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Autoimmunity and Cutaneous Disease
Autoimmunity and Cutaneous Disease RICHARD A. WALZER, M.D.*
It had long been assumed that a living organism was incapable of immunologically attacking its own tissue ("horror autoxicus"). However, in the past decade it has become apparent to both immunologists and clinicians that this concept does not hold true in all clinical or experimental situations. DiseaRe states involving such diverse tissues as thyroid epithelium, erythrocyte stroma and lens protein have been demonstrated to arise from the deleterious effects of antibodies produced by the individual and directed against its own tissue. This pathological circumstance has been referred to as "autoimmunity" and the disease states that arise as a result of this immunological flaw have been described as "auto immune diseases." Several mechanisms have been postulated to explain the development of autoimmunity.26. 31 Alterations or inherent characteristics of either the antigenic tissue or the antibody-producing cell may result in autoantibody formation. Tissues such as lens, central nervous system and thyroid, by virtue of their relative isolation from lymphatic and vascular channels, can in a sense be considered "foreign" to the host. If under abnormal circumstances these tissues gain access to lymphatic channels and consequently to the immunological system, autoantibodies directed against these tissues may be produced. In this situation unaltered tissue is antigenic. Autoantibody formation may also be induced if tissue alteration occurs. Normal tissue modified by factors such as infection, drugs or physical agents may become antigenic and induce the production of autoantibodies directed against normal, unaltered tissue as well as the antigen itself. This mechanism of autoantibody formation may play a role in some of the drug-induced blood dyscrasias. In this situation the drug may alter the formed blood element to the extent that it becomes antigenic and evokes the production of destructive autoantibodies.
* Instructor in Dermatology, College of Physicians and Surgeons, Columbia University;
Assistant Attending Dermatologist, Presbyterian Hospital, Columbia-Presbyterian Medical Center, New York, N.Y. This investigation was supported in whole by Public Health Service Research Grant AM 07241-02 from the National Institute of Allergy and Infectious Diseases.
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On the other hand, autoantibody formation may occur when a disordered immunological system produces antibodies entirely unrelated to antigenic stimulation and directed against normal tissue. This is apparently the case in certain malignant diseases involving lymphoid tissue. In some lymphomas, for example, autoantibodies against erythrocytes may be responsible for the development of hemolytic anemia. Similarly, systemic lupus erythematosus may represent a disease in which a spontaneously occurring or inherent defect in antibody synthesis results in autoantibody production against a variety of normal tissue antigens. One might speculate on the role of these various mechanisms in the production of autoantibodies directed against the multiple antigens that constitute the skin. Keratin and distal epidermal cells undergoing keratinization might be considered "foreign" to the immunological system by virtue of their remote location and relative avascularity. It would seem even more likely that epidermal cells altered by chemicals, radiation, burns or simple physical trauma would be antigenic if permitted to gain access to antibody-producing tissues. On the other hand, tissue antigens of the corium would be poor autoantigens since this area of the skin is relatively rich in vascular and lymphatic channels and less subject to alteration by external factors. It is possible that cutaneous antigens might be the target of spontaneously developing autoantibodies in diseases of abnormal antibody production. Exfoliative dermatitis seen in association with malignant lymphoma may arise in a manner analogous to the autoimmune hemolytic anemia associated with that disease. Finally the skin might serve as the "battleground" of an entirely unrelated autoantibody-antigen system and suffer the pathological alterations attendant upon such an event.
DETECTION OF AUTOIMMUNE DISEASE
The characteristics of auto immunity that serve as a guide to the detection of autoimmune disorders have been clearly defined.7, 36 These criteria as outlined by Davies and Gery are summarized in Table 1 and include the following: (1) the occurrence of a precipitating event followed by a period of sensitization prior to the onset of symptoms; (2) the suppression of symptoms by the administration of systemic corticosteroids; (3) the development of a pathological lesion characterized by lymphoid granulomatous infiltration; (4) the detection of antibodies directed against
Table 1. Characteristics of Autoimmune Disease7 1. Precipitating event and period of sensitization
2. 3. 4. 5. 6.
Suppression of symptoms by corticosteroids Allergic histopathology Presence of organ-specific antibodies Experimental counterpart in laboratory animal Passive transfer of experimental disease with lymphoid cells
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organ-specific antigens by tests for circulating antibodies, delayed type of skin reactivity or by the demonstration of gamma globulin (antibody) at the site of the lesion; (5) the production of a similar disease in an experimental animal by immunization with appropriate tissue antigens; and (6) the passive transfer of experimentally induced auto immune disease with lymphoid cells. Only a few of these criteria have been met in most of the systemic diseases considered to have an auto immunological pathogenesis. Of foremost importance in the detection of a possible auto immune disease is the consistent demonstration of autoantibodies. Although there are many tests available to demonstrate antibody-antigen reaction, only a few are used extensively in auto immune research and therefore are briefly described here. 10 GEL-DIFFUSION TEST. The basis of this method is a precipitin reaction in which the antibody and antigen diffuse toward one another in a thin layer of agar gel. A visible line forms in the gel where antibody and antigen meet in the proper concentration for a reaction to occur. This method permits the simultaneous testing of multiple antigens by filling a central well (cut into the agar) with a specific antiserum and surrounding this central well with six or more antigen-containing wells. When antigen from two adjacent wells diffuses toward antibody in the central well, the precipitate lines they form will fuse with one another perfectly if the antigens in the adjacent wells are identical ("reaction of identity"). Precipitin lines that do not fuse, but cross, indicate the absence of identical antigens in the adjacent wells ("reaction of nonidentity"). The gel-diffusion method is a rapid and simple means of studying multiple antigen-antibody systems and of demonstrating the cross reactivity of related but not identical antigens. IMMUNOELECTROPHORESIS. Immunoelectrophoresis is another method which uses the principle of the precipitin reaction to study multiple antibody-antigen systems. The first stage of immunoelectrophoresis is the electrophoretic separation of an antigenic mixture in agar gel. Antisera from troughs cut parallel to the line of electrophoretic separation diffuse toward the separated antigens. Precipitate in the form of arcs are produced where diffusing antibody reacts with its corresponding antigen. FLUORESCENT ANTIBODY TECHNIQUE. This method employs antibody chemically bound to a fluorescent dye (fluorescein or rhodamine) to demonstrate an antigen-antibody reaction under a microscope with an ultraviolet light source. In the "direct method" a specific labeled antiserum is used to demonstrate a specific antigen. For example, fluorescein-Iabeled antipneumococcal serum could be used to demonstrate pneumococci in sputum or in a tissue. In the "indirect method" labeled anti-gamma globulin serum can be used to identify the antibody (gamma globulin) of an antigenantibody reaction with a two-step procedure. In the first step antigen
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reacts with antibody. In the second step, labeled anti-gamma globulin identifies the antibody-antigen reaction by reacting with the antibody portion of this complex. The "indirect method" is used extensively in the study of auto immune disease since the demonstration of antibody globulin at the site of tissue pathology strongly suggests an autoimmune reaction. HEMAGGLUTINATION. This is a sensitive method of demonstrating small quantities of circulating antibody. One modification of this test employs human group 0 or sheep red blood cells that have been exposed to a dilute tannic acid preparation. These "tanned" cells are capable of adsorbing soluble protein antigen onto their surfaces. In the presence of homologous antibody, agglutination of cells will occur. PASSIVE CUTANEOUS ANAPHYLAXIS. The ability of circulating antibody to passively sensitize an experimental animal can be demonstrated by injecting small quantities of antiserum intradermally into an area of shaved skin on the back of a guinea pig. After four to 24 hours have elapsed, the homologous antigen and a marker dye such as Evans Blue are injected intravenously. If an antigen-antibody reaction occurs, dye will escape from damaged blood vessels at the site of the reaction and discolor the skin. This is best observed by sacrificing the animal, removing the skin and studying its undersurface. INTRADERMAL SKIN TESTING. The delayed type of hypersensitivity (no circulating antibody) can be demonstrated by intradermal testing with antigen and appropriate controls. The reaction becomes evident in 24 hours and reaches a maximum in 48 to 72 hours. A positive reaction is usually characterized by a nodule with surrounding erythema. Histopathological examination of the positive test site reveals a lymphoid granuloma. CLINICAL ASPECTS OF AUTOIMMUNITY
In any discussion of autoimmunity it should be emphasized that the demonstration of an auto antibody does not necessarily imply that the associated clinical state is auto immune or allergic in its pathogenesis. An autoantibody should be shown to be destructive of its homologous antigen in order to be considered causative of disease. Autoantibodies may arise as a consequence of disease as they presumably do in myocardial infarction, in which antibodies directed against cardiac tissue have been demonstrated. 7 They may arise also as an incidental consequence of a pathogenic agent as in the case of viral pneumonia. In the latter disease the production of cold autohemagglutinins has little to do with the clinical symptoms of the illness. In the field of cutaneous disease there are few if any diseases of undisputed autoimmune pathogenesis. The skin diseases to be discussed in the following sections can be considered to be possible examples of auto immune diseases on the basis of tentative experimental studies or clinical characteristics that will be described.
