Major Histocompatibility Complex
Major Histocompatibility Complex
- The genes, encoding the antigens of human major histocompatibility complex (or MHC), were first discovered as the genetic cluster coding for the glycoprotein molecules (transplantation antigens) responsible for the rapid rejection of tissue allografts transplanted between genetically non-identical donor and recipient.
- Nonetheless, it has become evident later that the main function of MHC molecules is to bind peptide antigens and present them to T cells.
- Thus, MHC molecules were shown to account for antigen recognition by T cell receptor.
- T cell receptor performs specific binding to the antigen only in case when it is presented in complex with MHC molecule. It is possible to conclude that TCR simultaneously recognizes antigenic peptide and self MHC molecule that matches this peptide (double recognition phenomenon).
- If the same antigen is presented by another allelic form of the MHC molecule (that can be realized only in experimental conditions), there is no recognition by the T cell receptor. The phenomenon is known as MHC restriction.
- The function of antigen presentation is realized by antigen-presenting cells (APCs) such as dendritic cells, B lymphocytes, or macrophages.
- In humans, MHC is organized as the large genetic cluster located on chromosome 6. It was entitled like HLA complex (human leukocyte antigens) as it was primarily studied in human leukocytes.
- The genes of the HLA complex encode the class I, class II, and class III MHC proteins. All of them are located on the short p arm of 6 chromosome – class I genes occupy more distal position; class II genes are presently closer to the centromere.
- HLA class, I molecules comprise three major (HLA-A, -B, and -C antigens) and three minor protein clusters encoded by corresponding genes.
- After gene expression the resulting molecule of HLA class I consists of two chains. Heavy chain with a molecular weight of 43 kDa is highly polymorphic – it has an extremely large amount of allelic variants for all three HLA-A, -B, and -C antigens.
- The heavy chain is non-covalently linked to a small 11 kDa β2-microglobulin peptide thus making membrane heterodimer. By contrast, the molecule of β2-microglobulin is the same for all variations of HLA class I molecules.
- The part of the heavy chain protruded outside the cellular membrane is composed of three globular domains (α1, α2 and α3) that are bound to β2-microglobulin.
- The molecules of HLA class I are expressed in various densities upon all nucleated somatic cells of humans.
- Class II HLA antigens comprises three main protein subsets – HLA II DP, DQ, and DR molecules encoded by respective genes.
- The molecules of HLA II class are the transmembrane glycoproteins composed of two non-covalently linked polypeptide sequences (α– and β-chains of molecular weight about 33 kDa and 29 kDa). Each chain has 2 external globular domains (α1 and α2 or β1 and β2, respectively). Both chains are highly polymorphic.
- Unlike class I proteins, they have a restricted tissue distribution. HLA class II antigens are predominantly expressed on the membranes of professional antigen-presenting cells (e.g., dendritic cells) as well as on В cells, macrophages, activated T cells.
- Their expression on other cells types (like endothelial cells) can be induced by gamma-interferon and some other cytokines.
- The class II MHC region also includes the genes encoding proteins involved into antigen processing (TAP-antigens).
- The genetic region of class III MHC encodes several complement proteins and certain cytokines (tumor necrosis factor).
- All the genes encoding HLA molecules exhibit a remarkable genetic diversity.
- Genetic HLA complex is polygenic – there are at least 3 kinds of major genes coding for I class (A, B, and C) and II class (DP, DQ, and DR) of HLA molecules.
- The HLA complex is also highly polymorphic. The genes encoding all the chains of HLA I and II class except β2-microglobulin have an enormously great number of allelic variants determined by the methods of genetic typing – more than 2 or 3 thousands for HLA-A, B or C and tens of thousands of combinations of allelic variations for 2 chains of HLA II class DP, DQ, and DR.
- Furthermore, HLA genes of I and II classes have a codominant expression – the sets of HLA genes inherited from both parents are expressed simultaneously thereby expanding the variability of individual HLA complex.
- In addition to the mentioned above, the set of HLA genes present in one chromosome is inherited as a single linkage group or haplotype. Every individual inherits one HLA haplotype from mother and father, thus resulting in final HLA phenotype.
- The main function of HLA molecules to bind foreign peptide antigens and deliver them for recognition by specific TCRs of T cells is realized in various ways.
- In all cases, the antigen should be degraded by proteolysis into a number of short peptides in the cytoplasm of the host cell (antigenic processing).
- The processed peptides are checked for matching with host HLA molecules. HLA of both classes has a deep cleft between their two chains, where the specific antigenic peptide is inserted after recognition.
- From the whole spectrum of antigenic peptides, only part of them can find and bind specifically to HLA molecules present in the individual host. Therefore, peptides incapable of matching with host HLA will escape T cell immune response.
- There are striking differences in recognition of foreign exo- and endo-antigens by host HLA molecules.
Exo-antigens (e.g., bacterial or fungal) are processed inside the endosomes of APCs (e.g., dendritic cells). Their peptides of 12-25 amino acids residues are coupled mainly with HLA II class molecules (HLA-DR, HLA-DP, HLA-DQ) and presented to T helper cells.
On the contrary, endo-antigens arisen inside the host cell after its viral infection or tumor transformation are processed within the proteasome – cytoplasmic protease complex. The fragments of viral or other endo-antigen of 9-10 amino acids residues are coupled predominantly with HLA I class molecules (HLA-A, HLA-B, HLA-C) to be presented to T-cytotoxic lymphocytes. Activation of cytotoxic T cells results in the killing of virus-infected or transformed host cell.
All these interactions provide the maximal stimulation for cell-mediated immunity.
- Determination of individual HLA-antigens (HLA typing) is necessary in certain cases. The main reason is the donor selection for organ transplantation.
- In addition, strong correlations between particular HLA-haplotype and some diseases are estimated. For instance, the presence of HLA-B27 antigen is observed in more than 95% of patients with spondyloarthritis (an autoimmune disease of spine and joints).
- Likewise, the combination of HLA-DR3 and HLA-DR4 is found with a high incidence in patients with diabetes mellitus type I.