Tissue Typing Education Primer

Part 2 of 6

Move to Part 1(Intro), 3(Genetics), 4(Methods), 5(Relevance), 6(References)

THE HLA ANTIGENS

Based on the structure of the antigens produced and their function, there are two classes of HLA antigens, termed accordingly, HLA Class I and Class II..

The overall size of the MHC is approximately 3.5 million base pairs. Within this the HLA Class I genes and the HLA Class II genes each spread over approximately one third of this length.

The remaining section, sometimes known as Class III, contains loci responsible for complement, hormones, intracellular peptide processing and other developmental characteristics.
Thus the Class III region is not actually a part of the HLA complex, but is located within the HLA region, because its components are either related to the functions of HLA antigens or are under similar control mechanisms to the HLA genes.

HLA Class I Antigens
The cell surface glycopeptide antigens of the HLA­A,-B and ­C series are called HLA Class I antigens. A listing of the currently recognised HLA Class I antigens are expressed on the surface of most nucleated cells of the body. Additionally, they are found in soluble form in plasma and are adsorbed onto the surface of platelets. Erythrocytes also adsorb HLA Class I antigens to varying degrees depending on the specificity (eg HLA-B7, A28 and B57 are recognisable on erythrocytes as so called "Bg" antigens).

Immunological studies indicate that HLA­B (which is also the most polymorphic) is the most significant HLA Class I locus, followed by HLA­A and then HLA-C. There are other HLA Class I loci (eg HLA-E,F,G,H,J,K and L), but most of these may not be important as loci for "peptide presenters".

The HLA Class I antigens comprise a 45 Kilodalton (Kd) glycopeptide heavy chain with three domains, which is non­covalently associated with Beta-2 microglobulin, which plays an important role in the structural support of the heavy chain.

The HLA Class I molecule is assembled inside the cell and ultimately sits on the cell surface with a section inserted into the lipid bilayer of the cell membrane and has a short cytoplasmic tail.

The general structure of HLA Class I, HLA Class II and IgM molecules show such similarity of subunits, that a common link between HLA and immunoglobulins, back to some primordial cell surface receptor is likely.

The full 3-dimensional structure of HLA­A Class I molecules has been determined from X­ray crystallography. This has demonstrated that the molecule has a cleft on it's outermost surface which holds a peptide.

In fact, if a cell becomes infected with a virus, the virally induced proteins within the cell are broken down into small peptides and these are the peptides which are then inserted into this cleft during the synthesis of HLA Class I molecules.

The role of HLA Class I molecules is to take these virally induced peptides to the surface of the cell and by linking to the T-Cell receptor of a Cytotoxic (CD8) T Cell, demonstrate the presence of this virus. The CD8 T Cell will now be "educated" and it will be able to initiate the process of killing cells which subsequently have that same viral protein/HLA Class I molecule on their surface.

This role of HLA Class I, in identifying cells which are changed (eg virally infected), is why they need to be present on all cells.

HLA Class II Antigens
The cell surface glycopeptide antigens of the HLA­DP,-DQ and ­DR loci are termed HLA Class II.

The tissue distribution of HLA Class II antigens is confined to the "immune competent" cells, including B­lymphocytes, macrophages, endothelial cells and activated T­lymphocytes.

The expression of HLA Class II, on cells which would not normally express them, is stimulated by cytokines and in a transplant, this is associated with acute graft destruction.

HLA Class II molecules consist of two chains each encoded by genes in the "HLA Complex" on Chromosome 6. The T Cells which link up to the HLA Class II molecules are Helper (CD4) T cells. Thus the "education" process which occurs from HLA Class II presentation, involves the helper-function of setting up a general immune reaction which will involve cytokines, cellular and humoral defence against the bacterial (or other) invasion.

This role of HLA Class II, in initiating a general immune response, is why they need only be present on "immunologically active" cells (B lymphocytes, macrophages, etc) and not on all tissue.

Move to Part 1(Intro), 3(Genetics), 4(Methods), 5(Relevance), 6(References)