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Autosensitization Dermatitis
The origin of the concept of auto immunity can be credited in part to a dermatologist. In 1921 Whit field suggested that generalized dermatitis might arise on the basis of autosensitization to autologous skin following a localized injury to the skin or the development of a limited area of dermatitis such as stasis eczema. 34 Unfortunately, this clinical concept has been given little in the way of experimental support. Although a precipitating event is implicit in the concept of autosensitization dermatitis and the disease can be suppressed with corticosteroid therapy, none of the other criteria detailed in Table 1 have been consistently demonstrated. Early studies of autosensitization dermatitis suggested that the antigen involved in this widespread reaction was probably bacteria that had infected the original site of dermatitis. ID More recently Parish et a1. noted the presence of a circulating antiskin antibody in two of 74 patients with autosensitization dermatitis. 23 These two patients had a serum factor that would agglutinate particles coated with a skin extract and a "cytotoxic factor" active against epidermal cells. Although the presence of a cytotoxic antibody favors a causal relationship between the autoantibody and autosensitization dermatitis, the limited number of positive patients in this study suggests that the factors demonstrated by Parish may be the incidental by-products of widespread dermatitis. One might speculate on the role of other mechanisms in the development of autosensitization dermatitis. For example, the rapid vascular dissemination of proteolytic enzymes from the original site of cutaneous injury might account for the sudden development of generalized skin lesions. Clearly an immunological mechanism need not be postulated to explain the pathogenesis of this disease. Bullous Diseases
Among the many skin diseases of undetermined etiology, the group of generalized bullous diseases would seem most likely to contain examples of true auto immune cutaneous disease. For the most part the bullous diseases are chronic illnesses, responsive to corticosteroid therapy and in some instances evidently allergic in origin (e.g., drug-induced bullous erythema multiforme). Pemphigus vulgaris, in particular, because of the very specific nature of the pathological lesion, has been investigated for autoantibodies directed against epidermal cells. In preliminary studies, Walzer and Einbinder 32 and Raskin27 were unable to demonstrate circulating antiepidermal cell antibodies in the serum of patients with pemphigus vulgaris using the fluorescent antibody technique. Jordan et al.,16 however, had positive findings in two of four patients using the same technique. It is evident that further investigation with emphasis on other methods is required before any conclusion can be reached.
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Gyrate Erythemas
This condition is characterized by the development of erythematous ringed lesions with elevated borders. These annular lesions enlarge and spread over large areas of the body and in some instances disappear and reappear in a manner similar to simple urticaria. Many appellations have been given to this condition. Most of these names describe the gross morphology and course of the lesion (erythema annulare centrifugum, erythema chronicum migrans, etc.).2
Figure 1. A, Breast hypertrophy, cutaneous pigmentation and lesions of erythema annulare centrifigum in a patient with circulating autoantibodies directed against autologous breast tissue. B, Close-up of migrating urticarial bands on the forearm. (Courtesy of Shelley, W. and Hurley, H. J.: A.M.A. Arch. Dermat. 81: 889, 1960.)
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Shelley and Hurley have described a remarkable patient with a generalized eruption composed of "constantly migrating urticarial bands," massive breast hypertrophy and generalized pigmentation30 (Fig. 1). Using a tanned cell hemagglutination test, Shelley and Hurley were able to demonstrate an autoantibody present in the patient's serum and directed against her own cystic breast tissue. The authors were of the opinion that the bizarre cutaneous eruption represented autoantibody reacting with breast antigen fixed in the skin. Although not representative of autoimmunity directed against cutaneous antigens, this case suggests that the skin may be the site of reaction of other auto immune systems.
Purpuric Eruptions It has been pointed out earlier that autoantibodies are rarely formed against constituents of tissue in close contact with the lymphatic apparatus. Consequently, autoimmune reactions involving the vascular system or elements of the blood would be unlikely to occur unless significant alterations of these tissues made them autoantigenic, or abnormal antibodies, the product of a defective immunological system, reacted with normal tissue. The latter situation may pertain in thrombocytopenic purpura seen in association with systemic lupus erythematosus, in which autoantibodies against platelets have been demonstrated. 20 Another category of purpura thought to be on an autoimmune basis has been documented by detailed clinical investigation in two patients. IS. 29 These patients developed spontaneous, painful hemorrhagic nodules on the extremities as a manifestation of hypersensitivity to deoxyribonucleic acid (DNA). In both cases skin testing with very small quantities of DNA reproduced the clinical lesion, although a circulating anti-DNA factor could not be demonstrated despite diligent efforts to do so. Schwartz et al. suggest that this reaction is similar to that seen in cutaneous anaphylaxis in which skin-fixed antibody reacts with small amounts of antigen and an immediate change in venous permeability ensues. 29 They postulate that the antibody in patients with DNA hypersensitivity has an unusual affinity for the skin but is unable to localize in other tissues. Other cutaneous diseases that require investigation for similar autoimmune phenomena are the chronic pigmented purpuric eruptions, HenochSchoenlein purpura and the many categories of dermal vasculitis of undetermined cause. Exfoliative Dermatitis It is possible that in some instances generalized exfoliative dermatitis is the clinical counterpart of what is described in the laboratory animal as "runt disease" (Fig. 2). This condition, characterized by wasting, diarrhea, hepatosplenomegaly as well as dermatitis and alopecia, is induced when the recipient of a graft of lymphoid tissue (immunologically competent
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Figure 2. A, A mouse with "runt disease." The cutaneous changes that characterize this condition are rufHed fur, alopecia and dermatitis. (Courtesy of Oliner, H. et al.: Blood 17: 20, 1961.) B, Same mouse viewed from above showing alopecia and dermatitis.
