HISTORY OF IMMUNOLOGY Ocular Immunology: On the Birth of a New Discipline’

Those who study the workings of science have long been interested in the nature of scientific disciplines, in how new disciplines are formed, and in how established disciplines differentiate to form further subspecialty areas ( 1). In some instances. the intellectual content of such subspecialty areas derives from developments within the parent discipline itselE in others, it is borrowed fully formed from the cognitive content of some other rapidly moving and highly popular discipline. In this respect, the field of immunology should be of special interest to sociologists of science, since during its I 10 years it has affected the course of so many biological and medical disciplines and spawned so many new specialties and subspecialties. Such new areas, represented variously by special conferences, textbooks, journals, and societies. include clinical allergy, immunophysiology. immunopathology. immunochemistry, immunogenetics. immunohematology. psychoneuroimmunology. and ocular immunology. among others. I shall show here how the chnical tieid ot‘ophthalmoiogy was mfluenced by the young and dynamic specialty of immunology early in this century. Ophthalmologists very quickly seized upon the concepts and techniques of the early immunologists, and slowly ocular immunology developed as a subdiscipline within the larger field of ophthalmology. Of equal interest is the fact that while many other clinical fields of medicine attempted to integrate the turn-of-century immunological excitement into their clinical and research programs. ophthalmology is perhaps unique in having maintained that interest from that time up to the present day. This was true even during the halfcentury or so when mainstream immunology abandoned its biomedical concerns in favor of more parochial immunochemical approaches (2). Throughout its history, ophthalmology continued to adapt newer advances in immunology to its own purposes. and occasionally immunologists utilized the special characteristics of the eye to design experiments to answer nonophthalmic questions. The interaction of these two disciplines accelerated when the immunobiological revolution got fully under way in the ’ Presented III pan at the b’ltih lnternatmnai Symposium on the Immunology and lmmunopathoiogy ot the Eye, Tokyo. March 1990. and at the 4merican Ophthalmic History Society. Bethesda, Maryland, March, 1990.

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early 1960s. Since these latest developments have been so fully recorded in numerous texts and monographs (3), a detailed history of the field beyond that point will not be attempted. Only those recent advances that provide endpoints to earlier research trails or that illustrate the continued borrowing by ophthalmic researchers of newer findings in immunology will be sketched briefly. CONCEPTUAL TRENDS IN EARLY IMMUNOLOGY Immunology was born as a laboratory science in 1880 at the hands of Louis Pasteur (4). His demonstrations of the ability to attenuate pathogens and utilize them for preventive vaccination in the case of chicken cholera, anthrax, rabies, and other diseases excited the interest of the world, and assured that many prominent scientists would interest themselves in this field. These successeswere further magnified by the discovery by von Behring, Kitasato, and Wemicke in 1890-l 892 that circulating antibodies can neutralize the toxins of diphtheria and tetanus, and that such antitoxins can even be administered passively to cure patients already infected by these organisms (5). Here were two approaches that seemed for a time to hold the promise of preventing or curing all of the infectious diseases whose etiologic agents were being discovered with great rapidity. No wonder that by the end of the 19th century, the doctrines of thisnot-yet organized or even named discipline were proving so popular and attracting the attention of the academic community in all of the medical specialties. Ophthalmology, one of the earliest of the medical specialties (6), was influenced by three components of the developing research program of the young field of immunology (7) and applied them in turn to the explanation of its own clinical disease problems. The first of these was the “doctrine” of cytotoxic antibodies. At the outset, the immune response had been viewed as an evolutionary development for the protection of the individual from harmful disease agents. Had not Ilya Metchnikoff with his phagocytic theory of immunity (8) emphasized, and Paul Ehrlich with his side chain theory of antibody formation (9) implied, the Darwinian nature of these developments, and was not evolution directed toward improvement of the species? So long as the immune response appeared to be limited to mechanisms aimed at the destruction of pathogenic organisms and the neutralization of their deadly toxins, this view seemed appropriate. But in the late 1890s antibody formation was found to be a more general phenomenon, and antibodies against such bland proteins as albumins were observed. Then came Jules Bordet, who showed in 1899 (10) that antibodies could even be formed against erythrocytes, which they destroy (hemolyse) with the help of the nonspecifically acting serum factor complement. Pandora’s box had been opened, and investigators everywhere asked themselves why other tissues and organs might not also stimulate an immune response that might account for the tissue destruction seen in so many diseases of unknown etiology and pathogenesis. Within a very short period, suspensions or extracts of almost every available tissue and organ were injected into animals to search for specific antibodies and for cytotoxicity, and theories were advanced to link the pathogenesis of one or another disease to this mechanism (11). The second relevant component of the immunological research program is the concept of autoimmunity. When Jules Bordet reported the finding of anti-erythrocyte antibodies able to hemolyze red blood cells, Ehrlich and Julius Morgenroth wasted no time in testing whether an animal could form antibodies against its own erytbrocytes (12). This they never observed, causing Ehrlich to advance the dictum of Horror Autotoxicus (13) which held that even if autoantibodies could be demonstrated, internal

