zero in Africa, Asia and Oceania. Because Rh-ve is rare, HDN was rare and not all cases were equally severe; nevertheless some 40 babies a year would die from this sort of anaemia - from a total of about 60,000 live births.

During the 1970s, as we got to understand the genetics and immunology involved in this distressing condition, someone had a bright idea for a cure/therapy/intervention. What about if, at the end of that first pregnancy, we flood the mother's circulation with anti-D antibodies. They will mop up the invading fetal RBCs so quickly that the mother's immune system won't cotton on that an invasion has taken place. And it was so! Blood transfusion services across the Western World began to offer anti-D injections at 28 weeks and shortly after delivery and that was the end of haemolytic disease of the newborn. Win!