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Immunology => Histocompatibility Groups
Histocompatibility Groups
INTRODUCTION
Histocompatibility Groups, also known as the major histocompatibility complex (MHC), a set of genes encoding for specific proteins on the surface of cells known as MHC molecules, or antigens, which help the immune system to distinguish between "self"cells (which belong to the body) and "non-self" cells (which are foreign to the body).
The ability of an organism to distinguish between self and non-self is vital for the body's protection and ensures that the defence mechanisms enacted by cells of the immune system destroy foreign cells-such as invading microbes, or cells in grafted or transplanted tissues from another individual-while leaving the host tissues unaffected.
Normally, MHC molecules encoded by the MHC genes attach themselves to whole, or fragments of, foreign proteins such as those which exist on the surface of bacteria or viruses entering the body during infection. This enables these foreign molecules to be presented to T-lymphocytes of the immune system so that the body can mount an appropriate immune response against the foreign proteins. T-lymphocytes on their own cannot recognize these antigens as foreign, and can only mount an immune response when the foreign antigens are bound to the body's own MHC antigens.
The great structural complexity of MHC molecules and their corresponding genes is such that they are only partly understood at present. The MHC genes are clustered in a particular region of the DNA on a specific chromosome, chromosome 6; this region is also known as the human leucocyte antigen (HLA) complex. MHC molecules are subclassified into three different categories according to their precise chemical structure, tissue distribution, and function. Class I and Class II molecules are located on the surface of cells; Class III molecules are involved in another crucial part of the body's immune system, the complement system. The genes encoding for Class I and Class II molecules can take many different forms.
CLASS I MHC MOLECULES
Class I MHC molecules are present on nearly all cells in the body and, as such, have an extremely widespread distribution. As they are manufactured and transported to the cell surface, MHC I molecules bind to foreign antigens expressed by microbes such as viruses, which have invaded the cell and are in the process of dividing and making new proteins for themselves in the cytoplasm of the host cell. This MHC I molecule-antigen complex, or mixture, is then inserted into the cell surface and is recognized by a type of T-lymphocyte known as a cytotoxic (cell-destroying) T-lymphocyte. Once activated in this manner, the T-lymphocyte delivers a fatal blow to the infected cell, killing both it and the microbes it harbours.
Three closely linked parts of the MHC code for proteins are termed HLA-A, HLA-B, and HLA-C. HLA-A and B each have more than 30 different genes and, depending on which of these genes have been inherited, it is possible to tissue-type the body's cells according to the different MHC antigens expressed. Usually these different genes are given numbers so that a person is said to be of, for example, tissue type HLA-A24.
CLASS II MHC MOLECULES
Class II MHC molecules are coded for by a region of the MHC called HLA-D. This region has three subregions called HLA-DP, HLA-DQ, and HLA-DR. Class II MHC molecules have a restricted tissue distribution and are found mainly on cells of the immune system, particularly those cells known as macrophages, which devour foreign microbes such as bacteria or intracellular parasites.
The function of Class II MHC molecules is much the same as that of Class I molecules, in that they are involved in the presentation of foreign antigens to T-lymphocytes. However, in this case the engulfed microbe becomes embedded in membrane-bound vesicles in the cytoplasm of the host cell, where it replicates and makes more of its own proteins. Some of these microbial proteins become bound to Class II MHC molecules of the host and are transported to the cell surface, where they activate helper T-lymphocytes rather than cytotoxic T-lymphocytes.
These two forms of T-lymphocyte perform very different immune functions. They are distinguished by the expression of two different forms of cell surface molecule: CD4 by helper T-lymphocytes, and CD8 by cytotoxic T-lymphocytes. CD4 will bind to Class II MHC molecules and CD8 will bind to Class I MHC molecules. This shows how these molecules help the right type of T-lymphocyte to bind effectively to a cell presenting the antigen combined with MHC on its surface.
Once activated, the T-lymphocyte then communicates chemically with the host cell to instruct it to fuse membrane-bound sacs of destructive enzymes (lysosomes) present in its cytoplasm with the vesicles in the cell containing the foreign microbes, thereby destroying them.