cells) is incapable of rejecting this graft. 8 , 22 Because of their immunological immaturity, animals grafted in utero or in the neonatal period cannot reject a lymphoid tissue graft. In this situation, however, the grafted lymphoid tissue is capable of reacting against ("rejecting") the host tissues which are antigenically foreign to the animal donating the lymphoid cells. Presumably the symptoms that develop are the result of the graft cells producing antibodies directed against the host's tissues. Dermatitis and alopecia are thought to develop because of cytotoxic properties of antibodies directed against cutaneous components. It seems possible that the generalized exfoliative dermatitis that develops in association with lymphomatous disease in human beings arises
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because of similar antiskin antibodies produced by primitive, disordered lymphoid cells in a manner analogous to runt disease. This hypothesis awaits clinical and experimental confirmation. Thermal Burns
It has been suggested that alteration of skin antigens by thermal injury might induce the formation of autoantibodies. However, experimental efforts to demonstrate specific autoantibodies following a burn have produced contradictory data. The finding of circulating precipitins against skin in postburn serum has been shown in some instances to be due to bacterial antigen-antibody reactions rather than cutaneous antigen-antibody systemsY Nevertheless the value of convalescent serum in the treatment of burns, although still controversial, is suggestive of the presence of antibodies or antitoxins against denatured skin components. Pyoderma Gangrenosum
This very destructive, ulcerative lesion of the skin occurs in association with various debilitating systemic diseases, particularly ulcerative colitis. Since patients with ulcerative colitis have been found to have circulating autoantibodies directed against colonic mucosa,4 one might speculate on the possibility of cross reactivity of these antibodies with common antigenic factors in the skin. Recently two patients with pyoderma gangrenosum (only one of whom had ulcerative colitis) were shown to reject transplants of their own normal-appearing skin and to manifest a delayed type of hypersensitivity reaction to autologous leukocytes. 19 Although these findings are suggestive of an immunological lesion, the nature of the antigen(s) involved is still open to question. Psoriasis
Psoriasis is associated with a rheumatoid arthritis syndrome in a significant number of patients. This association, as well as other characteristics of this disease (chronicity, response to corticosteroids and familial pattern) suggests a similarity to auto immune diseases of the collagen group. Two immunological techniques have been employed to detect the presence of circulating antibodies in the serum of patients with psoriasis. Passive cutaneous anaphylaxis (see section on methodology) studies have been performed by injecting serum from psoriatic patients intradermally and challenging several hours later with an intravenous injection of psoriatic tissue homogenate.1 2 , 21 These studies failed to demonstrate circulating antibody directed against psoriatic tissue antigens. Similarly, investigations using the fluorescent antibody technique were unable to detect a specific antigen-antibody reaction in the affected skin of psoriatic patientsY However, circulating antinuclear factors were demonstrated in
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two patients with psoriasis with arthritis and in one patient with psoriasis without arthritis. This latter finding, if confirmed, suggests that psoriasis may have immunological features in common with the collagen diseases.
Discoid Lupus Erythematosus Immunological evidence would tend to confirm the current clinical impression that discoid lupus erythematosus is a benign, cutaneous variant and infrequent precursor of systemic lupus erythematosus. Antinuclear antibodies have been demonstrated in discoid lupus erythematosus in more than 50 per cent of patients by the fluorescent antibody technique. 25 • 27 These antibodies were noted to be reactive against epidermal cell nuclei as well as the nuclear material of heterologous leukocytes. Since the lesions of discoid lupus erythematosus are limited to the skin, it is doubtful that antinuclear antibodies are of primary causal importance in this disease. Even in systemic lupus erythematosus in which auto antibodies directed against nuclear material, cellular cytoplasmic components, red blood cells, platelets, leukocytesand coagulation factors have been demonstrated, it is still questionable whether these antibodies are primary incitants of this complex disease. 2o
Atopic Eczema Atopic eczema has long been associated with diseases of allergic etiology and has, itself, been considered to be allergic in origin,. Although skin testing with food and inhalant allergens reveals hypersensitivity of the immediate type in individuals afflicted with eczema, efforts at desensitization or elimination of allergens are frequently ineffective in the management of this disease. Investigation of atopic eczema as a disease of auto immunization to cutaneous antigens was undertaken by Hashem et al. 13 The method employed in their study was based on the observations of Pearmain that lymphocytes from tuberculin-positive individuals when grown in tissue culture in the presence of tuberculin undergo mitosis and blastlike cells and plasma cells appear in the culture. 24 This event is interpreted as evidence that the sensitized lymphocyte responds to its homologous antigen by division and reversion to a more primitive form. Hashem found that lymphocytes obtained from infants with severe atopic eczema were induced to undergo mitosis when grown in a culture containing a cell-free skin extract. These investigators concluded that the lymphocyte of the eczematous infant was sensitized to a component of skin. Since the cutaneous extract in this study was derived from biopsy specimens, however, it would be difficult to say that a contaminating factor such as bacteria and/or fungi was not the sensitizing antigen rather than a component of the skin itself. Confirmation and elaboration of this work is required before any conclusions can be drawn.
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Systemic Diseases with Cutaneous Manifestations A review of the auto immune aspects of systemic diseases, many of which have cutaneous manifestations, is beyond the scope of this discussion. Some of the diseases that might be considered in this category are rheumatoid arthritis, rheumatic fever, systemic lupus erythematosus, scleroderma, Sjogren's syndrome and periarteritis nodosa. Dermatomyositis is worthy of special mention since the cutaneous aspects of this disease are paramount and the immunological findings of considerable interest. Dermatomyositis is associated with internal malignancy in approximately 50 per cent of adults with this disease. 3 This fact has prompted the study of patients with dermatomyositis and visceral carcinoma for an immunological relationship between the tumor and the skin and muscle disease.5, 11 In two patients studied, skin testing with an extract of autologous tumor tissue produced an immediate-type of skin reaction while other tissues failed to elicit this reaction. In both instances the presence of circulating antitumor antibody was confirmed by passive transfer studies. This finding, supported by the clinical observation that dermatomyositis tends to go into remission when the associated tumor is removed,6 suggests that this disease is auto immune in its origin. One might speculate further that the cutaneous and muscle lesions are the result of tumor antigen and antibody combination at these sites. Fluorescent antibody studies might yield information concerning this possibility. EXPERIMENTAL STUDIES IN AUTOIMMUNIZATION Valuable information concerning the pattern of development of human autoimmune cutaneous disease might be obtained by creating a model in an experimental animal. Unfortunately, efforts to immunize laboratory animals with autologous or homologous skin have met with only partial success. In early experiments by Hecht et al.,14 rabbit skin, adjuvant and staphylococcal toxin were used to immunize rabbits. Although circulating precipitins developed in the animals studied, these were directed against 24-hour old autolysates of the original antigen. Since no attempt was made to render the immunizing antigen bacteriologically sterile, it is likely that the precipitins demonstrated were against bacterial antigens. Subsequently Allgower was unable to demonstrate circulating precipitins or cytotoxins deleterious to epidermal cells in tissue culture after immunization with homologous skin.! Similarly, Rosenthal reported negative results in the immunization of animals with skin-adjuvant emulsions as evidenced by the failure of these animals to reject autografts following the attempted immunization. 28 More recently Wilhelmj et al. reported on the successful immunization of experimental animals with homologous and autologous skin. 35 Antibodies directed against the test antigen were demonstrated by complement fixation and hemagglutination tests as well as by intradermal testing with skin antigen. There was some degree of cross re'1ctivity when the immune sera were tested against other organs (lung, heart, kidney and brain) and some of the control animals injected with Freund adjuvant but no antigen developed low titers of antiskin antibody. Of
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particular interest in this study was the development of cutaneous lesions in the immunized animals. These lesions were characterized by an erythematous, scaling dermatitis with alopecia. On the other hand, Dikeacoy-Moschos et al. using comparable techniques were unsuccessful in reproducing Wilhelmj's findings. 9 These workers were unable to induce the formation of a circulating (complement fixing) antibody against skin antigen injected into guinea pigs. In addition, they noted only minimal hair loss without dermatitis not only in the animals in this study, but in control, nonimmunized animals as well. Similarly, Walzer et al. were unable to detect circulating antibody, delayed hypersensitivity or cutaneous lesions in rabbits immunized with sterile fetal rabbit skin and Freund adjuvant. 33 Investigations in progress by these investigators suggest that immunization with skin from a different species cannot induce the formation of autoimmune skin lesions although it does result in the production of nonorgan-specific antibodies.
