The Once and Future History of the Idea of Autoimmunity
Acting Chief, Autoimmunity Branch
National Institutes of Health
About the Lecture
Tracing the intellectual history of a research project, trying to find a direct path from where we are now – back through all the knowledge and discoveries – to the point where research on a certain thing actually started, is often difficult. In this presentation, the origins of the concept of autoimmunity, diseases in which one type of antibody (proteins that attach to harmful substances in the body so that the immune system can destroy them) — called autoantibodies — attach to the body’s own healthy tissues by mistake, will be presented. Possible future developments based on this concept will also be explored.
About the Speaker
PAUL PLOTZ is the Acting Chief of the Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health. He received his M.D. in 1963 from Harvard Medical School (Cum Laude for Thesis “Studies on the Actions and Interactions of Streptomycin and Penicillin”). He did his internship and residency in medicine at the Beth Israel Hospital, rheumatology training in the Arthritis and Rheumatism Branch (ARB), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and his post-doctoral research as a Helen Hay Whitney Fellow at Mill Hill in the United Kingdom. He returned to the ARB in 1970 as a Senior Investigator, and he currently serves as the Chief, Connective Tissue Diseases Section (since 1984) and the Chief, Arthritis and Rheumatism Branch (since 1994). In addition to his own Lab/Branch positions, he has also served as: the Acting Scientific Director and Acting Clinical Director, NIAMS (2005), Senior Advisor to the Deputy Director for Science, NIH (2006-present), and Acting Deputy Director, NIAMS, NIH (2007-present). In addition, he is a Part-time Adjunct Professor of Medicine at Johns Hopkins University School of Medicine (2005-present). Since returning to NIH in 1970, he has studied research questions on autoimmune diseases.
President Kenneth Haapala called the 2,244th meeting to order at 8:18 pm November 7, 2008 in the Powell Auditorium of the Cosmos Club. The minutes of the 2,243rd meeting were read and approved after a brief discussion and suggestions.
Mr. Haapala introduced the speaker of the evening, Mr. David Plotz of the National Institutes of Health. Mr. Plotz spoke on “The Once and Future History of Autoimmunity”.
Immunity, Mr. Plotz said, is the process by which the body defends itself against insults of various sorts; autoimmunity is what happens when the body turns that defense against its own tissues.
The idea that the body can learn from experience and do better the next time has existed thousands of years. Thucydides, during the Plague of Athens, observed that the recovered had the most compassion for the sick. Even in 430 BC, they knew they were safe from the disease once they recovered.
By the 17th century, smallpox inoculation was discovered. By the 18th century, inoculation with cowpox and later with smallpox was accomplished. Pasteur’s bold experiments on rabies and anthrax laid the foundation of modern immunology.
Eighteen ninety was chosen by historian Athur Silverstein as the inception date of immunology. Mr. Plotz counts 1901 as the date of inception of autoimmunity. That year saw the publication by Paul Ehrlich in Germany of his insight that individuals might make antibodies that were toxic to themselves. He called it “horror autotoxicus,” and gave us the idea the body must have a system to protect against that danger.
A short, very productive period ensued. A pair of Viennese doctors, Donath and Landsteiner, identified and described an autoimmune disease for the first time. August Wasserman, in Berlin, showed that sera from patients with syphilis could react with extracts of syphilitic tissue as well as with normal tissue. Therefore, they were genuine autoantibodies.
Just before the First World War, autoimmunity was sought and found in diseases of the brain, eyes, testicles, thyroid, and other organs.
Then there was a Dark Age in autoimmunity. For 30 to 40 years, progress stalled. Finally, in 1945, a paper by Coombs’ on autoimmune hemolytic anemia appeared. Also in that period, the center of gravity moved west, to Scandinavia, England, and America. Eric Waaler noted in 1943 that sera from patients with rheumatoid arthritis agglutinated sensitized horse and sheep red cells. In 1946, Harry Rose and Charles Ragan at Columbia University, not knowing of Waaler’s paper, found that the serum of their lab technician agglutinized sheep red cells. The technician had rheumatoid arthritis, and they thus accidentally and independently discovered what we now call rheumatoid factor. The Rose-Waaler test or the Waaler-Rose test led to understanding that rheumatoid factor was being caused by an autoantibody.
