~~~ What the Heck is an MHC Molecule ? ~~~

The acronym, MHC, stands for Major Histocompatibility Complex. MHC molecules are special inherited proteins expressed on the surface of an animal's cells. The overall pattern of expression of the various genetically determined forms of these inherited proteins can be used to identify an individual as unique. Among humans for example, there are many different variants of a given class of MHC molecules within the species. Consequently, these particular molecules are said to be highly polymorphic (exist in many forms). An exception would be the comparison of genetically identical, identical twins. In this case, all MHC molecules and therefore the pattern of cell surface expression between twins would be the same. These molecules not only serve to distinguish one individual from another, but they also play a vital role in an immune response. The presence of these molecules is an absolute requirement for an individual to successfully respond against and to subsequently eliminate foreign agents from the individual. Therefore, these molecules are critically important to whether or not an individual can generate an immune response against a foreign invader, such as a protein toxin molecule, a virus, or an infectious bacterium. A lack of MHC molecules would mean a lack of immune response - and therefore - a severe immunodeficiency.

What does the word, histocompatibility, mean?
The level of histocompatibility between and among individuals is primarily dependent upon the similarity of the pattern of structures of the MHC molecules uniquely expressed by the individuals involved. To be histocompatible literally means that if skin is grafted, one individual's skin is compatible with another, i.e., the donor skin will be accepted and will not be rejected by the recipient's immune system as foreign. The term "histocompatibility" therefore originally involved only skin compatibility between animals of varying degrees of genetic difference. However, as we know today, this term applies not only to the acceptance of foreign skin but also to the acceptance of foreign tissue of all types such as a liver, kidney, lung, heart, etc., - all manner of organ transplants. When an organ transplant is planned, both individuals must be carefully examined for their relative degree of genetic similarity. In this case, the degree of genetic sameness depends not only upon the blood group to which an individual belongs, but also depends upon the particular forms of MHC molecules among humans that are expressed upon the cell surfaces within each individual. Therefore, it is the expression of the various forms of MHC molecules unique to the individuals that ultimately determines whether or not the graft will be accepted by the recipient's immune system.

Are all MHC molecules identical to one another?
MHC molecules fall into two basic classes - known as MHC Class I (Roman numeral "one") and MHC Class II (Roman numeral "two") molecules. Every individual inherits two sets of each class, one set from the mother and one set from the father. Both sets of either MHC Class I or MHC Class II, or sometimes, both MHC Class I and MHC Class II, are expressed by cells within an organism. These molecules subsequently appear on the surface of each cell within the individual and participate in induction of an immune response against an invader. The class of each MHC molecule expressed on a given cell's surface, however, depends upon the type of cell involved.

Which cells within the individual express these molecules?
All nucleated cells (mature erythrocytes, i.e., red blood cells, within humans do not have a nucleus) equally express on their surface, both sets of inherited MHC Class I molecules. However, only certain cells of the immune system, i.e., B-lymphocytes, macrophages and certain dendritic cells additionally express both sets of MHC Class II molecules on their surface. Because of their capacity to express MHC Class II molecules, each of these three categories of immune system cells are also known as an antigen-presenting cell, or APC. This last term means that B-lymphocytes, macrophages and the appropriate dendritic cell can each present parts of proteins taken up (internalized) by the APC, to T lymphocytes.

How is the immune response dependent upon MHC molecules?
1. Humoral (antibody production) immune response

Here is how MHC molecules and the immune system work together to remove or kill foreign substances, cells, or microorganisms such as viruses and bacteria. We'll first take a look at how the immune system removes a foreign protein, such as something like tetanus toxin, a protein produced by the bacterium, Clostridium tetanii. If a deep puncture wound (little to no oxygen at the bottom of the wound because of trauma-induced cell death and lack of oxygen flow) becomes infected by this bacterium, the toxin will be produced and will enter the bloodstream. Once into the blood, the toxin will eventually be taken up by a neutrophil through a process known as phagocytosis (cell eating). If there is any material remaining, the toxin can eventually land inside a lymph node. There, dendritic cells and macrophages as well as toxin-specific B-cells can bind and internalize the toxin. Inside these cells, the toxin will be chopped into fragments by special enzymes and these fragments will finally associate with MHC Class II molecules. These MHC Class II molecules with their associated toxin fragment will be transported and displayed on the surface of these cells. At this point, a particular kind of T-cell, a helper T cell, with receptors that interact specifically and simultaneously with MHC Class II shapes and the toxin fragment shape will be activated to divide and to produce substances. These substances, known as cytokines, can stimulate activated B cells to produce antibody molecules - soluble molecules that bind specifically to molecular shapes on substances. The only B cells that will be activated are those B cells that reacted with the toxin in the first place. Therefore, the overall response will lead to production of millions of antibody molecules specific for various toxin fragments and similar shapes on the native toxin molecule. Once antibody binds to the native, non-fragmented toxin molecule anywhere the toxin is in the system, the toxin can easily be engulfed by macrophages and destroyed.

