The human body is capable of distinguishing self from non self and this is most apparent in rejection of grafted organs skin and blood transfusions. The immune surveillance system constantly checks the type of molecular structures present on cells and tissues throughout the body. So long as these cell surface antigens are familiar to the immune system and are part of self no inflammatory response is initiated. However, if the immune system finds cell surface antigens that it does not recognize as self then immune attack and destruction of the offending cells swiftly follows.

We have commented on the humoral immune system and the ability of antibodies to recognize foreign antigens and help in their destruction. However, in cell and tissue rejection, as in a graft, blood transfusion and most autoimmune diseases the dominant method of immune system rejection is cell mediated involving antigen presenting cells, T helper and T cytotoxic cells. This chapter looks at how these cell types recognize antigens and how they interact with each other, the rest of the immune system and other body cells via cytokines. First, we must consider the types of antigens T cells recognize and the T cell receptors they use to latch on to these antigens.

Major histocompatibility complex

There are several different classes of cell surface antigens that are important in acceptance or rejection of cells in grafts or blood transfusions. The most important is the "Major Histocompatibility Complex" or "MHC". The MHC goes under different names in different species. In mice it is called H-2, in humans it is called HLA for "Human Leucocyte Antigen". Whatever, we will call it MHC which is universally applied to all species. MHCs are coded for by a cluster of genes that in humans are situated together on chromosome 6. There are several hundred genes involved which are classically divided into three groups, genes involved in class I, class II or class III complexes. We will focus on just class I and class II. The class III gene group codes for some molecules involved in the complement system we mentioned in chapter 5. The genes are positioned in blocks adjacent to each other. In Humans the Class II genes are subdivided into three groups called DP, DQ and DR. Next, in the middle sits the class III genes and at the other end of the gene cluster the class I gene are subdivided into three groups A, B and C.

MHC class I type are distinct in structure from class II MHC. Class I MHCs are made up of one large polypeptide chain, the alpha chain which is coded for by MHC class I genes and about 45kilodaltons in weight. A small beta chain of 12kilodaltons sits on the alpha chain but is coded for by non-MHC genes. An alpha chain may come from genes in the A, B or C subgroup and so we can have more than one type of MHC molecule in our bodies. Class II MHC molecules are coded entirely by MHC genes and consist of two similar polypeptide chains each about 30kilodaltons, again one called alpha the other beta. The chains may come from the DP, DQ, or DR gene groups so again we can have more than one subtly different type of class II molecule. Throughout the human population there are around 40 different MHC class II molecules that we know about so far. All have the same basic structure but vary subtly in their molecular structure. In the same way there are at least 80 known variants on the Class I type MHC molecule.

It is possible to tissue type a person by serological or genetic analysis to define which MHC class I or II molecules each person has. MHC genes are a focus of extensive research because their the MHC structures they code for are so important in the immune system. When you hear about MHC molecules at conferences or in research reports you might hear one called for example HLA-B17. This means it is a human leucocyte antigen from the B gene group (hence a class I type MHC) gene position (known as a gene locus) number 17. Or gene HLA-DR11, this means Human Leucocyte Antigen coded by a gene from the DR region (hence a class II type MHC) locus number 11. For each gene position on a chromosome there can be several possible bits of DNA code that can be present and each is called an allele. For example, some people have an allele that codes for green eyes. A different allele that fits in the same gene position on a chromosome may code for brown eyes, another allele for blue eyes and so on. Also remember we have two alleles for each gene position because we get one from each parent.

Because MHC antigens are so fundamentally involved in the immune defense system they are also important in determining the overall response level of the immune system to an antigen. From the pool of different MHC genes available some genes code for MHC molecules with superior stimulatory properties compared to others. The reason for explaining this is that MHCs are probably involved in autoimmune conditions. Certain gene alleles seem to make people more susceptible to developing an autoimmune disease than others. MHC gene analysis in alopecia areata is being conducted by several research groups.

