Issues in Biology

Self / Non-self Discrimination of the Immune System

Animals have developed a defense mechanism which can adapt to a large variety of antigens, particles that find their way into our body causing an immune reaction. Because of the evolutionary relationship among all living organisms, most antigenic structures of infectious pathogenic organism are made of (macro-)molecules very similar to ours (this is also a concern for organ transplantation). As the immune system must be able to destroy invading pathogens, but not our own cells that may contain closely related cellular structures, it needs to learn to distinguish foreign components from its very own. This is known as the self/non self discrimination of the immune system. As simple as the concept appears, it comprises a mechanistically difficult to understand system. The issue is how our immune system learns to distinguish to make antibodies targeted only against foreign antigens, but not for self antigens?

From a molecular view point, one that a structural biochemist may take, this task seems almost impossible, unless parasitic and infectious organisms have radically different antigen structures (epitopes) than we have. While this is true for many bacterial and viral structures, it is not for all. Worse even, an individual's immune system recognizes the cellular components of an other person as foreign. Here, we certainly cannot assume that most of these components are radically different. In fact, they are very similar and the task of distinguishing cellular components among individuals of the same species falls to a few select molecular structures. These structures are often the sugar portions of cell surfaces, so called glycoproteins and glycolipids. A familiar specificity is provided by blood group markers. These provide compatibility between blood donor and recipient and are based on sugar structures of sphingolipids.

Back to the immune system. The immune system is partially based on white blood cells (lymphocytes) that provide the adaptive protection against novel pathogens. Part of the adaptation is the continuous maturation of naive cells into mature cells. This maturation process gets trained in the first few month of our lives not to recognize our own cells. The body uses a clever strategy offering the immune system samples of its own cells. Any lymphocyte in the making that will kill such exposed cells, will be eliminated themselves. Somehow, the immune systems not to produce any of these self-recognizing lymphocytes. Cells that do not attack our own sample cells make it through the screening process.

As biochemists, we really would like to know how this process works, i.e., understanding the molecular mechanism. Briefly, the maturing immune cells are presented with self markers and the interaction with these markers and the immune cell prevents an attack. Any cell that fails to present such self markers in addition to markers (antigens) known or unknown to the immune cells, will be engaged and destroyed. Mechanistically, this interaction is the result of a long series of multiple one-on-one interaction among many different (glyco-)proteins. Cells make use of their ability to cluster and assemble a variety of different marker to create recognition sites for other cells. Depending on the combination of markers, the immune fate of cells screened by lymphocytes lead either to distraction or has no further consequence.

It seems that the process of this learning by the immune system is well understood. However, the immune system sometimes attacks its own tissues anyway. We suffer an auto-immune disease. Familiar examples are lupus and multiple sclerosis. There are some good ideas of how this could happen, also almost nothing is know of how to prevent or even cure autoimmune diseases. The number of occurrences of these diseases is on the rise. This is surprising at first considering the improved standard of health and hygiene. But our success in keeping infections out of our lives may contribute to autoimmune diseases simply because the immune system has no clear foreign pathogens to 'learn' from. The antigens it comes in touch with are increasingly similar to each other and self and non-self discrimination may become harder or more error prone.

Read more about the immune system at ImmuneCentral


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