Immunology sheet # 8 - Sura Al-A3mar

By the Name of God
Lecture 8/Immunology 14/12/2010
Dc. Hassan

Major Histocompatibility Complex and Transplantation

The Human Major Histocompatibility (MHC) molecules are proteins, first discovered within the issues of Transplantation; if the structure of these molecules is differ during transplantation between donor's and recipient so the organ will be rejected, but if the same molecules are present so the transplanted organ will be accepted.

These proteins differ among humans, composed of Human leukocyte Antigen (HLA) Genes, located on the short arm of chromosome 6, and encode HLA proteins which will form MHC molecules. Sometimes they said that HLA is MHC molecule and vice versa. The main function of MHC is to present antigen and they are really playing an important role in the Immune Response.

MHC Classification and Structure

MHC molecules are of Three Classes... Class I, II and III.
All cells of the body -depending on its type- have either Class I alone or both Class I and II, on their surface (plasma membrane) except RBCs (red blood cells) which are not nucleated cells so NO MHC molecules are present.
Now between Class I and II there is Class III which is NOT present on surface of cells, it’s a soluble protein and many of them are produced by Complement system such as C2 and C4.

We are going to concentrate on MHC Class I and II because they are the really molecules associated with antigen presentation and they are present on the surface of cells.

MHC Class I Molecules Structure

This Type present on the surface of all nucleated cells except RBCs. It's composed of two polypeptide chains;
- One is constant known as B2 microglobulin (encoded on chromosome 15), doesn't play a big rule in the function of MHC I molecule and it's really like a wedge to support the structure of the molecule, so its main function is to maintain the configuration of MHC I molecule.
- The other is α chain which composed of 3 domains; α1, α2 and α3.
---This chain really play role in the function of MHC I molecule especially α1, α2. Now between α1 and α2 domains there is a Groove of MHC molecule (antigen presenting groove), in the groove there is a peptide -which is an antigen- that is a small polypeptide (12-18 amino acids) but its bigger than epitopes that are recognized by paratopes of Immunoglobulin, and this antigen is going to presented on the surface to recognize by Cytotoxic T-cell.

The TCR on T-cell which composed of α and B chains will recognize the antigen which is in the groove plus α1, α2 regions of α chain of MHC I and this is called MHC Restriction (to recognize antigen in association with MHC proteins structure ) and this restriction present in MHC I and II.
Note that the antigen is recognized only when it's presented in this groove in conjunction with MHC molecule.

Under normal condition, the cells produce Normal antigen (cell antigen), this antigen doesn't evoke an Immune response because T-cells when they come and inspect the cell, they look for the peptide; if they found cell peptides so they leave the cell and go to other cells for Inspection. If there is a foreign peptide in the groove so they know that there is something wrong here and they connect, producing an immune response.
So T-cells are always going to inspect the MHC molecule on cells and this is called Immune servaiance (survey).

--- α3 domain of MHC Class I molecule got a receptor for CD8 which is present on cytotoxic T-cell so in order to evoke an immune response, the interaction is going to be (with the presence of foreign antigen in the groove) between CD8+ on cytotoxic T-cell and α3 domain.
So the presence of these 3 components (foreign antigen, CD8+ and α3 domain) causes the interaction and Immune Response.

Note that α chain of MHC I molecule differ from that of TCR.


MHC Class II Molecules Structure

These proteins found on the surface of antigen presenting cells ONLY and they are Macrophages, Dendritic cells and B-cells, so these cells have MHC I (because they are nucleated cells) and MHC II (because they are antigen presenting cells).
But in general, we consider every cell in the body as antigen presenting cells because MHC I will present the antigen, but we called the cells (Macrophages, Dendritic cells and B-cells) as antigen presenting cells because they are the only cells to have MHC Class II.

This Class made of two polypeptide chains α and B chains, they are equal in size and both are on the plasma membrane. α chain made of two domains (α1, α2) and B chain made of two domains (B1, B2).
Specifically B2 domain has receptor to CD4 which present on Helper T-cells, so the antigen presenting cells will only present the antigen for helper T-cells because it has TCR which will recognize the peptide placed on MHC II groove and also has CD4 which is able to connect to B2 domain and finally get Immune response.

So… Cytotoxic T-cells recognize antigens on all cells of the body that contain MHC I, while helper T-cells recognize antigen on antigen presenting cells that contain MHC II.


The antigen presenting groove of MHC II is bigger than of MHC I and its between two separate chains α1 and B1. The peptide here is bigger than the one in MHC II, it contains 15-18 amino acids but it still a small peptide not a protein.

Note that in the structure of MHC Class I and II there is a disulfide bond S-S remind you with beta pleated structure (domains), this kind of structure is present on most of molecules that are concerned with Immune response. Any molecule that has this structure is known as a member of Immunoglobulin superfamily. The members are BCR, TCR, MHC Class I and II.


MHC Production In the Cell

How does the peptide get into the groove and where does MHC molecule produced?
Actually, These MHC molecules are produced in the endoplasmic reticulum of the cell.

MHC Class I production
The component of MHC I molecule (α chain and B2 microglobulin) will produce separately in the endoplasmic reticulum then mixed together and going to the Golgi apparatus.