In a healthy human body MHC class I molecules can be found on just about all cell types and vary in density from cell to cell. However, class II MHC molecules are much more exclusive limiting themselves to B lymphocytes, phagocytic cells especially ones involved in antigen presentation, occasional epithelial cells and a few T cells. However, while class II molecules are normally found on a few particular cell types, they can be induced and expressed on all almost any cell type under certain prolonged inflammatory or autoimmune conditions.

MHC molecules are first and foremost a method for immune systems to detect what is part of self and what is foreign tissue. Immune cells check the MHC molecules on cells. If the molecules tally with what is expected then the immune cells will not be activated. If the MHC molecules are foreign then the immune cells will respond. Of course this MHC molecule marker for self non-self distinction is not the only antigen system used to define histocompatibility. When blood or tissue is transplanted from individual to another doctors must check other histocompatibility molecules involved such as those in the ABO blood grouping, rhesus system.

MHC class I

MHC molecules have another function within our own body, they present other cell surface antigens to T cells for checking to see if they are self or non-self. T cells are practically blind. Although they can detect different MHC molecule types they can rarely independently recognize any other type of antigen, viral, bacterial or otherwise. They must have antigens presented to them and this is done by MHC molecules. The class I MHC molecules found on almost all cell types present antigens to T cytotoxic cells whereas Class II MHC molecules on antigen presenting cells present antigens to T helper cells.

The cell membrane is a very fluid structure. Molecules within it can move around and come in to contact with other. Class I MHC molecules migrate over the surface of cells and find other antigenic molecules. They have a particular preference for binding to viral antigens which of course will only be present if the cell is viral infected. MHC molecules associate themselves with other antigenic molecules too, they make no distinction between self and non-self antigens. MHC molecules are not like antibodies which only recognize one type of antigen. Each MHC molecule will attach to and present a wide range of antigens just not all antigens. As described above we have each have a number of subtly different types of MHC molecules. Each type will have a preference for what form of antigen they are best able to present to T cells.

Because MHC molecules are fairly flexible in how they bind to antigens different parts of the same antigenic molecule may be presented to T cytotoxic cells. Some MHC molecules will be more effective in their interaction than others because of their binding preferences. This will determine the ability of Tc cells to respond to the antigen and will help define how potent the immune response against an antigen will be. MHC molecule presentation of different parts of an antigen will ensure more than one type of Tc cell will be activated to target the same antigen.

MHC class II

MHC class I molecules are found on almost all cells and alert the Tc cells to any infection or damage in body tissues. MHC class II molecules have a different role as they are normally restricted to presence on antigen presenting cells (APCs). APCs are phagocytic cells that ingest any cellular debris or potentially antigenic particles. APCs make no distinction about what they phagocytose, it can be self or non-self material. The material is broken down inside the cells into small fragments and these are then released to the APCs cell surface. Here, MHC class II molecules bind to the antigenic fragments ready for presentation.

Because the antigens have been processed, they are much smaller than the antigens that MHC class I molecules present. Indeed, Structural differences in MHC class II molecules mean they can only present small, extensively processed antigens. As with MHC class I molecules, MHC class II molecules are quite flexible in how they bind to an antigen and what part of it they present. The same antigen can be presented in several different ways to elicit an immune response from different cells. The responding cells to MHC class II presentation are T helper cells. Th cells are involved in helping Tc cells in their activity and also in B cell production of antibodies. Th activation by MHC class II is therefore extremely important in our overall defense from pathogens.

