Conlemporaries Ernst H. Beutner, PhD It is a privilege to write this autobiography by invitation of the Editor. For the past 25 years, I have studied the role of autoimmunity, primarily in bullous and connective tissue diseases, and the use of immunofluorescent methods for detecting antibodies. This article gives me the opportunity to pay tribute to those who have contributed to the understanding of immunopathology of the skin, notably my teachers and my many colleagues. My parents were m y first teachers. M y father, Reinhard Beutner, was a chemical engineer in the Kaiser's Germany, moved into the biological sciences in the pre-World War I era of the Rockefeller Institute in New York, and later became a pharmacologist at several medical schools. His devotion to the principles of scientific research continues to serve as a model for my work. My mother, Hermine Aye Beutner, supported my father in his role as teacher; her father had been a pediatrician and her mother was chief nurse and assistant to Robert Koch at the University of Berlin teaching hospital. M y own career began with a doctorate in microbiology from the department of Stuart Mudd at the University of Pennsylvania. After some research experiences at different locations in the Boston area, including the dental division of Harvard's pharmacology department, I came to Ernest Witebsky's Department of Bacteriology and Immunology at the State University of New York at Buffalo in 1956 to teach medical and dental students. M y first research project under Witebsky's guidance was to learn about the immunofluorescent method of detecting antibodies from Albert Coons at Harvard. We used this method for studies on the experimental thyroiditis system of Witebsky and Noel Rose. Other studies that followed included some pioneering work on thyroid microsome antibodies of thyrotoxicosis, muscle antibodies of myasthenia gravis, and some experimentally induced autoantibodies. I wrote a review of immunofluorescence that netted more than 2000 reprint requests] About 7 years after my arrival in Buffalo, we beReprint requests: Ernst Bcumer, PhD, Department of Microbiology, University at Bult'alo, SUNY Medical School, 5219 Sherman Hall, Buffalo, NY 14214.
Ernst H. Beutner, PhD
gan studies on the immunopathology of the skin. In 1963, James Jordon, chairman of the Department of Dermatology, asked whether pemphigus was an autoimmune disease. (His son, Robert Jordon, and I were working on a thyroiditis project.) Bob and I began work on pemphigus sera and tissues using immunofluorescence with James Jordon advising on dermatologicquestions. Hans Kipping, of the S U N Y at Buffalo Dermatology Department, gave us our first positive blood sample from a patient with pemphigus. As Bob and I studied cases we found not one but two types of reaction patterns: (1) antibodies to the intercellular areas of stratified epithelia and (2) antibodies to their basement membrane zone. We struggled with many questions, including the validity of the immunofluorescent method. Fortunately, fate took us in several other directions at that time. John Holborow of the Royal Medical Council laboratories at Taplow, England, invited me to join him for a 6-month sabbatical. John and his associates joined forces with me to tackle the problem of defining and standardizing the variables in the immunofluorescent procedures to make them more reproducible. Like a musical medley, one tune was carried by the immunologists working on methods for the next five years and the other by dermatologists working on the immunopathology of bullous diseases. Walter Lever, who in the mid-1960s published a mono119
graph on pemphigus and pemphigoid, joined us on our second and third publications on the subject z, 3 and convinced us that the basement membrane zone antibodies were a marker for pemphigoid. Four international conferences were held on immunofluorescence between 1965 and 1970, yielding more than 100 publications and significant progress. The 1970 conference in Stockholm for which Astrid Fagraeus invited me to serve as Secretary General was reported in an issue of the Annals of the New York Academy of Sciences,4 the first on a meeting held outside the United States in the Academy's then 153-year history to be so reported. Special credit goes to those who devoted their efforts to defining immunofluorescence. Georg Wick and Boris Albini in Vienna, Suyu Shu and Jau-Shyong Deng, Russell Nisengard and the late William Hale in Buffalo, and many others in my laboratory and elsewhere laid one by one the foundation stones that provided the basis for the parallel progress in the immunopathology of the skin. Harold Goodman of the World Health Organization gave editorial guidance on some key studies on methods and assisted me in obtaining a visiting professorship in