MSB Review
SULZBERGER ON ALLERGY AND IMMUNOLOGY: THE YOUNG LION RETURNS TO NEW YORK WILLIAM L. EPSTEIN, M.I).
From the Department of Dertnatology, University ol Catilornia School of Medicine, 5an FrancisciK Ccilifnrnia
In the late 192O's, Sulzberger returned to New York from his (raining abroad into a seething intellectual ferment of allergists and immunologists struggling with the rapidly unfolding concept of allergy and hypersensitivity. The young lion was ready—^with an enormous intellect, a mind as sharp as a prosector's knife and a tongue to match, and the special advantage of training with the pioneer geniuses of dermatologic allergy, Joseph ladassohn and Bruno Bloch. These were tuniLiltuous times and his writings and the discussions afterward reflected the excitement and confusion that existed. What follows is a historical review of his publications in scientific journals on the subjects of allergy and immunology. In it, I wish to illuminate and assess Sulzberger's unique role in the marriage of allergy to dermatology and the evolution of their offspring, the subspecialty of immunodermntology. Of his 134 papers published before 1944, 99 were devoted to various aspects of allergy and immunology. They contain the essence of his famous book, Dermatologic Allergy, published in 1940. To simplify the discussion I have divided the paper into 4 major topics, (1) atopic dermatitis, (2) allergy of infection, (3) clinical contact dermatitis and (4) experimental contact dermatitis with some minor
headings, such as industrial derrnatitis, light eruptions and a final section on his penetrating and awesotiie reviews and getneral papers. Atopic Dermatitis Although Coca coined the word atopy, it is widely held that Sulzberger coined the term atopic dertnatitis. Yet he published only 8 early papers on this subject and did very little investigative work except for scratch and PK tests. However, in 1932 he tnasterfully set apart 2 groups of patients frotn the nebulous morass of "eczema," tiatnely those with contact eczema and "disseminated neurodermatitis," a fortn of atopy.' The choice of "neurodertnatitis" ptoved unfortutiate, because it led to further argument and acrimony and obscured Sulzbetger's brilliant clinical observations and laboratory correlations. Three years later, Lewis Webb Hill and he put the stoty straight with a classic description of the "Evolution of Atopic Dermatitis."- About this time, he began yearly reviews of dermatologic allergy in the lournal oi Altergy, but it was not until the second review in 1937' that he formally used the heading atopic dermatitis; so who is to say how the tertn really came about?
Address for reprints: William L. Epstein, M.D., l^eparlment of Dermatology, 1092 HSt-, University of Ciiliforni.i Medical Center, San francisco, C~A 94 143.
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In these papers he made several important and lasting clinical and laboratory observations about alopic skin, such as (1) the existence of fewer patch test reactions despite "highly irritable skins" and (2) papulopus(ular reactioiis to certain salts, including NiSO,, etc. During World War II, he attempted to develop vehicles for enhanced penetration of protein antigens to replace scratch tests,•'• •'' but this apparently fell through. After the war, he turned almost exclusively to therapy of atopic dermatitis as corticosteroids came along. Allergy of Infection This subject, more than any, preoccupied our young lion's pen and research energies. Approximately 20% of his early writings encompass this complex problem. As I read along from the beginning, I could not fathom why such a precise, logical mind would become intimately involved with a series of crude microbial antigens, recording immediate and delayed responses. Clearly, he failed to uncover the grand mechanistic design he has perceived so brilliantly with the eczemas. His very failure may have been the stimulus, for Sulzberger is a stubborn and persistent man. I believe an additional factor added a special piquancy. During the O'Leary Lecture in Ihe early :960's,'' he recalls vividly one of his most memorable moments, hearing the venerated Bruno Bloch extol the thrill and personal pleasure of discovery, after Sulzberger had reported on his own experimental results in isolating fungi from the blood stream.'- " These early experiments and the milieu in which they occurred surely fired his desire to make a lasting impact. He championed the idea of desensitization, but admitted that the results fell short of the mark. In 1943 he and Pascher
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published significant histologic observations on the late granulomatous responses to injections of Koch O.T.'; he was among the first to report on autoantibodies to skin which were produced by mixing skin with staphylococcus toxoid,'" but apparently he did not follow up this fascinating finding because it was not regularly reproducible. Clinical Contact Dermatitis Sulzberger was almost as prolific in this somewhat narrower field; 20 of his early papers were devoted to this subject. Obviously, he was taken with the power of patch and skin tests to sort out specilic causes of disease. With Wise, he established the concept of a patch test clinic" that later captivated the minds of such future leaders as Adolph Kostenberg, Jr., and Rudolph Baer. He seldom published simple case reports but was more interested in underlying mechanisms. By 1933, he had worked out a concept of periodicity in relation to exposure to a sensitizing chemical, such as refactory and incubation periods and the reaction time.'^ He very early reported on ragweed dermatitis and especially on desensitization with antigen injections," a favorite therapeutic approach in those days, but he also noted elsewhere how seldom this proved useful in contact eczema." Later, he again published articles on ragweed sensitivity, apparently because of a confusion among allergist': as to the significance of patch and scratch tests. He wrote sparingly on drug eruptions but was quick lo recognize that oral ingestion may cause flare in sites of previously occurring contact dermatitis; his long held penchant for "local hypersensitivity" or patching cosmetics near the face was recorded early on. He had an uncommon interest in wool fat sensitivity which spanned 20 years
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ALLfiRGY
and 3 papers. These writings failed to pinpoint the problem exactly, yet surely served as a stimulus for others. He wrote several papers on cheililis and contact sensitivity lo dyes. Here too he was frustrated in his attempts to identify (he specific antigen. But from these studies he formulated the concept, now widely accepted, that Linknown contaminants present in small amounts may be the true sensitizer. When he presented this idea to a group of allergists in 1938, it literally "blew their minds" and resulted in 5 printed pages of confused and confounding discussion.'"^ Sulzberger has told me that the scientific reasoning behind his several studies using skin and patch tests with fungal and other chemical extracts was a search for the "true" antigenic determinant, just as Landsteiner was doing in guinea pigs. How elusive that goal has been! Experimental Contact Dermatitis The most exciting reading occurs in papers on this subject, which include 16 reports before 1944. Here, we see the young genius grappling with a momentous basic problem, using the experimental method before most physicians could understand it in clinical terms. And it seems that negative findings and failures as much as anything shaped his thinking and subsequent research. Thus, in one of his earliest papers"' he clearly describes for the first time acquired tolerance. In his experiments, he gave arsphenamine inlracardially Lip to 24 hours after a sensitizing injection of the drug in guinea pigs. This important observation inexplicably did not capture Sulzberger's mind and is not mentioned again until more than 3 decades later, when tolerance had been rediscovered and was belter Linderstood. The observation, however, was the initial thrust into the problem.
