Why is it important to know, what’s your blood type, A, B, AB, or O? Even if you find out, what’s it all mean? It has to do with what sugar chains will be seen!

With Blood Type A, GalNAc says “Hey!”

If Type B’s your pal, you’ll see a Gal

Some of both there will be in those with AB

But if Type O, there’s only core H antigen to show

Apologies if some of those terms were a bit too complex, 

let me step back and break things down in a way less likely to perplex!

Today I did an at-home blood typing test with an “ELDONCARD.” And I want to tell you about how it works, what blood type is, and why it matters. I will start with a grossly oversimplified explanation for people who are only kinda sorta interested and then some more details for those of us proud geeks…

ABO blood type has to do with which sugar chains (aka glycans) a person’s red blood cells (RBCs) & other tissues have sticking off from them. These glycans are often referred to as antigens, because they can serve as antibody binding partners. Your immune system knows that the antigens you make are safe, but if you give someone blood with antigens that they don’t have, that someone’s immune system will see it as foreign & attack. To avoid such incompatibility problems, doctors “cross-type” blood donor & recipient making sure that people don’t get exposed to foreign antigens. 

Which ABO antigens a person has (and thus will see as “self” and thus safe) depends on which version of a sugar-adder (glycosyltransferase (GT-ase)) gene they inherit. Almost everyone makes a “basic version” of a sugar chain called the “H antigen” that gets attached to proteins and lipids (fats & oils like those making up your cell membranes). But, some people (those with Type A, B, or AB) have proteins that  “upgrade” that basic version by adding an extra sugar onto the end, giving you different antigens.

The instructions for this extra-sugar-adder are in the ABO gene. There are 3 main versions (alleles) of the ABO gene and you get one copy from each parent. Which alleles you inherit is called your genotype and the options are A/A; A/B; A/O; B/B; B/O; or O/O. So there are 6 genotypes – but what really matters is the phenotype – the traits or characteristics that come from having that combination of alleles – basically phenotype is how the genotype “presents itself.” So, in this case, the phenotype is which sugar chains get made & displayed. And that depends on which variant(s) of the sugar-adder you have, so back to the genotype… 

The “A” and “B” alleles both encode for functional sugar-adders, but minor genetic mutations occurred a really long time ago, making it so that they add *different* sugars: GTA adds a GalNAc (N-acteylglucosamine) to turn the H antigen into the A antigen & GTB adds a Gal (galactose) to H to give the B antigen. The O allele suffered a more dramatic mutation – instead of just some letter swaps, it got a whole chunk of its DNA deleted and this caused a frame shift that makes it so the gene is read “wrong” and the protein made is completely different – and completely incompetent when it comes to sugar-adding. So, people who inherit 2 copies of O can only display the core H antigen (no upgrades). 

So almost everyone makes the H antigen. For people with type O blood, that’s all they make (cuz it’s all they *can* make), so it’s aka the O antigen. But people with type A, B, or AB blood (most of the time) take things 1 sugar branch farther. Because they have a functional version of that glycosyltransferase the ABO gene codes for. So they use it. But, because of slight differences between the A version and the B version, just a light scattering of DNA letter differences that cause 4 protein letter differences, those transferases transfer *different* sugars – GTA adds a  adds an N-acetylglalactosamine (GalNAc) & GTB adds a galactose (Gal).

So, for people with Type A (either A/A or A/O), most of their H antigen gets “upgraded” with GalNAc. And for people with Type B (either B/B or B/O), most of their H antigen gets “upgraded” with Gal. For people with Type AB (just one way to get this phenotype: A/B), some of the time the GTA does the upgrading, and some of the time the GTB does it. And they have lots and lots of chances – there are over 2 million ABO antigens displayed per RBC. https://bit.ly/2WuOz7u 

There are so many chances that not all of the H antigens get modified – even in people who have 2 working GT-ases. So *everyone* displays the H antigen, but for Type O people, that’s *all* they display, whereas, for the other types, it’s just a small part of what they display. This is an important distinction to be aware of because it means that everyone’s* immune system is used to seeing the H antigen. So they’re friendly and you can give Type O blood to “anyone” and they’ll play nice. 

So, from our 6 genotypes we get to 4 phenotypes:

Type A: makes A antigen & H antigen; possible genotypes: A/A; A/O

Type B: makes B antigen & H antigen; possible genotypes: B/B; B/O

Type AB: makes A antigen, B antigen, & H antigen; possible genotypes: A/B

Type O: only makes H antigen; possible genotypes: O/O

note: this genetic inheritance mode is called co-dominance since both A & B are dominant over O but you can express both A & B without one dominating the other (pretty cool, eh?)

Cool, yes, but why does this matter?

If your body makes a certain sugar, such as the A antigen, your immune system will see A antigen as “self” even if that A antigen that comes from a different person. So if you give a Type A person blood from another type A person, the immune system won’t get suspicious. And a Type AB person will be used to it, and therefore fine with it, too.

