The immune system has been known to be capable of distinguishing self from non-self since the pioneering work of Paul Erhlich more than a century ago. Originally described in experiments studying blood transfusion compatibility, the principle of "horror autotoxicus" is still valid, although today the phenomenon is usually described in terms of tolerance or ignorance. A great deal has been learned about the various processes preventing self-reactivity normally. These include processes that operate during immune cell ontogeny and subsequently on reactivity of mature lymphocytes in the periphery. They encompass mechanisms that are intrinsic to potentially reactive lymphocytes and can result in central or peripheral deletion or the alteration of functional potential. In addition, there are influences that are extrinsic to potentially auto-reactive lymphocytes, including the function of regulatory cells, differentiation state of antigen-presenting cells, availability of self-antigen, the cytokine and chemokine milieu, as well as the trafficking patterns involved in generating productive immune interactions. It is clear that the immune system devotes a considerable effort to the avoidance of the development of potentially pathogenic self-reactivity.

Despite this, the development of self-reactivity is relatively common. Although the development of autoimmune disease is less frequent, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus ery-thematosus, psoriasis, thyroiditis, and myasthenia gravis, are all too common, and can cause considerable morbidity and even mortality. That the breakdown of self/non-self discrimination can result in autoimmunity and in some circumstances autoimmune disease has been known for more that 50years. In most circumstances, however, the precise mechanism underlying the development of autoimmune disease is unknown. Although many elegant animal models of autoimmune disease have been developed, some of which result from a single genetic defect, in most circumstances the relevance of these animal models to human autoimmune disease remains uncertain.

There has been great progress in the last few years in the development of more precise knowledge of the control of the function of the immune sys tem. Awareness of the complex interactions of the innate and the adaptive immune system, the role of apoptosis in regulating the evolution of immune reactivity, as well as the role of various regulatory cells in shaping and limiting immune reactivity has permitted the development of a better understanding of immune system biology. New insights have not only come from traditional immunologic studies, but also from genetic analyses of both immune responsiveness and autoimmune disease. In addition, new insights have emerged from studies of the control of cell signaling, biochemical analysis of the regulation of cellular differentiation, as well as the detailed analysis of the biology and biochemistry of the plethora of effector molecules involved in regulating the expression of immune reactivity.

The wealth of new insights has prompted a re-assessment of the mechanisms controlling self/non-self discrimination and the specific abnormalities that result in a breakdown of this fundamental and essential protective property of animals. The goal of this volume is to utilize the wealth of new information to re-assess self/non-self discrimination with the expectation that viewing this old challenge with more modern eyes may generate novel insights. It is anticipated that new hypotheses may emerge about the control of autoimmunity, and that novel potential targets maybe recognized as potential points of intervention to treat or even prevent autoimmune disease.

December 2005

Peter E. Lipsky and Andreas Radbruch

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