2. Cell mediated immune response
In this instance foreign cells or cells infected with an intracellular agent like a virus or intracellular bacterium will be eliminated from the body. This process of elimination of infected cells depends upon MHC Class I molecules - as well as MHC Class II molecules. When a virus infects a cell, viral proteins necessary for new virus particle assembly will be produced inside that cell. These viral proteins are treated exactly like all other intracellular proteins the cell makes for its survival. This treatment is to fragment a portion of all of the proteins that are synthesized inside the cell - no matter the origin of the protein. Some of these fragments end up associating with MHC Class I molecules and the complex is transported to the cell surface and displayed there. Consequently, each nucleated cell in a person's body is constantly displaying parts of itself. These parts are recognized by another kind of T cell, a cytotoxic (cell killing) T cell. Some of these cells will have receptors that can bind to MHC Class I shapes and simultaneously bind to foreign protein shapes that are complexed with MHC Class I molecules. There should not be any such T cells that can bind to any fragment shapes that belong to the cell itself. Therefore, whenever a fragment of a virus protein appears on the cell's surface in complex with a MHC class I molecule, there will be a cytotoxic T cell that can specifically interact with this complex. The interaction leads to activation of the cytotoxic T cell and this activation step prepares the cell to release cell killing substances. However, the cytotoxic T cell will not release these killing substances without "permission" from a helper T cell. Therefore, if a helper T cell has been activated by interaction with an antigen presenting cell that is presenting viral protein fragments via MHC Class II molecules, this T cell will release cytokines that will signal the cytotoxic T cell to release the killing substances. Then, the cytotoxic T cell will therefore kill the cell that contains the virus, and thus eventually will rid the body of the virus.

What does all of the above have to do with organ transplants?
Tissue - human or otherwise - genetically foreign to our body, means that the MHC Class I and II molecules expressed on the surface of the tissue that is foreign to us, are molecularly recognized by our helper and cytotoxic T cells. It is a quirk of nature that foreign histocompatibility molecules are recognized by our own immune system cells as if the histocompatibility molecules were our own that are presenting foreign protein fragments. Among all animal species and indviduals within species, histocompatibility molecules are actually very, very similar with respect to the variety of similar shapes. Because they possess so many similar shapes among them, each individual will have T cells that can interact with a portion of these molecules as if they were our own. But, the fact that histocompatibility molecules among species and individuals within a species also possess shapes that are different among them, these different shapes are responded against as if they were fragments of foreign protein being held by one of our own MHC molecules. Thus, the immune system is "fooled" into "thinking" that a foreign protein or fragment is beng presented by our own APC via Class II molecules, and/or by our own tissue via MHC Class I molecules. Foreign tissue is therefore "perceived" as our own tissue that is infected with a virus or intracellular bacterium. Consequently, the tissue wil be killed and therefore rejected. It is for these reasons that tissue transplants must be as closely matched as possible with respect to the inherited MHC molecules' shapes expressed by the donor and recipient of the transplant. One reason liver transplants are relatively more common is that liver cells for one reason or another, do not express a high level of MHC Class I molecules on their surface. Therefore, these cells are relatively more "hidden" from cytotoxic T cells and thus more readily escape detection. If the cytotoxic T cell cannot bind very well via its receptors to the target cell, the cytotoxic T cell will not be activated and will therefore not kill the target. Thus, the traspanted tissue can remain without harm.

Book: Don't Touch That Doorknob!

Copyright John (Jack) C. Brown, May, 2001

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