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What consumed his energy in this field for the next 6 years was a negative findi n g — neither he nor others such as Landsteiner (who emphatically told him so) coLild sensitize guinea pigs to arsphenamine in New York as SLilzberger could in Breslau. Animals were shipped all over, many experiments were done; in some places it worked and in others it failed. Diet was recognized as important; green fodder reduced sensitization and was thought to partially account for seasonal variation. Sulzberger also showed that scorbutic animals were more easily sensitized, while the feeding of large doses of vitamin C prevented sensitization. But when it was all said and done, he did not have the entire explanation for the variable results. There is a lesson here, however, that he repeats many times over the years, perhaps most succinctly in his presidential address before the Society of Investigative Dermatology of 1949'" on "Ideas, Design, CoinmLinication," to wit: an experiment is not necessarily invalidated because the findings cannot be reproduced elsewhere. Another attitude about dermatologic investigation emerges from these early papers, namely that experiments shoLild relate directly to understanding clinical problems. Very early'^ he attempted to predict dcvolopmcnt ni arsphena'nine hypersonsitivity by a 10% arsphenamine patch in man and failed. By 1936''' he made important observations on the variables responsible for patch test reactivity in a colleagLie pristinely sensitized to poison ivy. By 1938-1939, the flood gates on human experimentation had opened and extensive studies of experimental contact sensitization in man were underVvay with his young colleagues, Rostenberg and Baer. While some basic studies confirming animal data were reported,-" -•' Ihe paper that most clearly
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Stimulated Kligman and myself and subsequently others was a more clinically oriented study^^ in which it was shown that patients with contact eczema were about twice as easily sensitized to DNCB and NDMA as other types of patients. The war disrupted everything and everybody. Many new problems were posed which required immediate solutions— including industrial and military contact dermatitis. No more experimental studies were done except for the important finding that poison ivy blister fluid did not contain active allergen^^ and rapid spontaneous desensitization to contact allergens occasionally occurred.2'* After the war a few papers appeared on experimental sensitization in man to BAL,25 topical sulfa drugs^^ and vesicant sensitization.27 However, by now Sulzberger was about to become chairman at New York University and many problems vied for his attention. His research in allergic contact hypersensitivity almost ceased, but not quite. In 1952 with Baer he published another very important negative report^s on the failure to transfer contact sensitivity with viable leukocytes from sensitive donors. This finding significantly contrasted with the experience of others in infectious delayed hypersensitivity in man and both infectious and contact allergy in guinea pigs. Earlier he had argued, rather unpersuasively, that there is a fundamental difference between man and guinea pigs as relates to allergic contact dermatitis.2" He now argued that same point, but with more enthusiasm. This position stimulated a great debate and also some investigation. Today, most immunologists agree that the differences between man and guinea pigs are not fundamental to our understanding of cell-mediated immunity or of allergic contact dermatitis. In the same year a classic report on the effect of cortisone on patch test re-
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sponses was published,29 seemingly a herald to the "steroid era." Finally in 1962, Sulzberger published again about experimental contact sensitization in guinea pigs to the carcinogen methylcholanthrene. He speculated on the inter-relationship of delayed hypersensitivity and cutaneous carcinogenesis,-^" touching off yet another debate and opening another door. Industrial Dermatitis Sulzberger clearly recognized the role of contactants in industrial dermatitis. He wrote several papers on the subject, usually emphasizing the problems of interpretation of patch test results. His paper in 1940^' was particularly well written and Interesting. He proposed a "sensitizing index," or probability index for chemicals which was the forerunner of predictive tests, and a "sensitizing index" for workers to be implemented through pre-employment patch testing. The latter was not generally accepted. Light Sensitivity Before World War II Sulzberger seemed little concerned with the role of light in allergic skin reactions and it was summarily dismissed as an allergic phenomenon in his book Dermatologic Allergy. However, sometime while he was in the Navy, he and Rudolf Baer saw a patient with solar urticaria in whom they were able to demonstrate the presence of PK antibodies, confirming 2 earlier reports.^2 Later, a fortuitous contact with Blum, the photobiologist who also was in the Navy at the time, led to a second paper showing that the action spectra in this case was less than 3700° A (370 nm). In these 2 papers, his entire scientific output in the field, Sulzberger formulated an idea that still resides at the heart of thinking about the antigen in photoallergic reactions, namely that