SUMMARY The relationship of auto immunity to cutaneous disease is an area of dermatology worthy of more extensive clinical and laboratory investigation. An examination of some cutaneous diseases in which auto immunity may tentatively play a role suggests that the skin may serve as a "shock organ" for the reaction of autoantibodies and antigens of noncutaneous origin (annular erythema, purpura due to DNA hypersensitivity and dermatomyositis). There is only limited evidence, however, that would implicate the role of autoantibodies directed against cutaneous components in the pathogenesis of skin disease (pemphigus vulgaris, atopic eczema, autosensitization dermatitis). In the area of laboratory investigations, attempts to induce autoimmune cutaneous disease in experimental animals have met with only partial success. However, if achieved, experimental auto immune disease of the skin may point the way to presently unrecognized counterparts in the human being. REFERENCES 1. Allg6wer, M., Blocker, T. G., Jr. and Engley, B-W. D.: Some immunological aspects
2. 3. 4. 5.
of auto and homografts in rabbits, tested by in vivo and in vitro techniques. Plast. & Reconstr. Surg. 9: 1, 1952. Andrews, G. C. and Domonkos, A. N.: Disease of the Skin. 5th Ed. Philadelphia & London, W. B. Saunders Co., 1963. Arundell, F. D., Wilkinson, R. D. and Haserick, J. R.: Dermatomyositis and malignant neoplasms in adults. A.M.A. Arch. Dermat. 82: 772, 1960. Broberger, O. and Perlman, P.: Autoantibodies in human ulcerative colitis. J. Exper. Med. 110: 657, 1959. Curtis, A. C., Heckman, J. H. and Wheeler, A. H.: Study of the autuimmune reaction in dermatomyositis. J.A.M.A. 178: 571, 1961.
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6. Curtis, A. C., Blaylock, H. C. and Harrell, E. R.: Malignant lesions associated with dermatomyositis. J.A.M.A. 150: 844,1952. 7. Davies, A. M. and Gery, I.: Role of autoantibodies in heart disease. Am. Heart J. 60: 669, 1960. 8. Defendi, V., Steinmuller, D., Billingham, R. E. and Silver, W. K.: Pathogenesis and pathology of "runt" disease in rats. Fed. Proc. 19: A-208, 1960. 9. Dikeacoy-Moschos, T. A., Rosenthal, S. A. and Schroeder, H.: Attempts at sensitization to skin in guinea pigs. Arch. Dermat. In press. 10. Gell, P. G. H. and Coombs, R. R. A.: Clinical Aspects of Immunology. Philadelphia, F. A. Davis Co., 1963. 11. Grace, J. T. and Dao, T. L.: Dermatomyositis in cancer: a possible etiological mechanism. Cancer 12: 648, 1959. 12. Harber, L. C., March, C. and Ovary, Z.: Lack of passive cutaneous anaphylaxis in psoriasis. Arch. Dermat. 85: 716, 1962. 13. Hashem, N., Hirschorn, K., Sedlis, E. and Holt, L. E.: Infantile eczema-evidence of autoimmunity to human skin. Lancet 2: 269, 1963. 14. Hecht, R., Sulzberger, M. B. and Weil, H.: Studies in sensitization to Rkin. J. Exper. Med. 78: 59, 1943. 15. Hopkins, H. and Burkey, E. L.: Cutaneous autosensitization. Role of staphylococci in chronic eczema of the hands. Arch. Dermat. & Syph. 49: 124, 1944 16. Jordan, R. E., Beutner, E. H. and Aquilina, J. T.: Immunofluorescent studies of pemphigus vulgaris. Fed. Proc. 23: 342, 1964. 17. Kohn, J.: Biochemical and immunological aspects of human burns. In International Symposium on Injury, Inflammation and Immunity (L. Thomas, J. W. Uhr and L. Grant, Eds.). Baltimore, Williams & Wilkins Co., 1964. 18. Levin, M. Band Pinkus, H.: Autosensitivity to desoxyribonucleic acid (DNA): Report of case with inflammatory skin lesions controlled by chloraquine. New England J. Med. 264: 533, 1961. 19. Long, P. I. and Uesu, C. T.: Pyoderma gangraenosum. J.A.M.A. 187: 336,1964. 20. Meischer, P. A., Barker, L., Vainio, 1. and Wiedermann, G.: Immune mechanisms of cell and tissue damage in systemic lupus erythematosus. In International Symposium on Injury, Inflammation and Immunity (L. Thomas, J. W. Uhr and L. Grant, Eds.). Baltimore, Williams & Wilkins Co., 1964. 21. Moreci, A., Farber, E. and Raffel, S.: Further studies of immunologic reactions in psoriasis. A.M.A. Arch. Dermat. 85: 617,1962. 22. Oiiner, H., Schwartz, R. and Dameshek, W.: Studies in autoimmune disorders. I. Clinical and laboratory features of auto-immunization. Blood 17: 20,1961. 23. Parish, W. E. and Rook, A.: Skin autosensitization. In Clinical Aspects of Immunology (P. G. H. Gell and R. R. A. Coombs, Eds.). Philadelphia, F. A. Davis Co., 1963. 24. Pearmain, G., Lycette, R. R. and Fitzgerald, P. H.: Tuberculin induced mitosis in peripheral blood leukocytes. Lancet 1: 637, 1963. 25. Peterson, W. C. and Fusaro, R.: Antinuclear factors in chronic discoid lupus erythematosus. Arch. Dermat. 86: 783, 1962. 26. Raffel, S.: Immunity. 2nd Ed., New York, Appelton-Century-Crofts, 1961. 27. Raskin, J.: Fluorescent antibody studies of certain dermatoses. Arch. Dermat. 89: 569,1964. 28. Rosenthal, S. A., Baer, R. L. and Hagel, B.: Failure to sensitize to autologous skin. Proc. Soc. Exper. BioI. & Med. 97: 279, 1958. 29. Schwartz, R. S., Lewis, F. B. and Dameshek, W.: Hemorrhagic cutaneous anaphylaxis due to autosensitization to desoxyribonucleic acid. New England J. Med. 267: 1105,1962. 30. Shelley, W. and Hurley, H. J.: An unusual autoimmune syndrome: Erythema annulare centrifigum, generalized pigmentation and breast hypertrophy. A.M.A. Arch. Dermat. 81: 889, 1960. 31. Waksman, B. H.: Auto-immunization and the lesions of autoimmunity. Medicine 41: 93,1962. 32. Wnlzer, R. A. and Einbinder, J.: Unpublished data. 33. Wnlzer, R. A., Einbinder, J. and Nelson, C. T.: Response to immunization with homologous skin. Arch. Dermat., Dec., 1964.