Now the production of antigen occur at the same time, when the same cell produces other proteins different from MHC I molecule. Now these proteins will break down into small peptides in the proteosome, then taking up by transporter to Golgi apparatus SO every groove of MHC I molecule is filled now with one peptide.

In normal condition, all proteins that are present in cell are our own proteins (cell antigen). But under abnormal conditions, foreign proteins produced and will break into small peptides that will recognized by Cytotoxic T-cell as something wrong and destroy them, such as in Cancer cells and viral infections where the virus produce foreign proteins and some of these broken down to peptide from virus and recognized by Cytotoxic T-cell.
So as a result, the Cytotoxic T-cell will not interact with normal cell because they produce normal proteins.

These peptides, because they are endogenously produced in the cell (produce within the cell), they are known as Endogenous Antigen as always presented in conjunction with MHC Class I molecules.


MHC Class II production
Here is the same mechanism, the endoplasmic reticulum will produce α and B chain and push them into Golgi apparatus. Now in order to get out from Golgi apparatus, a constant peptide known as invariable chain (invariant chain) connect to it and push it out the Golgi apparatus in the form of vesicle inside the cell containing MHC II molecule and the peptide (invariable chain).

These cells which produce this vesicle is Phagocytic cells, they take up foreign antigen from outside and break it down in the phagolysosome. From the breaking down, we will get small peptides and these peptides are going to be presented.

Now there will be a fusion between vesicles (contain MHC II and invariable chain) which come out from Golgi apparatus AND products of phagolysosomes (contain digested foreign antigen such as bacteria), mixing occur and finally exchange, between invariable chain and peptide from the bacteria, occur.

In normal situation our own proteins will break down in the lysosome, replacing the variable chain in the vesicle. As a conclusion, in normal situation self peptides will be on Class I and II.

Peptide binding Groove of MHC Classes

As we know that the groove of MHC Class I molecule present between α1 and α2 domains and the groove of MHC Class II present between α1 and B1 domains. This groove contains polypeptide which has different sequence of amino acids in the cell.

Now, why we need some sort of variation in the Groove?
In order to be able to fit as many peptide as we can. But we don’t need that much variation, meaning, we don’t need thousands to million different peptides grooves, in order to let the T-cells recognize these antigens without confusion.
In contrast, the variation in Immunoglobulin occurs in order to recognize lots of antigens.

The variation of MHC Classes is due to allelic polymorphism (due to different alleles), while the variation in Immunoglobulin and TCR is due to Gene rearrangement.

Genetics of the MHC

As we said in the beginning that the genes for HLA proteins are clustered in MHC molecules, located on the short arm of chromosome 6. These genes are of four types;
HLA-A gene HLA-B gene HLA-C gene HLA-D gene.

The first three genes (HLA-A, HLA-B, HLA-C ) are associated with MHC Class I Molecule, where as HLA-D gene which composed of 3 part (DP, DQ, DR), is associated with MHC Class II Molecules.




Genetics of MHC Class I
There are three types of MHC Class I molecule encoded by three genes present on the short arm of chromosome 6 and each of these genes produce different type of MHC I :
MHC I type A encoded by HLA-A gene
MHC I type B encoded by HLA-B gene
MHC I type C encoded by HLA-C gene


HLA-A gene has 24 different (A) alleles among populations (A1,2,3….24) and since the gene is composed of two alleles so we inherit 2 (A) alleles; one allele from father and the other from mother. For example we take A1 allele from mother and A17 allele from father. We can take same alleles from father and mother based on relative relation.
HLA-B gene has 52 different (B) alleles among population (B1, 2, 3….52) while HLA-C gene has 11 different (C) alleles among population. And the inheritance of these two genes is the same as HLA-A gene as I discussed above. All these three genes are detected by serologic assays.

Because the expression of these genes is codominant ,(not recessive or dominant) meaning that both chromosomes from father and mother will produce their products, and because we take 3 Genes from mother and 3 Genes from father, THE Maximum number of different types and alleles of MHC Class I is 6 different alleles (6 different kind of MHC I ). If the parents have the same HLA alleles so we get less than 6 different types.
Note that the codominant is property of the expression applied for all genes including HLA-D for MHC II molecule.

These different types have the same B2 microglobulin and α chain, but the groove is different because we have different sequence of amino acids.

In transplantation, the type of As, Bs, Cs alleles must be the same in recipient and donor in order to avoid rejection and this is known as Tissue Typing (determine the closest MHC match between recipient and donor).


Genetics of MHC Class II
HLA-D gene codes for MHC Class II proteins. D referred to as Designated region, and this region composed of 3 parts (DQ, DP, DR); each part is composed of 2 genes (A and B genes); A genes code for α chain and B gene code for B chain of MHC Class II molecule, and both genes are present on the same chromosome on the short arm of chromosome 6.

The HLA-D gene is detected by the interaction of cells together in reaction known as mixed lymphocyte reaction (MLR). The maximum differences here are up to 18 different MHC Class II Molecules.








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The End
Done By Sura Al-A3mar