Sao Paulo, Brazil in 1968. There I worked on a combined teaching program on immunofluorescence methods with Otto Bier and on Brazilian pemphigus foliaceus. We offered the first documentation that this disease was characterized by typical pemphigus antibodies, 5 a finding for which they later gave me the Rocha Lima award. Tadeusz Chorzelski, a Polish dermatologist working with Walter Lever in 1964 and 1965, confirmed and extended our findings on pemphigus versus pemphigoid antibodies with the help of Albert Coons. Ted and I met in 1967 when he and Stephahie Jablonska invited me to come to Warsaw. They explained to me later that they had expected to recognize me at the airport by my "immunofluorescent green complexion." During the past 22 years, Ted, Stephanie, their associates, my associates, and I have published more than 120 literature reports; we have completed five books, are working on a sixth, and are planning a seventh. The tie that binds us to this group in Warsaw is their deep devotion to seeking a better understanding of those aspects of the basic science of skin immunology that have significance for human health and welfare. The Warsaw group laid the foundation for the practical clinical utilization of findings of both indirect immunofluorescence tests for the anti-
Journal of the American Academy of Dermatology bodies of pemphigus and pemphigoid and the A N A s of systemic lupus erythematosus as well as direct immunofluorescence findings on skin biopsy specimens in bullous and connective tissue diseases. Their leadership and the first book we wrote on the subject, Autosensitization in Pemphigus and Pemphigoid,6 provided a critically important cornerstone for the start of the summer conferences. In 1970 Ted, Stephanie, Bob Jordon, Russ Nisengard, Bill Hale, and I, then working under the microbiology chairmanship of Felix Milgrom, started a series of 10 annual summer conferences at Buffalo on the immunopathology of the skin. Also in the 1970s, we started to provide diagnostic tests for the bullous and connective tissue diseases we had studied using defined direct and indirect immunofluorescence tests on skin biopsy specimens and serum. The idea of these methods used as aids in the management of patients stimulated dermatologists to request such tests on specimens of their patients. In 1971, in response to a growing demand, we formed a private laboratory, the Immunofluorescence Testing Service. My associates, Russell Nisengard and Bill Hale, and I started this skin immunopathology laboratory with the help of my technician, Christa Nagy, to cope with increasing demand for these services. Eighteen years later, we are still working to improve the quality of these services. Immco Diagnostics (formerly IF Testing) has added our partner, Vijay Kumar, and other doctorates, including Susan Krasny, Margot Koelle, and other excellent workers. Much remains to be done and we are thankful that we can contribute to progress in the field. Four additional international conferences on labeled antibodies were held between 1974 and 1985; the eighth was held in Tokyo in 1986 under the leadership of Kyoichi Kano, director of the Institute for Immunology, a part of Japan's "NIH." These conferences on labeled antibodies yielded more than 200 reports and immunofluorescence procedures that can, under defined conditions, approach the reproductibility of biochemical tests. The A N A tests served as both a model system and a prime beneficiary of some of these international cooperative efforts to standardize immunofluorescence techniques. Groups of previously unrecognized skin autoantibodies in normal sera were noted with the improvements in methods, first to the cytoplasm of keratinocytes and then the corneocytes. At the same time that we were compiling compelling evidence for the
Volume 22 Number 1 January 1990 pathogenic role of pemphigus antibodies, we found that these other autoantibodies played a physiologic role. This mystery to which I was introduced during a short sabbatical in Warsaw in 1971 led us to 44 publications and an ongoing struggle with new concepts on the nature of autoimmunity during the past 18 years. These efforts in teaching, service, and research on skin immunopathology received strong and vitally important support from the leadership of the Dermatology Department, University at Buffalo, SUNY, including James Jordon, Edmund Klein, Hans Kipping, Richard Dobson, and Frederick Helm. This stimulating environment was also enriched by the strong support of our work from my own microbiology department, first under the chairmanship of Ernest Witebsky, who coauthored some of our original reports, and then by his successor, Felix Milgrom. Our summer conferences on skin immunopathology in the 1970s, the above-mentioned support, and our books, papers, and