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an antigen is produced in everybody's skin by exposure to light but only some people make antibodies to it. Miscellaneous Sulzberger wrote very few papers dealing specifically with granulomatous inflammation, but he was well acquainted with the hypoergic forms of tuberculosis from his experience in Europe and he discussed sarcoidosis in such terms.^'^ This subject received considerable attention in Dermatologic Allergy. In 1949 he suggested that BCG vaccination of patients with sarcoidosis led to indolent sarcoid-like lesions. Reviews and General Papers In many ways, these papers (15 before 1944) best illuminate Sulzberger's breadth and grasp of the field of dermatologic allergy. As mentioned before, in 1936 with Joseph Goodman, his first fellow, he began a yearly review of dermatologic allergy.-^'' The first review was 42 pages long with 143 references and was a tour de force that included everything and anything that might be relevant to dermatologic allergy. Sulzberger knew all the literature! By 1941, presumably because of the war, this intellectual exercise stopped. Earlier in 1935, Sulzberger unveiled his first classification of dermatologic allergy at a meeting in Michigan"; this posterlike presentation was quickly reprinted in JAMA.-^s The classification was predicated on the presumed shock tissue, i.e., epidermis, dermis, vessels, follicles, etc., and the time for a visible reaction to appear. This formed the basis for his book Dermatologic Allergy. However, in 1936 a more definitive classification was published in Medical Record^'^ adapted after an outline of Jonathan Forman of Columbus, Ohio. Even then he bemoaned the
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weakness of the classification, which was partly based on etiology (drug and infection) and partly on mechanism (atopy and contact dermatitis). He clearly rejected the "physical allergies" as bona fide because they were not caused by a "substance." After the war, he wrote numerous general articles in which he included his concepts of allergy. Perhaps the most exciting to read was his expansive Prosser White Oration in 1949.''o Here he emphasized the importance of the "shock tissue" and related in detail his important observations and experiences. He went one step further to speculate on allergy and cancer and organ specificity and selfantigens. It is heady music from the maestro who now very much resembled the king of beasts. A slightly earlier but probably more practical classification of contact dermatitis had been torn from the journal of Allergy,^^ mute evidence of its considered value. It reminded me of an earlier quote by Louis Schwartz: "To discuss a paper on allergy by Dr. Sulzberger is like discussing relativity with Einstein." Sulzberger's genius was respected by all those who loved, hated, feared and/or adored him. His brilliance pierced the field of allergy. He made innumerable important clinical observations, reported some highly significant scientific findings and failed significantly in a few experiments as befits a true investigator. But most importantly, he brought all the pieces together and formulated concepts that could be attacked or supported, and ultimately modified. He provided a tangible starting point for many of us who have explored allergy and immunology as it relates to dermatology and especially as it relates to common, practical problems. He is clearly, if not the father, the midwife of the rapidly developing science of immunodermatology.
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References 1. Sulzberger, M. B., Spain, W. C , Sammis, F., and Shahon, H. I.: Studies in hypersensitiveness in certain dermatoses. 1. Neurodcrmatitis (disseminated type). J. Allergy 3: 423, 1932. 2. Hill, L. W., and Sulzberger, M. B.: Evolution of atopic derrnaiitis. Arcb. Dermatol. Syphilol. 32:451, 1935. 3. Sulzberger, M. B., and Goodman, J.: Allergy in dermatology. J. Allergy 8:385, 1937. 4. Sulzberger, M. B., Hermann. F., and Baer, R. L.: New penetrating vehicles and solvents. Science 96:451, 1942. 5. Sulzberger, M. B., Hermann, F., and Baer, R. L.: Penetration of allergens into the human skin. N. Y. St. J. Med. 44:2452, 1944. 6. Sulzberger, M. B.: A third of a century in dermatology: Some personalities, problems and prospects. Arch. Dermatol. 85:695, 1962. 7. Sulzberger, M. B.: The pathogenesis of trichophytids. The spontaneous passage of formed elements (spores) from the primary lesion into the circulating blood. Arch. Dermatol. Syphilol. 18:891, 1928. 8. Sulzberger, M. B.: Experimentalle untersuchungen uber die dermatotropie der trichophytonpilze. Arch. Dermatol. Syphilol. 157:2, 1929. 9. Sulzberger, M. B., Pascher, F., and Satenstein, D. L.: Histoiogic studies of reactions to intracutaneous tests in allergy of infection in humans. J. Immunol. 46:195, 1943. 10. Hecht, R., Sulzberger, M. B., and Weil, H.: Studies in sensitization to skin. 1. The production of antibodies to skin by means of the synergistic action of homologous skin antigen in staph. toxin. J. Exp. Med. 78:59, 1943. 11. Sulzberger, M. B., and Wise, F.: The contact or patch test in dermatology; its uses, advantages and limitations. Arch. Dermatol. Syphilol. 23:519, 1931. 12. Sulzberger, M. B., and Kerr, P.: Sensitizations of eczematous type: Ten selected cases illustrating some uses of the patch test. J. Allergy 4:326, 1933. 13. Sulzberger, M. B., and Wise, F.: Ragweed dermatitis: with sensitization and desensitization phenomena. JAMA 94:93, 1930. 14. Sulzberger, M. B., and Pascher, F.: Ragweed dermatitis. Report of two cases. Arch. Dermatol. Syphilol. 28:223, 1933. 15. Sulzberger, M. B., and Goodman, J.: Acquired specific hypersensitivity to simple chemicals. I. Eczematous sensitivity to clothing and to cosmetics with special reference to dyes. J. Allergy 9:135, 1938. 16. Sulzberger, M. B.: Hypersensitiveness to
