The Cost of the Immune System Autoimmunity and Transplant Rejection

The complexity of the immune system undoubtedly reflects its great survival value. Microbial invaders and their toxins are rapidly neutralized and destroyed, using flexible combinations of antibody, phagocytosis, and T cellmediated killing of cells supporting the growth of viruses or other intracellular pathogens. Although the immune system uses thousands of genes and many different cell types, this is a small price for immediate, short-term and long-term defences that can deal with any external threat, as long as it can be recognized as nonself. In nature, there is generally little pressure for economy of genes or cells.

There are two much more important prices for having a good immune system. First, the protection against infectious disease given by the immune system makes transplantation between unrelated individuals impossible without the use of immunosuppressive drugs. Second, in a few individuals, the immune system turns its attack to the host.

Paroxysmal cold haemoglobinuria is a disease in which episodes of haemolysis are triggered by exposure to cold. In 1904, Donath and Landsteiner provided evidence from three patients that this disease was caused by haemolytic auto-antibodies to self red cells. However, most workers found the concept of Ehrlich's horror autotoxicus so persuasive that there was great reluctance to accept the possibility that autoimmunity might occur. Perhaps the thinking was oriented excessively along the lines of what would make sense for normal physiology, and insufficient consideration was given to the possibility that the immune system might make a mistake or be misled. Whatever the reason, the concept of auto-immunity met very great resistance, and it took nearly half a century before the concept of auto-immunity became generally accepted (Silverstein, 1989; Mackay, 1995).

There is now good evidence that juvenile onset diabetes, rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, thyrotoxicosis and numerous other diseases are auto-immune in nature. The reasons why immunological tolerance breaks down in these diseases are still poorly understood (Miller and Morahan, 1992; Nossal, 1992b; Sercarz and Datta, 1994; Theofilopoulos, 1995a,b). There is some evidence that auto-immunity is driven by antigen rather than being caused by an autonomous 'forbidden clone' of lymphocytes, as envisaged by Burnet (1959), because many autoantibodies have somatic mutations characteristic of antigen-driven secondary responses (Behar et al., 1991 ; van Es et al., 1991 ; Diamond et al., 1992).

In a few instances, notably thyrotoxicosis, myasthenia gravis, bullous pemphigoid and pemphigus vulgaris, the antibodies are directly pathogenic (Naparstek and Plötz, 1993). However, in the great majority of instances it is not clear whether the auto-antibodies are directly involved in the pathogenesis of the disease or are perhaps an indirect reflection of the inciting antigen or some other epiphenomenon. The understanding of auto-immune disease represents a major challenge for contemporary immunologists, but there is a widespread contemporary belief that we are now close to acquiring adequate knowledge and tools to be able to make real progress.

Whatever the answers to these questions, the evolution of the immune system has given biologists a set of specific and versatile tools. The exquisite specificity of antibodies allows the molecular dissection of mixtures of molecules that would be far too complex to analyse by conventional chemistry. The remainder of this book will focus on the generation of antibodies, their structure, function and application to biological problems.

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