diagnostic experience stimulated many outstanding contributions, such as those of the following investigators: Beno Michel, who developed a transport medium; Mark Dahl, who helped to pioneer the dermatologic immunology certification program; "Mitch" Sams, who pioneered immunofluorescence studies of vasculitis; Tom Burnham and the late Rudi Cormane and Jim Gilliam, who all took part in introducing the lupus erythematosus band test; Karl Holubar, who with Gary Wood helped us confirm the passive transfer of pemphigus (first shown by Ted Chorzelski and Maria Jazarbek Chorzelska); Bill Epstein and Denny Tuffanelli, who first reported on diseasespecific immunofluorescence findings in porphyria; and Jean-Claude Bystryn, who first demonstrated immunofluorescence differences between the two forms of pemphigus. These are only a few examples of the work of more than 300 participants and faculty in our summer conferences who enlarged the "medley" of findings into a "chorus" of contributions. We compiled these in the first edition of Immunopathology of the Skin in 197 3.7 With the rapid growth of the field we again compiled reviews of relevant findings for a second edition in 1979. At this time we turned our attention in other directions because courses and conferences on the subject were now being organized by the American Academy of Dermatology by our former participants and faculty. The 1980s saw fresh input into the standardiza-
Ernst I-1. Beutner, PhD 121 tion of ANA tests from Roger Taylor of the Centers for Disease Control, which I featured in 1982 at the International Congress for Dermatology in Tokyo and at our Seventh Defined Immunofluorescence Conference8 at Niagara Falls, New York, where I served as Secretary General. My friend Tadeusz Chorzelski started us in a new direction with his discovery of the IgA autoantibodies of dermatitis herpetiformis and celiac disease, the subject of more than 20 publications and of our next book, Serologic Diagnosis of Celiac Disease, authored by Ted, Vijay Kumar, me and our associates, to be published by CRC Press. 9 Many other new findings appeared, such as the differentiation of the antibodies of the two major forms of pemphigus with two substrates by Michael Sabolinski and improved methods for detecting antibodies to extractable nuclear antigens developed by Vijay Kumar. In 1987 we published the third edition of Immunopathology of the Skin l~ and it is already in need of extensive revision. This field and the methods used in it continue to be productive. Among the many needs for future developments in skin immunopathology is to clarify the interfaces between pathologic and physiologic forms of autoimmunity, to extend the use of defined immunofluorescent methods into tests for the antibodies of pemphigus, pemphigoid, and gluten-sensitive enteropathy, to integrate these with the rapidly growing number of serum tests for connective tissue diseases as well as infectious diseases of the skin (e.g., herpes simplex viruses and papillomas), and to explore a noninvasive in vitro tests for specific antigens of allergic contact dermatitis. The greatest asset to the past progress in skin immunopathology and the greatest impetus to future developments are those dermatologists who have the vision to recognize and utilize relevant new findings. I continue to enjoy the challenge of this ongoing dynamic adventure.
Ernst H. Beutner, PhD, Buffalo, New York REFERENCES
1. BeutnerEH. lmmunofluorescentstaining: the fluorescent antibody method.Bact Rev 1961;25:49-76. 2. BeutnerEH, LeverWF, WitebskyE, et al. Autoantibodies in pemphigusvulgaris. Responsesto an intercellularsubstance of epidermis.JAMA 1965;192:682-8. 3. JordonRE, BeutnerEH, WitebskyE, et al. Basementzone antibodiesin bullouspemphigoid.JAMA 1967;200:751-6. 4. BeutnerEH, ed. Definedimmunofluorescentstaining.Ann NY Acad Sci 1971;177: 1-529. 5. Beutner EH, PrigenziLS, Hale WL, et al. lmmunofluorescent studiesof autoantibodiesto intercellular areas ol
Journal of the American Academy of Dermatology
122 Beutner epithelia in Brazilian pemphigus foliaceus. Proc Soc Exp Biol Meal 1968;127:81-6. 6. Beutner EH, Chorzelski TP, Jordon RE, eds. Autosensitization in pcmphigus and bullous pemphigoid. Springfield, II1.: Charle.s C Thomas 1970. 7. Beutner EH, Chorzelski TP, Bean SF, et al. eds. lmmunopathology of the skin: labeled antibody studies. 1st ed. Stroudsburg, Pa.: Dowden, Hutchinson and Ross, 1973. 8. Beutner EH, Nisengard R J, Albini B, eds. Defined immu-
nofluorescence and related cytochemical methods. Ann NY Acad Sci 1983;420:1-432. 9. Chorzelski TP, Beutncr EH, Kumar V, et al. Serologic diagnosis of celiac disease, Boca Raton, Fla.: C R C Press (In press.) 10. Beutner EH, Chorzelski TP, Kumar V, eds. Immtmopathology of the skin, 3rd ed. New York: John Wiley & Sons, 1987.