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arsphenamine in guinea pigs. I. Experiments in prevention and in desensitization. Arch. Dermatol. Syphilol. 20:669, 1929. 17. Sulzberger, M. B.: Presidential address: Investigative dermatology. J. Invest. Dermatol. 17:4, 1951. 18. Chargin, L., and Sulzberger, M. B.: Hypersensitiveness of the skin to arsphenamine as determined by tbe contact test. Its relationship to arsphenamine dermatitis. Arch. Dermatol. Syphilol. 22:237, 1930. 19. Field, H., and Sulzberger, M. B.: Experiments in poison ivy sensitivity. J. Allergy 7:139, 1936. 20. Sulzberger, M. B., and Baer, R. L.: Sensitization to simple chemicals. 111. Relationship between chemical structure and properties, and sensitizing capacities in the production of eczematous sensitivity in man. J. Invest. Dermatol. 11:45, 1938. 21. Landsteiner, K., Sulzberger, M. B., and Rostenberg, A.: Individual differences in susceptibility to eczematous sensitization with simple chemical substances. J. Invest. Dermatol. 2:1, 1939. 22. Sulzberger, M. B., and Rostenberg, A.: Acquired specific hypersensitivity (allergy) to simple chemicals. IV A method of experimental sensitization and demonstration of increased suxceptibility in individuals with eczematous dermatitis of contact type. J. Immunol. 36:17, 1939. 23. Sulzberger, M. B., and Katz, H.: The absence of skin irritants in the content of vesicles. U. S. Naval Med. Bull. 41:1258, 1943. 24. Sulzberger, M. B., Kanof, A., and Baer, R. L.: Gomplication following tattooing. U. S. Naval Med. Bull. 43:899, 1944. 25. Sulzberger, M. B., Baer, R. L., and Kanof, A.: Clinical uses of 2.3 dimercaptopropanol (BLA) V. Sensitization to BAL. J. Glin. Invest. 25: 488, 1946. 26. Sulzberger, M. B., Kanof, A., Baer, R. L., and Lowenberg, C : Sensitization by topical application of sulfonamides. ). Allergy 18:92, 1946. 27. Sulzberger, M. B., Baer, R. L., Kanof, A., and Lowenberg, C : Skin sensitization to vesicant agents of chemical warfare. J. Invest. Dermatol. 8:365, 1947. 28. Baer, R. L., and Sulzberger, M. B.: Attempts at passive transfer of allergic eczematous sensitivity in man. J. Invest. Dermatol. 18:53, 1952. 29. Sulzberger, M. B., Witten, V. H., and Zimmerman, E. H.: The effects of oral cortisone acetate on patch test reactions to eczematogenous contact allergens. Acta Derm. Venereol. SuppI. 29:343, 1952.
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30, Sulzberger, M, B,, Sherwin, R, W,, and Hermann, F,: Delayed contact-type sensitization to methylocholanthrene in guinea pigs, |, Invest, Dermatol, 39:178, 1962, 31, Sulzberger, M, B,: Present-day concepts of allergy in occupational dermatoses, Indust, Med, 9:388, 1940, 32, Sulzberger, M, B,, and Baer, R, L,: Studies in hypersensitivity to light, I, Preliminary report, 1, Invest, Dermatol, 6:345, 1945, 33, Blum, H, F,, Sulzberger, M, B,, and Baer, R, L,: Studies in bypersensitivity to light, II, Urticaria solare, J, Invest, Dermatol, 7:99, 1946, 34, Sulzberger, M, B,: Sarcoid of boeck (benign military lupoid) and tuberculin anergy. Am, Rev, Tuberc, 28:6, 1933, 35, Leiden, M,, and Sulzberger, M, B,: Studies of the allergy of infection, 1, Responses of tbe skin to BCC vaccination in various cate-
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gories of tuberculin sensitivity, J, Invest. DermatoL 13:5, 1949, Sulzberger, M, B,: Allergy in dermatology. I, Allergy 7:385, 1936, Sulzberger, M, B,: A suggestion for the classification of certain allergic dermatoses, J. Mich, St, Med, Soc, 34:78, 1935, Sulzberger, M, B,, Wise, F,, and Wolf, |,: A tentative classification of allergic dermatoses. JAMA 104:1489, 1935, Sulzberger, M, B,: Nomenclature, definition and classification of allergic and allergic manifestations, Med, Record 1936, Sulzberger, M, B,: Allergy: A dermatologist's reminiscences and speculations, Br, J, Dermatol, Syphilol, 62:53, 1950, J, Allergy 21:85, 1950, Sulzberger, M, B,: Contact-type eczematous dermatitis; Modern classifications and remarks on therapy, J, Allergy 18:176, 1947,
Allergy
It is today permissible to say — just as was stated by V. Pirquet in 1906 — that these and similarly acquired specific alterations in the capacity of living tissues to react are all fundamentally related biologic phenomena, even though the resultant reactions and manifestations may vary in direction, in degree and in many of their other attributes and forms. Eurthermore, different types of specific alteration often accompany one another; and there are often transitions between the different forms. Thus, one and the same exposure may at the same time lead, for example, to specific alterations in the direction of both an increased and a decreased sensitivity; and it is, indeed, often impossible to say whether or not allergic sensitivity may not itself be conducive to increased resistance, or may not be a step on tbe path to increased resistance. V. Pirquet was impelled to coin the word allergy only because he recognized the need for a single term to include all forms and directions of specifically acquired alterations in capacity to react. For these reasons, the term "allergy," to be useful, must necessarily be non-prejudicial, and must cover all the related, but nevertheless often differing forms of specific acquired immunologic alterations. (Allergy means, literally, "different or altered energy or force.") — Sulzberger, M. B.: Dermatologic Allergy. Springfield, Cbarles C Tbomas, 1940, p. 4.
