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CONCEPTS OF AUTOIMMUNE DISEASE AND THEIR IMPLICATIONS FOR THERAPY SIR MACFARLANE BURNET* My assignment is to look at autoimmune disease as one ofthe growing points of medicine and as a field of perhaps even greater future importance . Briefly, I shall try first to state what I think are the essential features of the pathogenesis of this group of diseases and, second, to think aloud about possible preventive or therapeutic approaches. First, let me define autoimmune disease as any pathologic condition resulting from the interaction within the body ofantibody or immunologically competent cells—which henceforth I shall call immunocytes— on the one hand, and antigenic determinants carried by normal body components on the other. I became interested in autoimmune disease at the clinical level ten or twelve years ago, primarily from association with Ian R. Mackay of the Clinical Research Unit of our institute in Melbourne. Soon afterward I heard from workers in New Zealand that Dr. Marianne Bielschowsky had developed a strain ofmouse NZB which regularly developed a positive Coombs test. She kindly gave us a breeding stock ofthe NZB strain. Since then, in association with Dr. Margaret Holmes and other collaborators , I have been concerned mainly with experimental studies of autoimmune disease in mice. It would probably be more correct to say that we have been observing, almost as one would a series ofhuman patients, the spontaneously developing genetically determined autoimmune dis- * School ofMicrobiology, University ofMelbourne, Victoria, Australia. This paperwas presented at a symposiumjointlysponsored by Merck Sharp & Dohme Research Laboratoriesand the Columbia University College ofPhysicians and Surgeons held in New York, May, 1966, on the occasion ofthe dedication ofexpanded facilities of the Merck Sharp & Dohme Research Laboratories. This paper will be reprinted in Modern Medicine and will be included in the collection ofpapers to be published in book form by Merck & Co. Publication in PERSPECTIVES is supported by a grant from the trustees ofthe Foundation for Microbiology. I4I eases ofthe strain NZB and its Fl hybrids. This is perhaps the best model yet uncovered for an important human disease that demands therapeutic interference, and I shall end this paper with an account of some of our experimental studies in therapy. But my real interest has been in trying to understand the pathogenesis ofautoimmune disease. Now that I have retired from active experimental work and have no longer either a vested interest in my own field of experimentation or a supervisory control over experiments by myjuniors, I have found an increasing and almost detached interest in the flood of interesting experimental and clinical material against which one can test and, where necessary , modify one's theoretical ideas. I am an honest disciple of Karl Popper in believing that the function ofhypothesis in science is all important in providing clear statements that are susceptible ofdisproofby experimental or observational data, or both. No such thing as absolute truth exists, but there is always contemporary truth in the form ofthose axioms, generalizations, theories, and hypotheses that, in the opinion ofcompetent scholars, have not yet been disproved. Nine or ten years ago I became interested in the fact that some cases of macroglobulinemia gave serologic reactions of autoimmune type. This, plus ideas from Jerne and other thoughts arising from the behavior of chicken lymphocytes on the chorioallantoic membrane, led me to produce what I called the clonal selection theory of immunity [i]. An essential part of that general point of view was the "forbidden clone" approach to the interpretation of autoimmune disease. In the intervening years, I have used that general constellation ofideas as a framework on which to set out and ponder on the facts of experimental immunology and immunopathology . Now I want to look at the pathogenesis of autoimmune disease from this point of view and to discuss in particular the possibilities that this approach may open up for therapy. Clonal Selection Theory The essential features ofthe theoretical approach to immunology which I support at the present time are: i. The configuration of the combining site or antibody, which determines its specificity, is based on genetic information carried and phenotypically expressed by the immunocytes concerned. The variety of such 142 Sir Macfarlane Burnet · Autoimmune Disease Perspectives in Biology and Medicine · Winter 1967 information that is...

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