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34. Whitfield, A.: Some points in the etiology of skin disease. Lecture H. Lancet 2: 122, 1921. 35. Wilhelmj, C. M., Kierland, R. R. and Owen, C.: Production of hypersensitivity to skin in animals. Arch. Dermat. 86.' Hll, 1962. 36. Witebsky, K, Rose, N. R, Terplan, K., Paine, J. R. and Egan, R. W.: Chronic thyroiditis and autoimmunization. J.A.M.A. 164: 1439, 1957. 180 Fort Washington Avenue New York, N.Y. 10032
It had long been assumed that a living organism was incapable of immunologically attacking its own tissue ("horror autoxicus"). However, in the past decade it has become apparent to both immunologists and clinicians that this concept does not hold true in all clinical or experimental situations. DiseaRe states involving such diverse tissues as thyroid epithelium, erythrocyte stroma and lens protein have been demonstrated to arise from the deleterious effects of antibodies produced by the individual and directed against its own tissue. This pathological circumstance has been referred to as "autoimmunity" and the disease states that arise as a result of this immunological flaw have been described as "auto immune diseases." Several mechanisms have been postulated to explain the development of autoimmunity.26. 31 Alterations or inherent characteristics of either the antigenic tissue or the antibody-producing cell may result in autoantibody formation. Tissues such as lens, central nervous system and thyroid, by virtue of their relative isolation from lymphatic and vascular channels, can in a sense be considered "foreign" to the host. If under abnormal circumstances these tissues gain access to lymphatic channels and consequently to the immunological system, autoantibodies directed against these tissues may be produced. In this situation unaltered tissue is antigenic. Autoantibody formation may also be induced if tissue alteration occurs. Normal tissue modified by factors such as infection, drugs or physical agents may become antigenic and induce the production of autoantibodies directed against normal, unaltered tissue as well as the antigen itself. This mechanism of autoantibody formation may play a role in some of the drug-induced blood dyscrasias. In this situation the drug may alter the formed blood element to the extent that it becomes antigenic and evokes the production of destructive autoantibodies.
* Instructor in Dermatology, College of Physicians and Surgeons, Columbia University;
Assistant Attending Dermatologist, Presbyterian Hospital, Columbia-Presbyterian Medical Center, New York, N.Y. This investigation was supported in whole by Public Health Service Research Grant AM 07241-02 from the National Institute of Allergy and Infectious Diseases.
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On the other hand, autoantibody formation may occur when a disordered immunological system produces antibodies entirely unrelated to antigenic stimulation and directed against normal tissue. This is apparently the case in certain malignant diseases involving lymphoid tissue. In some lymphomas, for example, autoantibodies against erythrocytes may be responsible for the development of hemolytic anemia. Similarly, systemic lupus erythematosus may represent a disease in which a spontaneously occurring or inherent defect in antibody synthesis results in autoantibody production against a variety of normal tissue antigens. One might speculate on the role of these various mechanisms in the production of autoantibodies directed against the multiple antigens that constitute the skin. Keratin and distal epidermal cells undergoing keratinization might be considered "foreign" to the immunological system by virtue of their remote location and relative avascularity. It would seem even more likely that epidermal cells altered by chemicals, radiation, burns or simple physical trauma would be antigenic if permitted to gain access to antibody-producing tissues. On the other hand, tissue antigens of the corium would be poor autoantigens since this area of the skin is relatively rich in vascular and lymphatic channels and less subject to alteration by external factors. It is possible that cutaneous antigens might be the target of spontaneously developing autoantibodies in diseases of abnormal antibody production. Exfoliative dermatitis seen in association with malignant lymphoma may arise in a manner analogous to the autoimmune hemolytic anemia associated with that disease. Finally the skin might serve as the "battleground" of an entirely unrelated autoantibody-antigen system and suffer the pathological alterations attendant upon such an event.
DETECTION OF AUTOIMMUNE DISEASE
The characteristics of auto immunity that serve as a guide to the detection of autoimmune disorders have been clearly defined.7, 36 These criteria as outlined by Davies and Gery are summarized in Table 1 and include the following: (1) the occurrence of a precipitating event followed by a period of sensitization prior to the onset of symptoms; (2) the suppression of symptoms by the administration of systemic corticosteroids; (3) the development of a pathological lesion characterized by lymphoid granulomatous infiltration; (4) the detection of antibodies directed against
Table 1. Characteristics of Autoimmune Disease7 1. Precipitating event and period of sensitization
2. 3. 4. 5. 6.
Suppression of symptoms by corticosteroids Allergic histopathology Presence of organ-specific antibodies Experimental counterpart in laboratory animal Passive transfer of experimental disease with lymphoid cells
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organ-specific antigens by tests for circulating antibodies, delayed type of skin reactivity or by the demonstration of gamma globulin (antibody) at the site of the lesion; (5) the production of a similar disease in an experimental animal by immunization with appropriate tissue antigens; and (6) the passive transfer of experimentally induced auto immune disease with lymphoid cells. Only a few of these criteria have been met in most of the systemic diseases considered to have an auto immunological pathogenesis. Of foremost importance in the detection of a possible auto immune disease is the consistent demonstration of autoantibodies. Although there are many tests available to demonstrate antibody-antigen reaction, only a few are used extensively in auto immune research and therefore are briefly described here. 10 GEL-DIFFUSION TEST. The basis of this method is a precipitin reaction in which the antibody and antigen diffuse toward one another in a thin layer of agar gel. A visible line forms in the gel where antibody and antigen meet in the proper concentration for a reaction to occur. This method permits the simultaneous testing of multiple antigens by filling a central well (cut into the agar) with a specific antiserum and surrounding this central well with six or more antigen-containing wells. When antigen from two adjacent wells diffuses toward antibody in the central well, the precipitate lines they form will fuse with one another perfectly if the antigens in the adjacent wells are identical ("reaction of identity"). Precipitin lines that do not fuse, but cross, indicate the absence of identical antigens in the adjacent wells ("reaction of nonidentity"). The gel-diffusion method is a rapid and simple means of studying multiple antigen-antibody systems and of demonstrating the cross reactivity of related but not identical antigens. IMMUNOELECTROPHORESIS. Immunoelectrophoresis is another method which uses the principle of the precipitin reaction to study multiple antibody-antigen systems. The first stage of immunoelectrophoresis is the electrophoretic separation of an antigenic mixture in agar gel. Antisera from troughs cut parallel to the line of electrophoretic separation diffuse toward the separated antigens. Precipitate in the form of arcs are produced where diffusing antibody reacts with its corresponding antigen. FLUORESCENT ANTIBODY TECHNIQUE. This method employs antibody chemically bound to a fluorescent dye (fluorescein or rhodamine) to demonstrate an antigen-antibody reaction under a microscope with an ultraviolet light source. In the "direct method" a specific labeled antiserum is used to demonstrate a specific antigen. For example, fluorescein-Iabeled antipneumococcal serum could be used to demonstrate pneumococci in sputum or in a tissue. In the "indirect method" labeled anti-gamma globulin serum can be used to identify the antibody (gamma globulin) of an antigenantibody reaction with a two-step procedure. In the first step antigen
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reacts with antibody. In the second step, labeled anti-gamma globulin identifies the antibody-antigen reaction by reacting with the antibody portion of this complex. The "indirect method" is used extensively in the study of auto immune disease since the demonstration of antibody globulin at the site of tissue pathology strongly suggests an autoimmune reaction. HEMAGGLUTINATION. This is a sensitive method of demonstrating small quantities of circulating antibody. One modification of this test employs human group 0 or sheep red blood cells that have been exposed to a dilute tannic acid preparation. These "tanned" cells are capable of adsorbing soluble protein antigen onto their surfaces. In the presence of homologous antibody, agglutination of cells will occur. PASSIVE CUTANEOUS ANAPHYLAXIS. The ability of circulating antibody to passively sensitize an experimental animal can be demonstrated by injecting small quantities of antiserum intradermally into an area of shaved skin on the back of a guinea pig. After four to 24 hours have elapsed, the homologous antigen and a marker dye such as Evans Blue are injected intravenously. If an antigen-antibody reaction occurs, dye will escape from damaged blood vessels at the site of the reaction and discolor the skin. This is best observed by sacrificing the animal, removing the skin and studying its undersurface. INTRADERMAL SKIN TESTING. The delayed type of hypersensitivity (no circulating antibody) can be demonstrated by intradermal testing with antigen and appropriate controls. The reaction becomes evident in 24 hours and reaches a maximum in 48 to 72 hours. A positive reaction is usually characterized by a nodule with surrounding erythema. Histopathological examination of the positive test site reveals a lymphoid granuloma. CLINICAL ASPECTS OF AUTOIMMUNITY
In any discussion of autoimmunity it should be emphasized that the demonstration of an auto antibody does not necessarily imply that the associated clinical state is auto immune or allergic in its pathogenesis. An autoantibody should be shown to be destructive of its homologous antigen in order to be considered causative of disease. Autoantibodies may arise as a consequence of disease as they presumably do in myocardial infarction, in which antibodies directed against cardiac tissue have been demonstrated. 7 They may arise also as an incidental consequence of a pathogenic agent as in the case of viral pneumonia. In the latter disease the production of cold autohemagglutinins has little to do with the clinical symptoms of the illness. In the field of cutaneous disease there are few if any diseases of undisputed autoimmune pathogenesis. The skin diseases to be discussed in the following sections can be considered to be possible examples of auto immune diseases on the basis of tentative experimental studies or clinical characteristics that will be described.