SULZBERGER ON ALLERGY AND IMMUNOLOGY: THE YOUNG LION RETURNS TO NEW YORK WILLIAM L. EPSTEIN, M.I).
From the Department of Dertnatology, University ol Catilornia School of Medicine, 5an FrancisciK Ccilifnrnia
In the late 192O's, Sulzberger returned to New York from his (raining abroad into a seething intellectual ferment of allergists and immunologists struggling with the rapidly unfolding concept of allergy and hypersensitivity. The young lion was ready—^with an enormous intellect, a mind as sharp as a prosector's knife and a tongue to match, and the special advantage of training with the pioneer geniuses of dermatologic allergy, Joseph ladassohn and Bruno Bloch. These were tuniLiltuous times and his writings and the discussions afterward reflected the excitement and confusion that existed. What follows is a historical review of his publications in scientific journals on the subjects of allergy and immunology. In it, I wish to illuminate and assess Sulzberger's unique role in the marriage of allergy to dermatology and the evolution of their offspring, the subspecialty of immunodermntology. Of his 134 papers published before 1944, 99 were devoted to various aspects of allergy and immunology. They contain the essence of his famous book, Dermatologic Allergy, published in 1940. To simplify the discussion I have divided the paper into 4 major topics, (1) atopic dermatitis, (2) allergy of infection, (3) clinical contact dermatitis and (4) experimental contact dermatitis with some minor
headings, such as industrial derrnatitis, light eruptions and a final section on his penetrating and awesotiie reviews and getneral papers. Atopic Dermatitis Although Coca coined the word atopy, it is widely held that Sulzberger coined the term atopic dertnatitis. Yet he published only 8 early papers on this subject and did very little investigative work except for scratch and PK tests. However, in 1932 he tnasterfully set apart 2 groups of patients frotn the nebulous morass of "eczema," tiatnely those with contact eczema and "disseminated neurodermatitis," a fortn of atopy.' The choice of "neurodertnatitis" ptoved unfortutiate, because it led to further argument and acrimony and obscured Sulzbetger's brilliant clinical observations and laboratory correlations. Three years later, Lewis Webb Hill and he put the stoty straight with a classic description of the "Evolution of Atopic Dermatitis."- About this time, he began yearly reviews of dermatologic allergy in the lournal oi Altergy, but it was not until the second review in 1937' that he formally used the heading atopic dermatitis; so who is to say how the tertn really came about?
Address for reprints: William L. Epstein, M.D., l^eparlment of Dermatology, 1092 HSt-, University of Ciiliforni.i Medical Center, San francisco, C~A 94 143.
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In these papers he made several important and lasting clinical and laboratory observations about alopic skin, such as (1) the existence of fewer patch test reactions despite "highly irritable skins" and (2) papulopus(ular reactioiis to certain salts, including NiSO,, etc. During World War II, he attempted to develop vehicles for enhanced penetration of protein antigens to replace scratch tests,•'• •'' but this apparently fell through. After the war, he turned almost exclusively to therapy of atopic dermatitis as corticosteroids came along. Allergy of Infection This subject, more than any, preoccupied our young lion's pen and research energies. Approximately 20% of his early writings encompass this complex problem. As I read along from the beginning, I could not fathom why such a precise, logical mind would become intimately involved with a series of crude microbial antigens, recording immediate and delayed responses. Clearly, he failed to uncover the grand mechanistic design he has perceived so brilliantly with the eczemas. His very failure may have been the stimulus, for Sulzberger is a stubborn and persistent man. I believe an additional factor added a special piquancy. During the O'Leary Lecture in Ihe early :960's,'' he recalls vividly one of his most memorable moments, hearing the venerated Bruno Bloch extol the thrill and personal pleasure of discovery, after Sulzberger had reported on his own experimental results in isolating fungi from the blood stream.'- " These early experiments and the milieu in which they occurred surely fired his desire to make a lasting impact. He championed the idea of desensitization, but admitted that the results fell short of the mark. In 1943 he and Pascher
June 1977
Vol. 16
published significant histologic observations on the late granulomatous responses to injections of Koch O.T.'; he was among the first to report on autoantibodies to skin which were produced by mixing skin with staphylococcus toxoid,'" but apparently he did not follow up this fascinating finding because it was not regularly reproducible. Clinical Contact Dermatitis Sulzberger was almost as prolific in this somewhat narrower field; 20 of his early papers were devoted to this subject. Obviously, he was taken with the power of patch and skin tests to sort out specilic causes of disease. With Wise, he established the concept of a patch test clinic" that later captivated the minds of such future leaders as Adolph Kostenberg, Jr., and Rudolph Baer. He seldom published simple case reports but was more interested in underlying mechanisms. By 1933, he had worked out a concept of periodicity in relation to exposure to a sensitizing chemical, such as refactory and incubation periods and the reaction time.'^ He very early reported on ragweed dermatitis and especially on desensitization with antigen injections," a favorite therapeutic approach in those days, but he also noted elsewhere how seldom this proved useful in contact eczema." Later, he again published articles on ragweed sensitivity, apparently because of a confusion among allergist': as to the significance of patch and scratch tests. He wrote sparingly on drug eruptions but was quick lo recognize that oral ingestion may cause flare in sites of previously occurring contact dermatitis; his long held penchant for "local hypersensitivity" or patching cosmetics near the face was recorded early on. He had an uncommon interest in wool fat sensitivity which spanned 20 years
No. 5
ALLfiRGY
and 3 papers. These writings failed to pinpoint the problem exactly, yet surely served as a stimulus for others. He wrote several papers on cheililis and contact sensitivity lo dyes. Here too he was frustrated in his attempts to identify (he specific antigen. But from these studies he formulated the concept, now widely accepted, that Linknown contaminants present in small amounts may be the true sensitizer. When he presented this idea to a group of allergists in 1938, it literally "blew their minds" and resulted in 5 printed pages of confused and confounding discussion.'"^ Sulzberger has told me that the scientific reasoning behind his several studies using skin and patch tests with fungal and other chemical extracts was a search for the "true" antigenic determinant, just as Landsteiner was doing in guinea pigs. How elusive that goal has been! Experimental Contact Dermatitis The most exciting reading occurs in papers on this subject, which include 16 reports before 1944. Here, we see the young genius grappling with a momentous basic problem, using the experimental method before most physicians could understand it in clinical terms. And it seems that negative findings and failures as much as anything shaped his thinking and subsequent research. Thus, in one of his earliest papers"' he clearly describes for the first time acquired tolerance. In his experiments, he gave arsphenamine inlracardially Lip to 24 hours after a sensitizing injection of the drug in guinea pigs. This important observation inexplicably did not capture Sulzberger's mind and is not mentioned again until more than 3 decades later, when tolerance had been rediscovered and was belter Linderstood. The observation, however, was the initial thrust into the problem.
