Q. I have a question on MHC receptors being polymorphic. Does this mean your MHC receptors are all the same, but just different from all of mine, which are the same as each other? Or are all MHC receptors polymorphic?
A. That’s a great question! The short answer is: there are many different kinds of MHC receptors, and we each have a mixture of a bunch of different types. It’s not like all of my MHC I receptors are identical, and all of yours are identical. I’ll try to explain a bit more.
Polymorphic
The word “polymorphic” is usually used to describe genes. It indicates that there are different “normal” variants of a gene. So if a gene is polymorphic, it means that there are a bunch of slightly different alleles out there in the population, all of which are considered “normal.”
To me, it’s always useful to make a food analogy (maybe that’s just because I’m a pathologist, and pathologists love to make food analogies). So let’s say that we as humans have a gene for ice cream. That would be awesome.
If this ice cream gene was polymorphic, that would mean that there are several different alleles for that gene: maybe one is a vanilla ice cream gene, another is a chocolate gene, another is super fudge chunk…you get the idea. A highly polymorphic gene is one that has a lot of different variants. If the ice cream gene was highly polymorphic, there might be genes for say, 50 or 100 different flavors.
MHC loci – what exactly do they encode?
Each locus (or region, or gene) within the MHC I region (A, B, and C) codes for everything you need to make an MHC I receptor. I used to think, way back when I was a medical student, that the A locus probably encoded one part of the MHC receptor, and the B and C loci encoded other parts of the receptor. Not so! The A locus encodes an entire MHC receptor (so does the B locus, and the C locus).
As an aside, you’ll see the acronym HLA used pretty much interchangeably with MHC, at least in humans. MHC stands for major histocompatibility complex, and HLA stands for human leukocyte antigen. In humans, the MHC receptors were originally described as being present on the surface of leukocytes – hence the name human leukocyte antigen. As it turns out, they’re on the surface of most other cells too – but the HLA name stuck.
By convention, we usually use “MHC” when we’re talking about the receptor (the gene product), and “HLA” when we’re talking about the gene (check out the diagram below!). But really, the terms MHC and HLA refer to the same set of genes and gene products.
Back to what the genes encode. For the MHC I receptor, since you have two A loci, two B loci, and two C loci, that means you have the capability to make 6 very slightly different kinds of MHC I receptors. That’s assuming that you don’t have any “repeats” – that is, your A genes are different from each other, and so are your Bs and your Cs.
Since MHC genes are highly polymorphic (there are a lot of normal variants), it’s quite likely that you have two different HLA-A genes, two different HLA-B genes, and two different HLA-C genes (see what I did there with the HLA acronym?). Check out this diagram from Wikipedia – it shows all the different MHC I and II receptors present on a cell (as well as the different genes inside the nucleus):
These MHC I receptors vary just a tiny bit in their antigen binding domain, so each one has a slightly different ability to bind any given antigen. This is good. You want to have a lot of variability so that you’re prepared for any potential antigen that comes your way.
Same thing goes for the MHC II receptor. There are three gene loci (DP, DQ, and DR), and usually you’ll inherit two different DP alleles, two different DQ alleles and two different DR alleles (sometimes you’ll inherit an additional DR allele or two just for the heck of it). That means you have the ability to make six (or maybe up to 8) slightly different MHC II receptors.
Codominant
The weird thing about the expression of these genes is that you express all of them! This usually doesn’t happen with genes. Usually, you pick one allele out of your two paired alleles, and you express that one. Sometimes, though, you express both alleles; this is called codominant expression.
One easy to understand example of codominance is the ABO blood group system. You inherit two genes, one from mom and one from dad (you might have 2 A genes, or 2 B genes, or one A gene and one O gene, and so on). Instead of just picking one or the other gene, you express both genes. If you have an AB genotype, for example, you express both the A gene and the B gene, making both A and B antigens for the surface of your red cells. Weird!
It turns out that this is true for MHCÂ genes too. Instead of just picking one of your HLA-A genes and transcribing that one, you always transcribe both of your HLA-A genes. What’s more, you also express both of your HLA-Bs and Cs! Check out the diagram above for a nice picture of how this works. SO: every cell that expresses MHC I receptors will have 6 different MHC I receptors on its surface, and every cell that expresses MHC II receptors will have at least 6 different MHC II receptors on its surface!
This explanation is awesome. I wish I had learned this before hearing about all the DR, DQ, etc associations with the various autoimmune disorders
OMG, this explanation was awesome!! Thank you, thank you thank you. This stuff never made a bit of sense when I was in medical school.
I love you!
Thanks, Elaine!!! I’m so glad you found it helpful
Oh boy, I’m so confused with this and your explanation is great! Just now more question: so 6 HLA class I molecules are expressed on all nucleated cells (no RBCs) and 6 HLA class II molecules are expressed on antigen-presenting cells, some thymus epithelial and some endothelial cells maybe. Does this mean that i.e. an antigen-presenting cell expresses in fact 12 HLA molecules on their surface? All at the same time? Both class I and II?
Yes! Exactly! All non-antigen-presenting cells have 6 different types of class II MHC (HLA) molecules on their surface, and all antigen presenting cells have 12 MHC molecules on their surface (6 MHC I and 6 MHC II)!
Great information. Thanks . I wished it was available when I studies them