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Autosensitization Dermatitis
The origin of the concept of auto immunity can be credited in part to a dermatologist. In 1921 Whit field suggested that generalized dermatitis might arise on the basis of autosensitization to autologous skin following a localized injury to the skin or the development of a limited area of dermatitis such as stasis eczema. 34 Unfortunately, this clinical concept has been given little in the way of experimental support. Although a precipitating event is implicit in the concept of autosensitization dermatitis and the disease can be suppressed with corticosteroid therapy, none of the other criteria detailed in Table 1 have been consistently demonstrated. Early studies of autosensitization dermatitis suggested that the antigen involved in this widespread reaction was probably bacteria that had infected the original site of dermatitis. ID More recently Parish et a1. noted the presence of a circulating antiskin antibody in two of 74 patients with autosensitization dermatitis. 23 These two patients had a serum factor that would agglutinate particles coated with a skin extract and a "cytotoxic factor" active against epidermal cells. Although the presence of a cytotoxic antibody favors a causal relationship between the autoantibody and autosensitization dermatitis, the limited number of positive patients in this study suggests that the factors demonstrated by Parish may be the incidental by-products of widespread dermatitis. One might speculate on the role of other mechanisms in the development of autosensitization dermatitis. For example, the rapid vascular dissemination of proteolytic enzymes from the original site of cutaneous injury might account for the sudden development of generalized skin lesions. Clearly an immunological mechanism need not be postulated to explain the pathogenesis of this disease. Bullous Diseases
Among the many skin diseases of undetermined etiology, the group of generalized bullous diseases would seem most likely to contain examples of true auto immune cutaneous disease. For the most part the bullous diseases are chronic illnesses, responsive to corticosteroid therapy and in some instances evidently allergic in origin (e.g., drug-induced bullous erythema multiforme). Pemphigus vulgaris, in particular, because of the very specific nature of the pathological lesion, has been investigated for autoantibodies directed against epidermal cells. In preliminary studies, Walzer and Einbinder 32 and Raskin27 were unable to demonstrate circulating antiepidermal cell antibodies in the serum of patients with pemphigus vulgaris using the fluorescent antibody technique. Jordan et al.,16 however, had positive findings in two of four patients using the same technique. It is evident that further investigation with emphasis on other methods is required before any conclusion can be reached.
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Gyrate Erythemas
This condition is characterized by the development of erythematous ringed lesions with elevated borders. These annular lesions enlarge and spread over large areas of the body and in some instances disappear and reappear in a manner similar to simple urticaria. Many appellations have been given to this condition. Most of these names describe the gross morphology and course of the lesion (erythema annulare centrifugum, erythema chronicum migrans, etc.).2
Figure 1. A, Breast hypertrophy, cutaneous pigmentation and lesions of erythema annulare centrifigum in a patient with circulating autoantibodies directed against autologous breast tissue. B, Close-up of migrating urticarial bands on the forearm. (Courtesy of Shelley, W. and Hurley, H. J.: A.M.A. Arch. Dermat. 81: 889, 1960.)
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Shelley and Hurley have described a remarkable patient with a generalized eruption composed of "constantly migrating urticarial bands," massive breast hypertrophy and generalized pigmentation30 (Fig. 1). Using a tanned cell hemagglutination test, Shelley and Hurley were able to demonstrate an autoantibody present in the patient's serum and directed against her own cystic breast tissue. The authors were of the opinion that the bizarre cutaneous eruption represented autoantibody reacting with breast antigen fixed in the skin. Although not representative of autoimmunity directed against cutaneous antigens, this case suggests that the skin may be the site of reaction of other auto immune systems.
Purpuric Eruptions It has been pointed out earlier that autoantibodies are rarely formed against constituents of tissue in close contact with the lymphatic apparatus. Consequently, autoimmune reactions involving the vascular system or elements of the blood would be unlikely to occur unless significant alterations of these tissues made them autoantigenic, or abnormal antibodies, the product of a defective immunological system, reacted with normal tissue. The latter situation may pertain in thrombocytopenic purpura seen in association with systemic lupus erythematosus, in which autoantibodies against platelets have been demonstrated. 20 Another category of purpura thought to be on an autoimmune basis has been documented by detailed clinical investigation in two patients. IS. 29 These patients developed spontaneous, painful hemorrhagic nodules on the extremities as a manifestation of hypersensitivity to deoxyribonucleic acid (DNA). In both cases skin testing with very small quantities of DNA reproduced the clinical lesion, although a circulating anti-DNA factor could not be demonstrated despite diligent efforts to do so. Schwartz et al. suggest that this reaction is similar to that seen in cutaneous anaphylaxis in which skin-fixed antibody reacts with small amounts of antigen and an immediate change in venous permeability ensues. 29 They postulate that the antibody in patients with DNA hypersensitivity has an unusual affinity for the skin but is unable to localize in other tissues. Other cutaneous diseases that require investigation for similar autoimmune phenomena are the chronic pigmented purpuric eruptions, HenochSchoenlein purpura and the many categories of dermal vasculitis of undetermined cause. Exfoliative Dermatitis It is possible that in some instances generalized exfoliative dermatitis is the clinical counterpart of what is described in the laboratory animal as "runt disease" (Fig. 2). This condition, characterized by wasting, diarrhea, hepatosplenomegaly as well as dermatitis and alopecia, is induced when the recipient of a graft of lymphoid tissue (immunologically competent
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Figure 2. A, A mouse with "runt disease." The cutaneous changes that characterize this condition are rufHed fur, alopecia and dermatitis. (Courtesy of Oliner, H. et al.: Blood 17: 20, 1961.) B, Same mouse viewed from above showing alopecia and dermatitis.