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What consumed his energy in this field for the next 6 years was a negative findi n g — neither he nor others such as Landsteiner (who emphatically told him so) coLild sensitize guinea pigs to arsphenamine in New York as SLilzberger could in Breslau. Animals were shipped all over, many experiments were done; in some places it worked and in others it failed. Diet was recognized as important; green fodder reduced sensitization and was thought to partially account for seasonal variation. Sulzberger also showed that scorbutic animals were more easily sensitized, while the feeding of large doses of vitamin C prevented sensitization. But when it was all said and done, he did not have the entire explanation for the variable results. There is a lesson here, however, that he repeats many times over the years, perhaps most succinctly in his presidential address before the Society of Investigative Dermatology of 1949'" on "Ideas, Design, CoinmLinication," to wit: an experiment is not necessarily invalidated because the findings cannot be reproduced elsewhere. Another attitude about dermatologic investigation emerges from these early papers, namely that experiments shoLild relate directly to understanding clinical problems. Very early'^ he attempted to predict dcvolopmcnt ni arsphena'nine hypersonsitivity by a 10% arsphenamine patch in man and failed. By 1936''' he made important observations on the variables responsible for patch test reactivity in a colleagLie pristinely sensitized to poison ivy. By 1938-1939, the flood gates on human experimentation had opened and extensive studies of experimental contact sensitization in man were underVvay with his young colleagues, Rostenberg and Baer. While some basic studies confirming animal data were reported,-" -•' Ihe paper that most clearly
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Stimulated Kligman and myself and subsequently others was a more clinically oriented study^^ in which it was shown that patients with contact eczema were about twice as easily sensitized to DNCB and NDMA as other types of patients. The war disrupted everything and everybody. Many new problems were posed which required immediate solutions— including industrial and military contact dermatitis. No more experimental studies were done except for the important finding that poison ivy blister fluid did not contain active allergen^^ and rapid spontaneous desensitization to contact allergens occasionally occurred.2'* After the war a few papers appeared on experimental sensitization in man to BAL,25 topical sulfa drugs^^ and vesicant sensitization.27 However, by now Sulzberger was about to become chairman at New York University and many problems vied for his attention. His research in allergic contact hypersensitivity almost ceased, but not quite. In 1952 with Baer he published another very important negative report^s on the failure to transfer contact sensitivity with viable leukocytes from sensitive donors. This finding significantly contrasted with the experience of others in infectious delayed hypersensitivity in man and both infectious and contact allergy in guinea pigs. Earlier he had argued, rather unpersuasively, that there is a fundamental difference between man and guinea pigs as relates to allergic contact dermatitis.2" He now argued that same point, but with more enthusiasm. This position stimulated a great debate and also some investigation. Today, most immunologists agree that the differences between man and guinea pigs are not fundamental to our understanding of cell-mediated immunity or of allergic contact dermatitis. In the same year a classic report on the effect of cortisone on patch test re-
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sponses was published,29 seemingly a herald to the "steroid era." Finally in 1962, Sulzberger published again about experimental contact sensitization in guinea pigs to the carcinogen methylcholanthrene. He speculated on the inter-relationship of delayed hypersensitivity and cutaneous carcinogenesis,-^" touching off yet another debate and opening another door. Industrial Dermatitis Sulzberger clearly recognized the role of contactants in industrial dermatitis. He wrote several papers on the subject, usually emphasizing the problems of interpretation of patch test results. His paper in 1940^' was particularly well written and Interesting. He proposed a "sensitizing index," or probability index for chemicals which was the forerunner of predictive tests, and a "sensitizing index" for workers to be implemented through pre-employment patch testing. The latter was not generally accepted. Light Sensitivity Before World War II Sulzberger seemed little concerned with the role of light in allergic skin reactions and it was summarily dismissed as an allergic phenomenon in his book Dermatologic Allergy. However, sometime while he was in the Navy, he and Rudolf Baer saw a patient with solar urticaria in whom they were able to demonstrate the presence of PK antibodies, confirming 2 earlier reports.^2 Later, a fortuitous contact with Blum, the photobiologist who also was in the Navy at the time, led to a second paper showing that the action spectra in this case was less than 3700° A (370 nm). In these 2 papers, his entire scientific output in the field, Sulzberger formulated an idea that still resides at the heart of thinking about the antigen in photoallergic reactions, namely that