In 1939, Elvin Cabot, the most famous immunologist of his generation, showed antibodies in the gamma globulin fraction of sera. About then, chromatography, electrophoresis, radioactivity, ultracentrifugation, and gel filtration were invented. They led to the understanding of antibody structure not long after the end of the Second World War. A young Australian, J. F. A. P. Miller, in 1961 wrote a paper on the thymus, enabling us to understanding the thymus’s role in immunology, mainly the production of T-cells. Organisms not known, such as polio, were progressively brought to understanding. These originally chance discoveries of autoantibodies and the new concepts of connective tissue and then collagen disease took a firm grip on rheumatology. Soon myositis, scleroderma, and other rarer rheumatologic diseases were drawn together. The mechanism of rheumatic fever – both an infectious and an immunologic disease – was understood. Rapidly the wider world of medicine recognized that many other diseases characterized by chronic inflammation were apparently accompanied by autoantibodies. Then antibodies, many of them naturally occurring autoantibodies, became effective tools. There was an era of over-discovery, too – autoantibodies everywhere, in every disease, with boundless explanatory power. Three have defied understanding to date: tuberculosis, malaria, and HIV.
McFarland Burnett posited, in 1957, the critical property of antibody specificity. It developed in cells, he theorized, that had mutated their antibody genes and whose proliferation was controlled by antigen, not the variable folding of the antibodies. This proposition has framed immunological thinking ever since.
One interesting line of research was made possible by the U.S. Army’s policy of storing serum from recruits. This enabled the discovery that antibodies were present in the blood long before rheumatoid arthritis actually exhibited in patients.
He discussed the increasing importance of genes in the study of immunology. He noted that we are able to identify genes causing phenomena, but not why particular phenomena, such as diseases, turn up in response to particular genes. One possibility of great interest about genes is that the genetic diseases discovered so far are the ones involving factors that are quickly regulated up and down, that is in hours. He mentioned also that introduction of autoantibodies, such a single burst of interferon, can produce a lifetime effect, setting in motion a chain which does not reverse and does not stop in the organism’s lifetime.
He closed with a quote from Emerson: Beneath every deep a lower deep opens. For us in science, he said, that’s just what we want.
In the question period, one person asked about the effect of nanotechnology such as carbon fibers mimicing parts of the autoimmune system. It’s a good question, he said, and he does not know the answer. He is concerned. He said there is a good chance that we will find such effects of nanoparticles. He said basically nothing is known about it. He is sort of glad he doesn’t know what nanoparticles are floating around in his own system.
Another asked about gender bias in autoimmune diseases. “Maybe,” Mr. Plotz said. A few years ago gender studies were popular; they are not now. He noted that men and women do not differ much in their genes; only a few genes relate to sex, Klinefelter’s syndrome is one disease that does come from genes. They have an extra X and an extra Y chromosome.
One person asked about the possibility of the personality disorders being genetic diseases. He thought it is definitely possible, and said there are single-gene causes of very particular psychological phenomena.
Another person asked about producing artificial bodies to serve as targets for antibodies. Mr. Plotz was not optimistic about this. The reaction between antibody and antigen releases peptides that cause havoc that you don’t want in the organism if you can help it.
Responding to a question about aging possibly being an autoimmune response, he said it’s not likely to turn out to result from one thing. Although antigens probably go up with time, the processes involved are generally not those we find in autoimmune diseases, he said.
Can a person develop antibodies with nonbiological materials such as plastics? Could this cause allergy?
He couldn’t speak for plastics. There are, though, many things you can get an allergy to, such as nickel, an element. That’s very common. Poison ivy is a reaction to a very small chemical, a little sugar alcohol.
He mentioned that many genes can be turned on rapidly or slowly. That’s different from autoantibodies, which is a complex process involving cells. When you make an antibody, you splice your own genes. It’s very hard to turn that process back or to kill just those cells.
To another question, he said he is a strong advocate of sensible nutrition and exercise. However, he does not think it’s likely that a normal range of diet has much effect on immunity.
Mr. Haapala presented to Mr. Plotz a plaque commemorating the occasion. His own mother having died of lupus, he wished Mr. Plotz godspeed in his work.
He made the parking announcement and hinted that the parking proceeds might pay off the debt of Mexico. He announced a seminar in a different venue he will give November 22 on a timely subject, “The Vocabulary of Economic Recession.” (I don’t think he was talking about cuss words, but I’m not sure.) He announced the upcoming nominations for offices in the Society. He announced the next meeting. Finally, at 9:23 pm, he adjourned the 2,245th meeting to the social hour.
The weather: Cool and crisp
The temperature: 10°C
Ronald O. Hietala,