cells) is incapable of rejecting this graft. 8 , 22 Because of their immunological immaturity, animals grafted in utero or in the neonatal period cannot reject a lymphoid tissue graft. In this situation, however, the grafted lymphoid tissue is capable of reacting against ("rejecting") the host tissues which are antigenically foreign to the animal donating the lymphoid cells. Presumably the symptoms that develop are the result of the graft cells producing antibodies directed against the host's tissues. Dermatitis and alopecia are thought to develop because of cytotoxic properties of antibodies directed against cutaneous components. It seems possible that the generalized exfoliative dermatitis that develops in association with lymphomatous disease in human beings arises
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because of similar antiskin antibodies produced by primitive, disordered lymphoid cells in a manner analogous to runt disease. This hypothesis awaits clinical and experimental confirmation. Thermal Burns
It has been suggested that alteration of skin antigens by thermal injury might induce the formation of autoantibodies. However, experimental efforts to demonstrate specific autoantibodies following a burn have produced contradictory data. The finding of circulating precipitins against skin in postburn serum has been shown in some instances to be due to bacterial antigen-antibody reactions rather than cutaneous antigen-antibody systemsY Nevertheless the value of convalescent serum in the treatment of burns, although still controversial, is suggestive of the presence of antibodies or antitoxins against denatured skin components. Pyoderma Gangrenosum
This very destructive, ulcerative lesion of the skin occurs in association with various debilitating systemic diseases, particularly ulcerative colitis. Since patients with ulcerative colitis have been found to have circulating autoantibodies directed against colonic mucosa,4 one might speculate on the possibility of cross reactivity of these antibodies with common antigenic factors in the skin. Recently two patients with pyoderma gangrenosum (only one of whom had ulcerative colitis) were shown to reject transplants of their own normal-appearing skin and to manifest a delayed type of hypersensitivity reaction to autologous leukocytes. 19 Although these findings are suggestive of an immunological lesion, the nature of the antigen(s) involved is still open to question. Psoriasis
Psoriasis is associated with a rheumatoid arthritis syndrome in a significant number of patients. This association, as well as other characteristics of this disease (chronicity, response to corticosteroids and familial pattern) suggests a similarity to auto immune diseases of the collagen group. Two immunological techniques have been employed to detect the presence of circulating antibodies in the serum of patients with psoriasis. Passive cutaneous anaphylaxis (see section on methodology) studies have been performed by injecting serum from psoriatic patients intradermally and challenging several hours later with an intravenous injection of psoriatic tissue homogenate.1 2 , 21 These studies failed to demonstrate circulating antibody directed against psoriatic tissue antigens. Similarly, investigations using the fluorescent antibody technique were unable to detect a specific antigen-antibody reaction in the affected skin of psoriatic patientsY However, circulating antinuclear factors were demonstrated in
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two patients with psoriasis with arthritis and in one patient with psoriasis without arthritis. This latter finding, if confirmed, suggests that psoriasis may have immunological features in common with the collagen diseases.
Discoid Lupus Erythematosus Immunological evidence would tend to confirm the current clinical impression that discoid lupus erythematosus is a benign, cutaneous variant and infrequent precursor of systemic lupus erythematosus. Antinuclear antibodies have been demonstrated in discoid lupus erythematosus in more than 50 per cent of patients by the fluorescent antibody technique. 25 • 27 These antibodies were noted to be reactive against epidermal cell nuclei as well as the nuclear material of heterologous leukocytes. Since the lesions of discoid lupus erythematosus are limited to the skin, it is doubtful that antinuclear antibodies are of primary causal importance in this disease. Even in systemic lupus erythematosus in which auto antibodies directed against nuclear material, cellular cytoplasmic components, red blood cells, platelets, leukocytesand coagulation factors have been demonstrated, it is still questionable whether these antibodies are primary incitants of this complex disease. 2o
Atopic Eczema Atopic eczema has long been associated with diseases of allergic etiology and has, itself, been considered to be allergic in origin,. Although skin testing with food and inhalant allergens reveals hypersensitivity of the immediate type in individuals afflicted with eczema, efforts at desensitization or elimination of allergens are frequently ineffective in the management of this disease. Investigation of atopic eczema as a disease of auto immunization to cutaneous antigens was undertaken by Hashem et al. 13 The method employed in their study was based on the observations of Pearmain that lymphocytes from tuberculin-positive individuals when grown in tissue culture in the presence of tuberculin undergo mitosis and blastlike cells and plasma cells appear in the culture. 24 This event is interpreted as evidence that the sensitized lymphocyte responds to its homologous antigen by division and reversion to a more primitive form. Hashem found that lymphocytes obtained from infants with severe atopic eczema were induced to undergo mitosis when grown in a culture containing a cell-free skin extract. These investigators concluded that the lymphocyte of the eczematous infant was sensitized to a component of skin. Since the cutaneous extract in this study was derived from biopsy specimens, however, it would be difficult to say that a contaminating factor such as bacteria and/or fungi was not the sensitizing antigen rather than a component of the skin itself. Confirmation and elaboration of this work is required before any conclusions can be drawn.
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Systemic Diseases with Cutaneous Manifestations A review of the auto immune aspects of systemic diseases, many of which have cutaneous manifestations, is beyond the scope of this discussion. Some of the diseases that might be considered in this category are rheumatoid arthritis, rheumatic fever, systemic lupus erythematosus, scleroderma, Sjogren's syndrome and periarteritis nodosa. Dermatomyositis is worthy of special mention since the cutaneous aspects of this disease are paramount and the immunological findings of considerable interest. Dermatomyositis is associated with internal malignancy in approximately 50 per cent of adults with this disease. 3 This fact has prompted the study of patients with dermatomyositis and visceral carcinoma for an immunological relationship between the tumor and the skin and muscle disease.5, 11 In two patients studied, skin testing with an extract of autologous tumor tissue produced an immediate-type of skin reaction while other tissues failed to elicit this reaction. In both instances the presence of circulating antitumor antibody was confirmed by passive transfer studies. This finding, supported by the clinical observation that dermatomyositis tends to go into remission when the associated tumor is removed,6 suggests that this disease is auto immune in its origin. One might speculate further that the cutaneous and muscle lesions are the result of tumor antigen and antibody combination at these sites. Fluorescent antibody studies might yield information concerning this possibility. EXPERIMENTAL STUDIES IN AUTOIMMUNIZATION Valuable information concerning the pattern of development of human autoimmune cutaneous disease might be obtained by creating a model in an experimental animal. Unfortunately, efforts to immunize laboratory animals with autologous or homologous skin have met with only partial success. In early experiments by Hecht et al.,14 rabbit skin, adjuvant and staphylococcal toxin were used to immunize rabbits. Although circulating precipitins developed in the animals studied, these were directed against 24-hour old autolysates of the original antigen. Since no attempt was made to render the immunizing antigen bacteriologically sterile, it is likely that the precipitins demonstrated were against bacterial antigens. Subsequently Allgower was unable to demonstrate circulating precipitins or cytotoxins deleterious to epidermal cells in tissue culture after immunization with homologous skin.! Similarly, Rosenthal reported negative results in the immunization of animals with skin-adjuvant emulsions as evidenced by the failure of these animals to reject autografts following the attempted immunization. 28 More recently Wilhelmj et al. reported on the successful immunization of experimental animals with homologous and autologous skin. 35 Antibodies directed against the test antigen were demonstrated by complement fixation and hemagglutination tests as well as by intradermal testing with skin antigen. There was some degree of cross re'1ctivity when the immune sera were tested against other organs (lung, heart, kidney and brain) and some of the control animals injected with Freund adjuvant but no antigen developed low titers of antiskin antibody. Of
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particular interest in this study was the development of cutaneous lesions in the immunized animals. These lesions were characterized by an erythematous, scaling dermatitis with alopecia. On the other hand, Dikeacoy-Moschos et al. using comparable techniques were unsuccessful in reproducing Wilhelmj's findings. 9 These workers were unable to induce the formation of a circulating (complement fixing) antibody against skin antigen injected into guinea pigs. In addition, they noted only minimal hair loss without dermatitis not only in the animals in this study, but in control, nonimmunized animals as well. Similarly, Walzer et al. were unable to detect circulating antibody, delayed hypersensitivity or cutaneous lesions in rabbits immunized with sterile fetal rabbit skin and Freund adjuvant. 33 Investigations in progress by these investigators suggest that immunization with skin from a different species cannot induce the formation of autoimmune skin lesions although it does result in the production of nonorgan-specific antibodies.