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an antigen is produced in everybody's skin by exposure to light but only some people make antibodies to it. Miscellaneous Sulzberger wrote very few papers dealing specifically with granulomatous inflammation, but he was well acquainted with the hypoergic forms of tuberculosis from his experience in Europe and he discussed sarcoidosis in such terms.^'^ This subject received considerable attention in Dermatologic Allergy. In 1949 he suggested that BCG vaccination of patients with sarcoidosis led to indolent sarcoid-like lesions. Reviews and General Papers In many ways, these papers (15 before 1944) best illuminate Sulzberger's breadth and grasp of the field of dermatologic allergy. As mentioned before, in 1936 with Joseph Goodman, his first fellow, he began a yearly review of dermatologic allergy.-^'' The first review was 42 pages long with 143 references and was a tour de force that included everything and anything that might be relevant to dermatologic allergy. Sulzberger knew all the literature! By 1941, presumably because of the war, this intellectual exercise stopped. Earlier in 1935, Sulzberger unveiled his first classification of dermatologic allergy at a meeting in Michigan"; this posterlike presentation was quickly reprinted in JAMA.-^s The classification was predicated on the presumed shock tissue, i.e., epidermis, dermis, vessels, follicles, etc., and the time for a visible reaction to appear. This formed the basis for his book Dermatologic Allergy. However, in 1936 a more definitive classification was published in Medical Record^'^ adapted after an outline of Jonathan Forman of Columbus, Ohio. Even then he bemoaned the
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weakness of the classification, which was partly based on etiology (drug and infection) and partly on mechanism (atopy and contact dermatitis). He clearly rejected the "physical allergies" as bona fide because they were not caused by a "substance." After the war, he wrote numerous general articles in which he included his concepts of allergy. Perhaps the most exciting to read was his expansive Prosser White Oration in 1949.''o Here he emphasized the importance of the "shock tissue" and related in detail his important observations and experiences. He went one step further to speculate on allergy and cancer and organ specificity and selfantigens. It is heady music from the maestro who now very much resembled the king of beasts. A slightly earlier but probably more practical classification of contact dermatitis had been torn from the journal of Allergy,^^ mute evidence of its considered value. It reminded me of an earlier quote by Louis Schwartz: "To discuss a paper on allergy by Dr. Sulzberger is like discussing relativity with Einstein." Sulzberger's genius was respected by all those who loved, hated, feared and/or adored him. His brilliance pierced the field of allergy. He made innumerable important clinical observations, reported some highly significant scientific findings and failed significantly in a few experiments as befits a true investigator. But most importantly, he brought all the pieces together and formulated concepts that could be attacked or supported, and ultimately modified. He provided a tangible starting point for many of us who have explored allergy and immunology as it relates to dermatology and especially as it relates to common, practical problems. He is clearly, if not the father, the midwife of the rapidly developing science of immunodermatology.
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References 1. Sulzberger, M. B., Spain, W. C , Sammis, F., and Shahon, H. I.: Studies in hypersensitiveness in certain dermatoses. 1. Neurodcrmatitis (disseminated type). J. Allergy 3: 423, 1932. 2. Hill, L. W., and Sulzberger, M. B.: Evolution of atopic derrnaiitis. Arcb. Dermatol. Syphilol. 32:451, 1935. 3. Sulzberger, M. B., and Goodman, J.: Allergy in dermatology. J. Allergy 8:385, 1937. 4. Sulzberger, M. B., Hermann. F., and Baer, R. L.: New penetrating vehicles and solvents. Science 96:451, 1942. 5. Sulzberger, M. B., Hermann, F., and Baer, R. L.: Penetration of allergens into the human skin. N. Y. St. J. Med. 44:2452, 1944. 6. Sulzberger, M. B.: A third of a century in dermatology: Some personalities, problems and prospects. Arch. Dermatol. 85:695, 1962. 7. Sulzberger, M. B.: The pathogenesis of trichophytids. The spontaneous passage of formed elements (spores) from the primary lesion into the circulating blood. Arch. Dermatol. Syphilol. 18:891, 1928. 8. Sulzberger, M. B.: Experimentalle untersuchungen uber die dermatotropie der trichophytonpilze. Arch. Dermatol. Syphilol. 157:2, 1929. 9. Sulzberger, M. B., Pascher, F., and Satenstein, D. L.: Histoiogic studies of reactions to intracutaneous tests in allergy of infection in humans. J. Immunol. 46:195, 1943. 10. Hecht, R., Sulzberger, M. B., and Weil, H.: Studies in sensitization to skin. 1. The production of antibodies to skin by means of the synergistic action of homologous skin antigen in staph. toxin. J. Exp. Med. 78:59, 1943. 11. Sulzberger, M. B., and Wise, F.: The contact or patch test in dermatology; its uses, advantages and limitations. Arch. Dermatol. Syphilol. 23:519, 1931. 12. Sulzberger, M. B., and Kerr, P.: Sensitizations of eczematous type: Ten selected cases illustrating some uses of the patch test. J. Allergy 4:326, 1933. 13. Sulzberger, M. B., and Wise, F.: Ragweed dermatitis: with sensitization and desensitization phenomena. JAMA 94:93, 1930. 14. Sulzberger, M. B., and Pascher, F.: Ragweed dermatitis. Report of two cases. Arch. Dermatol. Syphilol. 28:223, 1933. 15. Sulzberger, M. B., and Goodman, J.: Acquired specific hypersensitivity to simple chemicals. I. Eczematous sensitivity to clothing and to cosmetics with special reference to dyes. J. Allergy 9:135, 1938. 16. Sulzberger, M. B.: Hypersensitiveness to