Study of plasminogen activator activity in aquagenie pruriginous syndromes Brunetti L, Bianchini G, Lotti T. G Ital Dermatol Venereol 1988;123:1-3 (Italian) Cutaneous fibrinolytic activity was autohistographically evaluated in eight patients affected with aquagenic pruritus, in two patients with polycythemia vera, and in 10 control subjects. Cutaneous fibrinolytic activity was increased in approximately 100% in all patients with aquagenie pruritus after water challenge. Normal subjects showed no difference in cutaneous fibrinolytic activity before and after contact with water. Yehudi M. Fehnan, MD
Immunologic alterations in vitiligo Vignale R, Paciel J, Calandria L. Med Cutan lbero Lat A m 1988;343-7 (Spanish) This study of cellular immunity in vitiligo found an increase in the number of epidermal in the number of epidermal Langerhans cells. In the blood eytotoxic T lymphocytes, activated T lymphocytes (DR.+), and B lymphocytes are increased. Total T lymphocytes and helper T cells (CD4 +) were not increased. These results suggest that immune mechanisms mediated by eytotoxic T lymphocytes may be the cause of the destruction of melanocytc,s in vitiligo. Yehudi M. Felman, MD
Hypergammaglobulinemic purpura Stringa S, Peppe H, Stringa O, et al. Arch Argent Dermatol 1988;36:171-8 l (Spanish) Four patients with hypergammaglobulinemic purpura are presented. Hypergammaglobulinemia of the lower extremities may be preceded by pain, mild itching, or burning. During the course of several days, lesions become brown, leaving reticular discoloration. Polyarthralgias, increased erythroeyte sedimentation rate, and anemia may be present. The rise in levels of serum globulins is due to an increase in monoclonal or polyclonal IgG. The histologic changes in early stages consist of a leukocytoelastic vasculitis. After several days the perivascular cuffs are composed of mononuclear inflammatory cells. Two &the four cases re-
ported demonstrate hypergammaglobulinemia in association with systemic lupus erythematosus a nd one with chronic active hepatitis. Immunofluore.scence of the lesions has shown IgA, IgM, lgG, and C3 in the dermal vessels in 50% of eases. These findings, in addition to the high levels of rheumatoid factor, suggest that circulating immune complexes play an important role in the pathogenesis of the vascular damage. Yehudi M. Fehnan, MD
Acquired plaque elastolysis of middermis Heudes AM, Boullie MC, Thomine E, et al. Ann Dermatol Venereol 1988;115:1041-5 (French) A young woman in good health noted wrinkled plaques on the trunk and limbs. A biopsy specimen revealed absence of elastic fibers in the mid derails. Five similar cases have been reported. Yehudi M. Felman, MD
Therapy for subcorneal pustular dermatosis (SneddonWilkinson disease) with mebhydrolin Dorittke P, Wassilew SW. Z Hautkr 1988;63:1025-7 (German) A 60-year-old man with subcorneal pustular dermatosis had a rapid and lasting remission after treatment with mebhydrolin, a new antihistalnine. Yehudi M. Felman, MD
In situ immunologic identification of Treponemapallidum as an aid in the diagnosis of syphilis Barbareschi M, Burberi A, Motta S, et al. G llal Dcrmatol Venereol 1988;123:315-8 (Italian) Treponema pallidum was detected directly in fixed paraffinembedded tissue by means of an immunologic technique. The complement was stained with antihuman C3 fluoresceinatcd rabbit serum after incubation of the sections with serum positive for trcponemal antigen. This technique is easy to perform and can help solve problems in the diagnosis of syphilis. Yehudi M. Felman, MD