But if you give a Type A person’s blood to someone whose body doesn’t make A antigen (i.e. a Type O or Type B person), the Type A person’s immune system will see that blood as foreign and attack it.

And the same goes with Type B – if you give Type B blood to someone who is Type A or Type O, their immune system will go after it. 

But, you can give Type O blood to “anyone” because everyone* recognizes the H antigen. For this reason, Type O is called the “universal donor” and Type AB, which will recognize it all as “self” is called the “universal recipient.”

It’s actually Type O negative that’s the universal donor and Type AB positive that’s the universal receptor. The negative and positive refer to whether or not the blood has a different antigen, the Rh factor. That’s a totally separate thing. The Rh stands for Rhesus as in Rhesus monkeys because scientists originally found different antigens when they injected monkey blood into other animals, and they thought it was the same thing. Turns out it’s not really the same thing, but the name stuck. So go with it (they did).

“Rh factor” is membrane protein, and it’s encoded for by a different gene, and thus inherited independently of the ABO type. It’s actually kinda complicated and there are multiple Rh antigens, but the one that really matters most, and the one implied to by the negative and positive, is Rh(D). So, someone who’s “positive” has a gene that makes the Rh(D) protein and someone who’s “negative” has 2 dud genes that are mutated so they don’t make the Rh(D) protein.  

The ABO system was worked out in 1901 by an Austrian scientist name Karl Landsteiner. It made it possible to give blood transfusions without the frequent adverse effects that came from early attempts at it… The work won him the Nobel Prize in 1930, and you can read his lecture: https://bit.ly/2ZDI9Fi 

But it would be another 40 years or so before scientists (Landsteiner & others) pieced together the Rh thing. And during that interval, thousands and thousands of transfusions were given, yet the bad outcomes weren’t that common which I think is in part because the negative is a lot rarer so when they had a rare bad outcome they could blame bacterial contamination and/or improper blood typing. 

It’s actually kinda a wonder that blood transfusions work at all – ever –  because, in addition to ABO & Rh there are lots and lots of different antigens. According to the Red Cross, there are over 600! Most of them are less immunogenic (immune system provoking) so doctors don’t have to match them all. But, when it comes to tissue donations, you have to match more and there are a bunch of other types of antigens you have to worry about there, too, like “HLA types” which is a whole different thing I’m not gonna get into. 

If you go read that lecture you’ll see that Landsteiner refers to the antigens as “agglutinogens” and the antibodies as “agglutinins.” This is because if you mix the blood serum (the cell-less part of blood that has the antibodies) of someone one blood type with the blood of someone with a non-compatible blood type, they’d clump up “agglutinate.” He used this feature to figure out all the ABO stuff by mixing and matching his colleagues’ blood and sera. If you’re wondering, as I was, why the person’s blood would have antibodies against ABO antigens already if they’ve (presumably) never eaten a person before? Turns out that bacteria make sugars that look similar so our immune system has antibodies that’ll recognize them. People who make the similar-looking antigens won’t have those specific antibodies though – more on why in the details. 

But first I want to tell you about how I used that agglutination property today  in order to figure out my blood type using an ELDONCARD. The card has 4 spots and at the center of each are dried antibodies. After adding drops of water to dissolve them, you add drops of blood, mix & watch as things do or do not happen. The first spot has anti-A antibodies and will agglutinate if the blood contains the A antigen. The second spot has anti-B antibodies & will agglutinate if the blood has B antigen. The 3rd spot has anti-Rh(D) antibodies so will agglutinate if the blood has Rh(D) (i.e. if it’s “positive”). And the 4th spot is a negative control that should never agglutinate and, if it does, the test is invalid. 

When I did the test I saw clumps in the first 2 spots, indicating that my blood has both A & B antigens. No clumps in the 3rd spot, so I’m Rh(D) negative, and no clumps in the 4th spot so the test worked. So the test says I’m AB negative. Since there’s only one genotype that can give me that phenotype, I know my genotype (A/B). But if it was A or B you still wouldn’t know your genotype even though you know your phenotype. To figure that out, you’d need genetic testing.

I “think” I’m AB- but I can’t be sure without some more accurate lab-y tests. You can get such official tests when you go to donate blood – but I’m not eligible to. And even my doctor doesn’t know because they don’t test you unless there’s a reason to, like if you need a blood transfusion. So, for now, I’m going with what I got (which is the same result I got when I did this a few years ago, so at least it’s consistent!)

now, a more detailed version: 

Last week I told you about glycobiology (sugar science!). Aka carbohydrates, sugars come in basic “building blocks” called monosaccharides. Some common examples are glucose (aka blood sugar aka dextrose) and galactose. They often take on ring shapes, and monosaccharides are the individual rings. They can hang out by themselves or they can link together. Link up just 2 and you get a disaccharide (like sucrose (table sugar), which is glucose linked to fructose). But, why stop at 2? You don’t have to! You can keep adding sugars to build up complex carbohydrates – polysaccharides. These sugar chains can serve functions like storing energy or sturdifying structures. And they can get hooked onto other molecules such as proteins and lipids (fats/oils such as those in your cell membranes). These sugar + non-sugar combos are called glycoconjugates and some of the most famous (and notorious) are the ABH antigens (the source of the ABO blood types).

