The molecular perspective: major histocompatibility complex.

The Oncologist 2005;10:80-81 www.TheOncologist.com Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell@scripps.edu Website: http://www.scripps.edu/pub/goodsell Received November 15, 2004; accepted for publication November 15, 2004. ©AlphaMed Press 1083-7159/2005/$12.00/0 The human body is a dangerous place for viruses. When infecting a cell, viruses have to deal with our sticky antibodies, patrolling lymphocytes, and many other defenses. But once a virus gets comfortably inside a cell, it is insulated from these dangers by the cell membrane. But fortunately for us, our cells are not this hospitable. They have a powerful system to advertise all of the things going on inside, and when this includes a growing virus, they use this system to alert the immune system. Our cells continually display small pieces of their own internal proteins, carrying them outside the cell membrane where the immune system can see them. Most of the time, these peptides are just pieces of the normal proteins found inside the cell. Each person’s immune system, early in life, is customized to ignore these peptides, so healthy cells are left alone to go about their business. However, if any of these peptides is unusual, it is recognized by the immune system, starting a series of events that will eventually lead to the death of the problematic cell. The process starts inside the cell, where proteosomes break all different kinds of proteins into small peptides. These little peptides are transported into the endoplasmic reticulum where they are combined with the two subunits of the major histocompatibility complex (MHC) to form a nice stable complex. Then, the MHC is delivered to the surface of the cell, where it displays its peptide for several hours. The complex is designed so that it is only stable when the peptide is bound, which cleverly ensures that only peptides from inside the cell are displayed. If the peptide is lost once the complex reaches the surface, the whole thing falls apart before it can pick up random peptides from the surrounding environment. The peptide is then recognized by T cell receptors on the surface of lymphocytes (Fig. 1). A series of coreceptors confirm the interaction and strengthen the link between the faulty cell and the lymphocyte. The cells are brought into close contact, and then large secretory granules are released into the narrow gap (Fig. 2). These granules include several noxious proteins, including perforin, which forms holes in the cell surface, and granzymes, which enter the cell and cut proteins inside. Some of these granzymes make strategic cuts in caspases inside the cell, triggering the process of apoptosis. The faulty cell then proceeds to destroy itself. This system is a vital part of our defense against viruses. Inside an infected cell, viruses will be rapidly multiplying, forcing the cell to build viral proteins. MHC carries little fragments of these proteins outside, planting a warning flag on the cell surface. Without MHC, this problem would be invisible to the immune system. The prevalence of Kaposi’s Fundamentals of Cancer Medicine The Oncologist