Hundred years ago, Paul Ehrlich speculated whether an individual is able to produce toxic autoantibodies and about the implications of such antibodies for disease. The contention that an alteration of the body fluids causes disease followed the traditional teachings of Hipppocrates and Galen that disease results from dysfunction of the four humors. However, Ehrlich introduced the novel concept of antigen specificity that was based on his side chain theory of antibody formation: (1) antibodies are naturally occuring substances that serve as receptors on the cell surface; (2) the specificity of antibody for antigen is determined by a unique stereochemical configuration of atoms that permits the antibody to bind tightly and chemically to its appropriate antigen; (3) the number of different combining sites structures available is so great that each one differs from the others, with little or no cross reactivity among them; (4) and in order to induce active antibody formation, it is only necessary that appropriate receptors be present on the cells for antigen to interact with them and so stimulate their overproduction and liberation into the blood. According to this description by Paul Ehrlich, the antibody ap-peared to be a polymorphous cytoplasmic agent with a unique feature - a highly organized combining site (the haptophore group) that determined its unique antigen specificity.
It was Bordet who showed that anti-erythrocyte antibodies were capable of mediating immune hemolysis giving rise to the idea that self-produced hemolytic antibodies might assist in destroying autologous erythrocytes.
This and similar findings including the description of cytotoxic antibodies against a variety of other cell types prompted Ehrlich to say: "... the organism possesses certain contrivances by means of which the immunity reaction, so easily produced by all kinds of cells, is prevented from acting against the organism's own elements and so giving rise to autotoxins .so that we might be justified in speaking of a 'horror autotoxicus' of the organism. These contrivances are naturally of the highest importance for the individual" (P. Ehrlich and J. Morgenroth, Berlin. Klin. Wochenschr., 1901).
When Metalnikov was the first to demonstrate the generation of autoantibodies that were cytotoxic against spermatozoa in vitro, Ehrlich questioned that they were able to induce pathology in vivo.
It took, however, more than fourty years that some distinct organ-specific immune disorders were categorized as true autoimmune diseases. Among the first identified were autoimmune orchitis, allergic encephalomyelitis, autoimmune thyroiditis, pemphigus vulgaris and bullous pemphigoid. Noteworthy, some of these disorders are exclusively mediated by circulating autoantibodies such as the hemolytic anemias, thrombocytopenia, pemphigus, and pemphigoid while others, such as allergic autoimmune encephalomyelitis and autoimmune thyroiditis require the transfer of immunocompetent cells in addition to auto-antibodies.
The existence of immunological tolerance was the logical consequence of Paul Ehrlich's postulate that there was a "horror autotoxicus" a mechanism that inhibited formation of potentially harmful autoantibodies to self in vivo. It was Owen to show that dizygotic calves whose circulation was connected in utero were unable to respond to each other's antigens after birth. Out of this and similar observations, the clonal deletion theory was invented by Burnet meaning that antigen present during embryonic life would somehow cause destruction of self-reactive clones. The observation that adult animals could be rendered unresponsive to foreign antigens by the administration of large doses of the antigen led to the notion that immunological tolerance could be also acquired.
The recognition of different central and peripheral immune mechanisms leading to immunological tolerance are all based on Ehrlich's concept of "horror autotoxicus", i.e. acquired or active immune regulation of unwanted immune responses against self. The finding that B lymphocytes generally require the help of T lymphocytes in their antibody response to a defined antigenic stimulus led to the discovery of distinct immune cell subsets including helper cells, cytotoxic cells and regulatory cells. The identification of the idiotype-anti idiotype network was born out of the discovery that the antigen binding site of the antibody itsself can act as an antigen for anti-idiotypic antibodies. Anti-idiotypic immune responses are part of the physiological immune surveillance aimed at limiting the extent of an immune response.
The identification of different lineages of antigen presenting cells has taken away much attention from T lymphocytes as the exclusive regulators of immune and autoimmune responses. Major interest has recently focused on dendritic cells, bone marrow-derived antigen presenting cells with potent capacity to induce primary T-cell-mediated immune responses. However, accumulating evidence has demonstrated that the dendritic cell system bears much more plasticity than originally thought. Dendritic cells can arise from several different types of progenitor cells and different functional types of dendritic cells can be generated from the same precursor. It thus appears that dendritic cells have the potential to modulate immune responses within the wide spectrum of immunity on the one hand and immunological tolerance on the other hand.
The rapid development of immunological research has also provided major insights in the pathogenesis of autoimmune disorders which has implications for classification, diagnosis and therapy of these disorders. Classical examples for well-characterized autoimmune disorders are myasthenia gravis, pemphigus vulgaris, and hemolytic anemia. Furthermore, the availability of recombinant forms of the major autoantigens of these disorders has provided critical tools to investigate autoimmunity versus immunological tolerance to these self proteins in affected patients and healthy individuals.
The increasing understanding of the mechanisms that lead to immunologi-cal tolerance to self and the role that HLA and non-HLA alleles play in antigen recognition by autoaggressive T cells may also lead to novel therapeutic strategies. Several clinical studies have sought to restore immunological tolerance to self by the administration of modified self peptides, such as the administration of altered peptide ligands of myelin proteins in multiple sclerosis. Immature dendritic cells hold great promise as highly efficient tools to induce immuno-logical tolerance to defined self proteins or peptides as demonstrated in murine allograft rejection models. They may induce tolerance by inducing antigen-specific anergy of autoreactive T cells and/ or by the induction of regulatory T lymphocytes that inhibit the activation of autoaggressive T cells.
I am very grateful that internationally leading experts in the field of cutaneous autoimmune disorders spontaneously agreed to provide comprehensive and well-illustrated overviews of the major autoimmune disorders of the skin. It was truly fun to interact with all of them! In addition, I would like to acknowledge the support and efforts of Springer Verlag in making this kind of book possible. We hope that the concept of this book will indeed help to broaden the understanding of cutaneous autoimmune disorders for those working in the many clinical disciplines which are involved in the care of these patients. Finally, I thank my wife for her continous support and her help and criticism during the development of this book.
Erlangen, July 2001 Michael Hertl
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