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arsphenamine in guinea pigs. I. Experiments in prevention and in desensitization. Arch. Dermatol. Syphilol. 20:669, 1929. 17. Sulzberger, M. B.: Presidential address: Investigative dermatology. J. Invest. Dermatol. 17:4, 1951. 18. Chargin, L., and Sulzberger, M. B.: Hypersensitiveness of the skin to arsphenamine as determined by tbe contact test. Its relationship to arsphenamine dermatitis. Arch. Dermatol. Syphilol. 22:237, 1930. 19. Field, H., and Sulzberger, M. B.: Experiments in poison ivy sensitivity. J. Allergy 7:139, 1936. 20. Sulzberger, M. B., and Baer, R. L.: Sensitization to simple chemicals. 111. Relationship between chemical structure and properties, and sensitizing capacities in the production of eczematous sensitivity in man. J. Invest. Dermatol. 11:45, 1938. 21. Landsteiner, K., Sulzberger, M. B., and Rostenberg, A.: Individual differences in susceptibility to eczematous sensitization with simple chemical substances. J. Invest. Dermatol. 2:1, 1939. 22. Sulzberger, M. B., and Rostenberg, A.: Acquired specific hypersensitivity (allergy) to simple chemicals. IV A method of experimental sensitization and demonstration of increased suxceptibility in individuals with eczematous dermatitis of contact type. J. Immunol. 36:17, 1939. 23. Sulzberger, M. B., and Katz, H.: The absence of skin irritants in the content of vesicles. U. S. Naval Med. Bull. 41:1258, 1943. 24. Sulzberger, M. B., Kanof, A., and Baer, R. L.: Gomplication following tattooing. U. S. Naval Med. Bull. 43:899, 1944. 25. Sulzberger, M. B., Baer, R. L., and Kanof, A.: Clinical uses of 2.3 dimercaptopropanol (BLA) V. Sensitization to BAL. J. Glin. Invest. 25: 488, 1946. 26. Sulzberger, M. B., Kanof, A., Baer, R. L., and Lowenberg, C : Sensitization by topical application of sulfonamides. ). Allergy 18:92, 1946. 27. Sulzberger, M. B., Baer, R. L., Kanof, A., and Lowenberg, C : Skin sensitization to vesicant agents of chemical warfare. J. Invest. Dermatol. 8:365, 1947. 28. Baer, R. L., and Sulzberger, M. B.: Attempts at passive transfer of allergic eczematous sensitivity in man. J. Invest. Dermatol. 18:53, 1952. 29. Sulzberger, M. B., Witten, V. H., and Zimmerman, E. H.: The effects of oral cortisone acetate on patch test reactions to eczematogenous contact allergens. Acta Derm. Venereol. SuppI. 29:343, 1952.
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30, Sulzberger, M, B,, Sherwin, R, W,, and Hermann, F,: Delayed contact-type sensitization to methylocholanthrene in guinea pigs, |, Invest, Dermatol, 39:178, 1962, 31, Sulzberger, M, B,: Present-day concepts of allergy in occupational dermatoses, Indust, Med, 9:388, 1940, 32, Sulzberger, M, B,, and Baer, R, L,: Studies in hypersensitivity to light, I, Preliminary report, 1, Invest, Dermatol, 6:345, 1945, 33, Blum, H, F,, Sulzberger, M, B,, and Baer, R, L,: Studies in bypersensitivity to light, II, Urticaria solare, J, Invest, Dermatol, 7:99, 1946, 34, Sulzberger, M, B,: Sarcoid of boeck (benign military lupoid) and tuberculin anergy. Am, Rev, Tuberc, 28:6, 1933, 35, Leiden, M,, and Sulzberger, M, B,: Studies of the allergy of infection, 1, Responses of tbe skin to BCC vaccination in various cate-
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gories of tuberculin sensitivity, J, Invest. DermatoL 13:5, 1949, Sulzberger, M, B,: Allergy in dermatology. I, Allergy 7:385, 1936, Sulzberger, M, B,: A suggestion for the classification of certain allergic dermatoses, J. Mich, St, Med, Soc, 34:78, 1935, Sulzberger, M, B,, Wise, F,, and Wolf, |,: A tentative classification of allergic dermatoses. JAMA 104:1489, 1935, Sulzberger, M, B,: Nomenclature, definition and classification of allergic and allergic manifestations, Med, Record 1936, Sulzberger, M, B,: Allergy: A dermatologist's reminiscences and speculations, Br, J, Dermatol, Syphilol, 62:53, 1950, J, Allergy 21:85, 1950, Sulzberger, M, B,: Contact-type eczematous dermatitis; Modern classifications and remarks on therapy, J, Allergy 18:176, 1947,
Allergy
It is today permissible to say — just as was stated by V. Pirquet in 1906 — that these and similarly acquired specific alterations in the capacity of living tissues to react are all fundamentally related biologic phenomena, even though the resultant reactions and manifestations may vary in direction, in degree and in many of their other attributes and forms. Eurthermore, different types of specific alteration often accompany one another; and there are often transitions between the different forms. Thus, one and the same exposure may at the same time lead, for example, to specific alterations in the direction of both an increased and a decreased sensitivity; and it is, indeed, often impossible to say whether or not allergic sensitivity may not itself be conducive to increased resistance, or may not be a step on tbe path to increased resistance. V. Pirquet was impelled to coin the word allergy only because he recognized the need for a single term to include all forms and directions of specifically acquired alterations in capacity to react. For these reasons, the term "allergy," to be useful, must necessarily be non-prejudicial, and must cover all the related, but nevertheless often differing forms of specific acquired immunologic alterations. (Allergy means, literally, "different or altered energy or force.") — Sulzberger, M. B.: Dermatologic Allergy. Springfield, Cbarles C Tbomas, 1940, p. 4.