“Antigen” is just the name we give to things which get recognized by little immune system proteins called “antibodies.” Antibodies have a constant region and variable regions. And there are a lot of possibilities for that variable region because they’re the result of (randomly) mixing and matching various gene part options. Different antibody making cells try out different combos, making different antibodies, and you have a virtually limitless number of possible antibodies that allow you to recognize “anything” (theoretically and eventually (it can take time for your body to find the right ones).

By “recognize” I just mean that the antibodies bind to the antigen (such as a viral protein) – and then they can do things like call for immune system reinforcement to destroy the antigen and/or antigen-infected cells and initiate an inflammatory response. It’s great for getting rid of microbial invaders like bacteria or viruses, whose proteins serve as antigens, but you have to keep it in check so it doesn’t try to get rid of your own cells. Therefore there’s a sort of 2-check system. The cells making antibodies are themselves destroyed if those antibodies recognize the body’s own cells as foreign (meaning that the antibodies bind to self molecules). So in order to survive, an antibody-making cell has to make an antibody that doesn’t bind to anything the body sees as “self.” Then, in order to get selected for and amplified, an antibody has to be able to bind something “non-self” (like a viral protein). 

But antigens don’t have to be proteins. And they don’t have to come from microbes. Some of the most medically important antigens are sugars – and ones made by humans! The ABO blood type system refers to which sugars people have on their Red Blood Cells (RBCs) (as well as other cells as we’ll talk about – RBCs get most of the attention, and they do have a LOT of these, but ABH antigens are also displayed from the surface of a variety of epithelial cells (cells of tissues making up the linings of things like your veins and intestines) – either because they’re attached directly to the cells that made them or they were made by other cells, those cells secreted them and then they stuck to the surface of the new cells. This “adsorption” can happen because in some cases ABH antigens are added onto secreted proteins, allowing them to be found in saliva, tears, etc.

Sugars are able to serve as antigens because they can be really diverse. Sugars are made up of hydrated carbon (hence the name). This means that the basic formula for a sugar is the equivalent of 1 water molecule per carbon atom: Cx(H₂O)x, and you end up with a chain of carbons with a bunch of hydroxyl (-OH) groups sticking out. And those -OH groups can be further modified through things like sulfation, phosphorylation, amidation, etc. The details don’t matter here, but just know that these modifications can slightly alter the characteristics of the sugar, changing their shape, charge, etc. and allowing them to serve different functions. The modifications also allow the protein workers (enzymes) in your cells to tell them apart. So enzymes can specialize in adding specific modified versions in specific places, and GTA & GTB (the A and B versions of the ABO gene protein) can tell apart and use different sugars even though the proteins are almost identical. 

But their job comes downstream of the work of another enzyme. FUcosylTransferase 1 (Fuc-T I or FUT1) is aka the H enzyme. You need this to make that “basic antigen” – the no-frills version.  Almost everyone has this, but there are some super rare cases where people don’t have it, so they can’t even turn the starter chain into the the basic model let alone upgrade it. Such h/h people have what’s termed the “Bombay Phenotype” (named after the place they first discovered it). But that’s super duper rare.

So almost everyone makes the H antigen. For people with type O blood, that’s all they make (cuz it’s all they *can* make), so it’s aka the O antigen. But people with type A, B, or AB blood (most of the time) take things 1 sugar branch farther. 

You know how I told you how Fuc-T I’s that initial fucosal transferrer that adds the fucose onto the basic chain to give you the precursor? Well, there’s another Fuc-T that can do this also, Fuc-T II. This one is expressed in secretory cells. So the ABH antigens can get added onto proteins that get secreted – like the mucin protein that’s in your mucus. Some people have mutated versions of Fuc-T II that can’t make these secreted versions so you won’t find them in such “non-secretor”’s secretions – but for other people you can find ABH antigens in saliva, tears, sweat – basically every fluid in your body except that in your cerebrospinal fluid (the liquid in & around your brain/spinal cord)

Here’s a good source for some more details on all of this: https://bit.ly/2WuOz7u 

more on glycobiology: https://bit.ly/sugarssci 

This post is part of my weekly “broadcasts from the bench” for The International Union of Biochemistry and Molecular Biology. Be sure to follow the IUBMB if you’re interested in biochemistry (@the_iubmb)! They’re a really great international organization for biochemistry.⠀

If you want to learn more about all sorts of things: #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0 

Leave a Reply

Your email address will not be published.