SUMMARY The relationship of auto immunity to cutaneous disease is an area of dermatology worthy of more extensive clinical and laboratory investigation. An examination of some cutaneous diseases in which auto immunity may tentatively play a role suggests that the skin may serve as a "shock organ" for the reaction of autoantibodies and antigens of noncutaneous origin (annular erythema, purpura due to DNA hypersensitivity and dermatomyositis). There is only limited evidence, however, that would implicate the role of autoantibodies directed against cutaneous components in the pathogenesis of skin disease (pemphigus vulgaris, atopic eczema, autosensitization dermatitis). In the area of laboratory investigations, attempts to induce autoimmune cutaneous disease in experimental animals have met with only partial success. However, if achieved, experimental auto immune disease of the skin may point the way to presently unrecognized counterparts in the human being. REFERENCES 1. Allg6wer, M., Blocker, T. G., Jr. and Engley, B-W. D.: Some immunological aspects
2. 3. 4. 5.
of auto and homografts in rabbits, tested by in vivo and in vitro techniques. Plast. & Reconstr. Surg. 9: 1, 1952. Andrews, G. C. and Domonkos, A. N.: Disease of the Skin. 5th Ed. Philadelphia & London, W. B. Saunders Co., 1963. Arundell, F. D., Wilkinson, R. D. and Haserick, J. R.: Dermatomyositis and malignant neoplasms in adults. A.M.A. Arch. Dermat. 82: 772, 1960. Broberger, O. and Perlman, P.: Autoantibodies in human ulcerative colitis. J. Exper. Med. 110: 657, 1959. Curtis, A. C., Heckman, J. H. and Wheeler, A. H.: Study of the autuimmune reaction in dermatomyositis. J.A.M.A. 178: 571, 1961.
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6. Curtis, A. C., Blaylock, H. C. and Harrell, E. R.: Malignant lesions associated with dermatomyositis. J.A.M.A. 150: 844,1952. 7. Davies, A. M. and Gery, I.: Role of autoantibodies in heart disease. Am. Heart J. 60: 669, 1960. 8. Defendi, V., Steinmuller, D., Billingham, R. E. and Silver, W. K.: Pathogenesis and pathology of "runt" disease in rats. Fed. Proc. 19: A-208, 1960. 9. Dikeacoy-Moschos, T. A., Rosenthal, S. A. and Schroeder, H.: Attempts at sensitization to skin in guinea pigs. Arch. Dermat. In press. 10. Gell, P. G. H. and Coombs, R. R. A.: Clinical Aspects of Immunology. Philadelphia, F. A. Davis Co., 1963. 11. Grace, J. T. and Dao, T. L.: Dermatomyositis in cancer: a possible etiological mechanism. Cancer 12: 648, 1959. 12. Harber, L. C., March, C. and Ovary, Z.: Lack of passive cutaneous anaphylaxis in psoriasis. Arch. Dermat. 85: 716, 1962. 13. Hashem, N., Hirschorn, K., Sedlis, E. and Holt, L. E.: Infantile eczema-evidence of autoimmunity to human skin. Lancet 2: 269, 1963. 14. Hecht, R., Sulzberger, M. B. and Weil, H.: Studies in sensitization to Rkin. J. Exper. Med. 78: 59, 1943. 15. Hopkins, H. and Burkey, E. L.: Cutaneous autosensitization. Role of staphylococci in chronic eczema of the hands. Arch. Dermat. & Syph. 49: 124, 1944 16. Jordan, R. E., Beutner, E. H. and Aquilina, J. T.: Immunofluorescent studies of pemphigus vulgaris. Fed. Proc. 23: 342, 1964. 17. Kohn, J.: Biochemical and immunological aspects of human burns. In International Symposium on Injury, Inflammation and Immunity (L. Thomas, J. W. Uhr and L. Grant, Eds.). Baltimore, Williams & Wilkins Co., 1964. 18. Levin, M. Band Pinkus, H.: Autosensitivity to desoxyribonucleic acid (DNA): Report of case with inflammatory skin lesions controlled by chloraquine. New England J. Med. 264: 533, 1961. 19. Long, P. I. and Uesu, C. T.: Pyoderma gangraenosum. J.A.M.A. 187: 336,1964. 20. Meischer, P. A., Barker, L., Vainio, 1. and Wiedermann, G.: Immune mechanisms of cell and tissue damage in systemic lupus erythematosus. In International Symposium on Injury, Inflammation and Immunity (L. Thomas, J. W. Uhr and L. Grant, Eds.). Baltimore, Williams & Wilkins Co., 1964. 21. Moreci, A., Farber, E. and Raffel, S.: Further studies of immunologic reactions in psoriasis. A.M.A. Arch. Dermat. 85: 617,1962. 22. Oiiner, H., Schwartz, R. and Dameshek, W.: Studies in autoimmune disorders. I. Clinical and laboratory features of auto-immunization. Blood 17: 20,1961. 23. Parish, W. E. and Rook, A.: Skin autosensitization. In Clinical Aspects of Immunology (P. G. H. Gell and R. R. A. Coombs, Eds.). Philadelphia, F. A. Davis Co., 1963. 24. Pearmain, G., Lycette, R. R. and Fitzgerald, P. H.: Tuberculin induced mitosis in peripheral blood leukocytes. Lancet 1: 637, 1963. 25. Peterson, W. C. and Fusaro, R.: Antinuclear factors in chronic discoid lupus erythematosus. Arch. Dermat. 86: 783, 1962. 26. Raffel, S.: Immunity. 2nd Ed., New York, Appelton-Century-Crofts, 1961. 27. Raskin, J.: Fluorescent antibody studies of certain dermatoses. Arch. Dermat. 89: 569,1964. 28. Rosenthal, S. A., Baer, R. L. and Hagel, B.: Failure to sensitize to autologous skin. Proc. Soc. Exper. BioI. & Med. 97: 279, 1958. 29. Schwartz, R. S., Lewis, F. B. and Dameshek, W.: Hemorrhagic cutaneous anaphylaxis due to autosensitization to desoxyribonucleic acid. New England J. Med. 267: 1105,1962. 30. Shelley, W. and Hurley, H. J.: An unusual autoimmune syndrome: Erythema annulare centrifigum, generalized pigmentation and breast hypertrophy. A.M.A. Arch. Dermat. 81: 889, 1960. 31. Waksman, B. H.: Auto-immunization and the lesions of autoimmunity. Medicine 41: 93,1962. 32. Wnlzer, R. A. and Einbinder, J.: Unpublished data. 33. Wnlzer, R. A., Einbinder, J. and Nelson, C. T.: Response to immunization with homologous skin. Arch. Dermat., Dec., 1964.
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34. Whitfield, A.: Some points in the etiology of skin disease. Lecture H. Lancet 2: 122, 1921. 35. Wilhelmj, C. M., Kierland, R. R. and Owen, C.: Production of hypersensitivity to skin in animals. Arch. Dermat. 86.' Hll, 1962. 36. Witebsky, K, Rose, N. R, Terplan, K., Paine, J. R. and Egan, R. W.: Chronic thyroiditis and autoimmunization. J.A.M.A. 164: 1439, 1957. 180 Fort Washington Avenue New York, N.Y. 10032