Learning Objectives:

• Learning terminology about MHC (HLA)
• Learning classification of MHC molecules
• Learning differences between MHC Class I and MHC Class II molecules
• Learning their molecular structures
• Learning cells expressing these molecules
• Functions of MHC I and MHC II class molecules

The Major Histocompatibility Complex (MHC) is a group of molecules represented on cell surfaces. They play role in "antigen presentation" and lymphocyte recognition. The MHC molecules are very important for regulating the immune response through recognition of "self" and "non-self". Therefore, they serve as targets in transplantation rejection. The Class I and Class II MHC molecules belong to a group of molecules known as the Immunoglobulin Supergene Family, which includes immunoglobulins, T-cell receptors, CD4, CD8, and others. This lecture will describe the MHC molecules in previous to lecture of the process of antigen presentation. Since they were discovered in human lymphocytes at first, we named them as Human Lymphocytes Antigens (in a short form, HLA). Later, scientists, McDevitt, Gorer and Snell showed by studying on transplant genetics that they were present in all cells.

The major histocompatibility complex is encoded by several genes located on human chromosome 6. They are very important for tumor clearance and graft rejection. In order to understand graft rejection and autoimmune diseases, you have to know something about the MHC.

CLASS I MOLECULES

Class I molecules are composed of two polypeptide chains; alpha and beta chains. Alpha chain has three separate domains called alpha-1, alpha-2 and alpha-3. ß2-microglobulin is non-covalently associated with the alpha-3 domain. Its function is stabilizing molecular structure of MHC I. A small peptide of about 10 amino acids binds a region between the alpha-1 and alpha-2 domains. This small peptide is "presented" to a T-cell and defines the antigen "epitope" that the T-cell recognizes.

CLASS II MOLECULES

Class II molecules are composed of two polypeptide chains. These polypeptides (alpha and beta) each fold into two separate domains; alpha-1 and alpha-2 , beta-1 and beta-2. Domain between the alpha-1 and beta-1  chains is very similar to that seen on the class I molecule. This region, is capable of binding (via non-covalent interactions) a small peptide of about 10 amino acids. This small peptide is "presented" to a T-cell and defines the antigen "epitope" that the T-cell recognizes

CLASS I vs CLASS II MOLECULES

While class I and class II molecules appear somewhat structurally similar and both present antigen to T-cells, their functions are really quite distinct.

We can list these differences as below:

1. Class I molecules are found on virtually every cell in the human body. In contrast, class II molecules are only found on B-cells, macrophages and other "antigen-presenting cells" (professional APCs).
2. Class I molecules present antigen to cytotoxic T-cells (CD8+ Tc) while class II molecules present antigen to helper T-cells (CD4+ Th).
3. Class I molecules present "endogenous" antigen while class II molecules present "exogenous" antigens. An endogenous antigen might be fragments of viral proteins or tumor proteins. Presentation of such antigens would indicate internal cellular alterations that if not contained could spread throughout the body. Hence, destruction of these cells by Tcs is advantageous to the body as a whole. On contrary, exogenous antigens might be fragments of bacterial cells or viruses that are engulfed and processed by e.g. a macrophage and then presented to helper T-cells. The Th-cells, in turn, could activate B-cells to produce antibody that would lead to the destruction of the pathogen.

I should mention about MHC Class III and IV molecules a bit. Molecules of complement system and many inflammatory molecules are placed in MHC Class III group. On the other hand, MHC Class IV genes work only during embryological period, then they stay silent during life time. Therefore, I call them ‘Sleeping Genes’. Class III and IV will not be discussed here.

In human, as I mentioned above, they are also known as HLA. In medical texbooks, you will see very often the terms HLA-A, HLA-B and so on. We classify MHC molecules, Class I and II, as shown below:

           HLA Molecules

Class I                          Class 2

HLA-A                          HLA-DP

HLA-B                          HLA-DQ

HLA-C                          HLA-DR

In particular, HLA-A, -B and C, as well as HLA-DR molecules are very important in transplantation. When we transfer any organ and tissues from donors to recipients, we have to evaluate mismatches amongst these. You can imagine these molecules like fingerprints of a person.

MHC and combinational art

• If approximately,  60 HLA-A, 100 HLA-B and 40 HLA-C allel genes are present in a population

5 x 10¹⁰ allelic combination may be possible

However observed combination is less than this number  (linkage disequilibrium)

In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is not the same as linkage, which describes the association of two or more loci on a chromosome with limited recombination between them. Linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies. Non-random associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium (LD). Numerically, it is the difference between observed and expected (assuming random distributions) allelic frequencies.

Otherwise, transplantation from one to another would not be easy job. For instance, a person, who had kidney failure and needed kidney transplant, would have one in 50 million chance in probability. It would mean that a person was able to find an appropriate donor one or two in Turkish population.

In order to obtain my lecture notes and power point presentations, please go to the link given in the first page or as shown below.

İmmünolojiyle ilgilenen öğrenciler aşağıdaki bağlantıdan grubuma üye olabilirler ve dosyaları indirebilirler.

http://health.groups.yahoo.com/group/immunologystudents/