Another form of immune cell, the B-lymphocyte, also expresses Class II MHC molecules. Each type of B-lymphocyte is coated with an antibody which recognizes only one or a small number of foreign proteins. When it encounters one of these proteins, it takes it up, degrades it, and recycles it back on to its surface now bound to Class II MHC molecules. Helper T-lymphocytes then recognize these complexes on the surface of the B-lymphocyte-and proceed to activate it, in order to divide and release large quantities of its antibody to that specific foreign protein.
CLASS III MHC MOLECULES
Unlike Class I and Class II MHC molecules, Class III MHC molecules are proteins found in the blood rather than on the surface of cells. Class III genes code for proteins that form components of the complement system of the blood, which is a complex group of proteins involved in the body's defence against bacterial infection. It also has a wider role to play in immune reactions in general.
The complement system can be activated by a number of mechanisms either by contact with an antigen-antibody complex (the classical pathway of activation) or by direct contact with a microbe's surface (the alternative pathway of activation). This system consists of 20 component proteins, each of which has a specific role to play in an immune response that leads to inflammation-an inflammatory response. These proteins work by various mechanisms. Some are important chemical attractants, meaning that they attract inflammatory cells to the site of an infection by acting as a chemical message. Others work by increasing the permeability of blood vessels at the site of the infection, which enables inflammatory cells to migrate from inside the blood vessel into the wounded or diseased tissues where the infection resides. Others act by attaching themselves directly to the bacteria, thereby increasing its mass and making it more prone to being engulfed by immune cells. Activation of the complement system is a powerful and crucial link in the body's immune system and is vital in the body's defence against infection.
MHC AND TRANSPLANT REJECTION
The MHC antigens expressed on the surface of the donor's cells and the recipient's cells usually determine whether or not a transplanted organ is likely to be rejected by the recipient's immune system. This is because MHC molecules are likely to provoke an immune response to a transplanted organ given to a patient whose HLA type is different from that of the donor organ. In effect the donor organ is expressing or contains one HLA type, while the patient's own cells contain or express a different HLA type.
When transplantation is carried out, the host body's immune system recognizes the donor MHC antigens as foreign. It therefore mounts an immune response against them, which results in the donor organ becoming inflamed and the tissue destroyed, leading to rejection of the donor organ. It is therefore vital to have as close a match as possible between the two HLA types of the donor organ and the recipient patient. If the match is close, the likelihood of the organ being rejected is reduced. If there is a big difference between the two types, the transplant is at a much greater risk of being rejected. It is for this reason that transplants which occur between siblings-such as brother and sister-have a much lower chance of being rejected, because the HLA types inherited by two offspring from their parents tend to be very similar.
In determining the compatibility of two HLA types, Class II molecules are more important than Class I molecules because they are more antigenic-that is, more likely to provoke an immune response. In transplant rejection, the Class II antigens on the donated organ are recognized as foreign and are then presented to the host body's T-cells, in conjunction with host MHC antigens, as described above. The T-cells of the host body then initiate an immune response and cause the transplant to be rejected. The crucial cells involved in rejection are dendritic cells, which are part of the mononuclear phagocyte system. The cells in this system are capable of expressing large amounts of Class II antigens. The higher the quantity of dendritic cells in the donated organ, the more likely it is to be rejected, if there is incompatibility between the HLA types.
MHC AND DISEASE
It is now well recognized that a person who has inherited certain HLA types is far more susceptible to developing autoimmune diseases. In this group of diseases, the body's immune system fails to recognize its own antigens as belonging to itself and instead regards them as foreign. The body then mounts an immune response to these antigens which results ultimately in the destruction of the cells expressing them. In other words, the body "attacks itself".
Diseases associated with certain HLA types include ankylosing spondylitis (HLA-B27); rheumatoid arthritis (HLA-DR4); and coeliac disease (HLA-B8). Several immunological mechanisms have been proposed to explain these associations; none have been proven conclusively, nor have they found widespread acceptance, mainly because a strong association may exist in most cases, but on some occasions is missing.
See also Acquired Immune Deficiency Syndrome; Immunology.
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