T cell receptors

We know that B cells use antibodies attached to their cell surface to detect foreign antigens that they should respond to and start to produce more antibodies for release in to the blood stream. T cells also have receptors to detect foreign antigens. These T cell receptors (TCRs) are somewhat similar in their structure and antigen binding mechanisms to antibodies. Indeed antibodies and TCRs are evolutionary related to each other. In fact MHC class I and class II, TCRs, antibodies, CD4 and CD8 T cell receptors are all similar in structure and are described as belonging to the "immunoglobulin superfamiliy". You might remember I mentioned some confusion over calling antibodies immunoglobulins. Strictly speaking although immunoglobulins are antibodies, they are also TCRs, MHCs etc. The word immunoglobulin describes the nature of the molecular structure. Antibodies, TCRs etc are all made from one or more polypeptide chains linked and looped together by disulfide bonds. The loops of polypeptides are "globular" domains and the overall structures are important in the immune system, hence the word "immunoglobulin" describes more than just antibodies.

TCRs bind to antigens but only when they are presented by MHC molecules. Each T cell may express numerous TCRs on its cell surface but the TCRs are only able to bind to one antigen. A different T cell will have TCRs that bind to a different antigen structure. So the T cell population is much like the B cell population. Each cell can only recognize and respond to one type of antigen but as a whole the T cell population can respond to practically all types of antigen we are ever likely to be challenged by during our lives.

CD4 and CD8 molecules

TCRs will not recognize antigen on its own, it must be presented physically attached to an MHC molecule. Plus of course TCRs on Th cells will only recognize MHC class II and TCRs on Tc cells will only recognize MHC class I. In addition there is another mechanism to ensure this clear distinction between which class type MHC molecules Tc or Th cells will respond to. When a TCR binds to an MHC molecule and an attached antigen the CD4 or CD8 molecules come in to play. As mentioned before Th cells are also called CD4 cells because they have CD4 molecules on their surface. Tc cells are also called CD8 cells due to the presence of CD8 molecules. When a TCR binds to MHC the CD4 or CD8 molecules must also bind to the MHC to make a strong bond. CD4 will only bind to MHC class II. CD8 we are less sure about but probably it only binds to MHC class I.

Enforcing this distinction between what MHC molecule a Th or a Tc cells will recognize makes sense. Tc cells are destroyer cells directly involved in removing damaged or viral infected cells. Class I MHC is found on all cells and presents antigens on these cells so Tc cells must be able to recognize MHC class I to ensure that Tc cells can remove infected cells whatever or wherever they are in the body.

Th cells are regulator cells they help amplify a Tc and/or B cell response or stop an inappropriate one from developing. Its important that Th cells are only activated by a limited set of specialized APCs. If a wide range of cells were able to activate Th cells there may be the possibility of an inappropriate immune response. Unfortunately this can be the case in prolonged inflammatory events. All nucleated cells of the body have a full set of chromosomes and genes. The fate of a cell, whether it becomes a fibroblast, a brain cell, a lymphocyte etc. depends on which genes are switched off or on inside the cell. Some genes will dictate the cell should be a lymphocyte other genes dictate it should be brain cell. Sometimes inappropriate genes can be switched on in the wrong cells (as occurs in cancer). MHC class II genes can be switched on in tissue cells if given the right stimuli. Prolonged inflammation is one known method of inducing MHC class II expression on tissue cells in the area of inflammation. Sometimes this is a good thing as it may Further stimulate Th cells in the area and encourage a more potent immune response to damaged or infected cells. A prolonged inflammatory response suggests the immune system is having trouble removing the antigenic challenge so an extra boost from localized MHC class II expression can be beneficial. However, MHC class II can equally promote inappropriate immune activity such as in autoimmune conditions. Prolonged autoimmune activity will stimulate expression of MHC class II on healthy tissue cells. Cells of the hair follicle when inflamed in alopecia areata are known to express MHC class II.

This promotion of MHC class II expression is the result of chemical molecule stimulation by inflammatory cells in the area. So far we have looked at communication between cells in terms of physical contact or presentation of antigen and activation of immune cells through cell surface receptors. However, the immune system has a long distance communications network involving production of numerous different molecules. Different types of molecule have different actions on other immune cells, tissue cells and even directly on invading pathogens. These molecules are "cytokines".

Dr Darius H Umrigar MD ( AM )

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