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regulatory mechanisms would operate to prevent self-destructive consequences. So great was Ehrlich’s prestige that his concept was accepted as law, and even the demonstrations of autocytotoxic antispermatozoa by Metalnikoff ( 14) and of autoantibodies that cause paroxysmal cold hemogiobinuria by Donath and Landsteiner (15) failed to shake this belief. As a result, progress in autoimmune disease research was retarded for over 50 years (16). Only the ophthalmologists worked consistently on this problem during this period. The third important component of the immunologica research program that rnfluenced ophthalmology was that of anuphylaxis and related disease mechanisms. In 1902, Paul Portier and Charles Richet reported that animals could be sensitized by a first exposure to antigen, such that a second challenge with the same antigen would lead to shock-like symptoms and even death ( 17). Shortly thereafter, Maurice Arthus demonstrated that bland antigens injected repeatedly into the skin could cause local necrotizing lesions, a dermal antigen-antibody interaction thenceforth known as the Arthus phenomenon (18). Finally, in 1906. Clemens von Pirquet and Bela Schick showed that the pathogenesis of human serum sickness involves an antibody response in the host to the injection of large quantities of foreign protein antigens (19). Anaphylaxis the word and anaphylaxis the concept became so popular that they penetrated into all branches of medicine, and not least into ophthalmological concepts of disease. This spread of interest in anaphylaxis was accelerated when it became apparent that those scourges of mankind, hayfever and asthma, were also related to similar mechanisms (20). We shall now see how the field of ophthalmology was in1luenced by these three concepts. I shall discuss them in terms of their influence on the major trends in ocular immunopathology. and show how they affected the concepts of pathogenesis in a number of clinically important ophthalmic diseases. AUTOIMMUNE

DISEASES OF THE EYL

Sympathetic Ophthaimin Ophthalmologists were not long in responding to the doctrine of‘cytotoxic antibodies. In 1906, Santueci drew attention to the possibility that sympathetic ophthalmia might be caused by the formation of cytotoxic antibodies, following resorption of damaged ocular tissue in the first eye. These antibodies would then attack the hitherto normal contralateral eye (2 1). Santucci presented experiments showing that injection of emulsified ocular tissue into rabbits and guinea pigs would cause endophthalmitis. No sooner had this thesis begun to attract attention than a counterclaim for priority appeared from the pen of S. Golowin in Russia (22) who pointed out that he had advanced this idea in 1904. in a Russian journal apparently unread in the West (23). Golowin claimed that the seat of attack in the sympathizing eye was the iris and ciliary body, and so named these antibodies “cyclotoxins.” It was then that the famous ophthalmologist Elschnig of Prague entered the fray. Elschnig quickly became the leading advocate of an autoimmune pathogenesis of sympathetic ophthalmia (24), with the collaboration of the prominent Prague immunologist Weil. They suggested that the resorption of antigen in the damaged eye led to a “hypersensitivity” that also involved the second eye. Thus, the mildest disturbance in the sensitized second eye might lead to inflammation and blindness. In the course of numerous animal experiments, Elschnig ultimately identified uveal pigment as the offending antigen

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For many years thereafter, students of sympathetic ophthalmia continued to concentrate on a pathogenesis based upon an autoimmune response to uveal pigment. The foremost American supporter of this thesis was ophthalmologist Alan Woods at Johns Hopkins, who published extensively on this subject starting as early as 1916 (25). Woods later employed uveal pigment as antigen in an intracutaneous test for sensitization in patients with sympathetic ophthalmia, and reported positive results (26). Woods’ colleague Jonas Friedenwald demonstrated that the histopathology of the uveal pigment skin test was “consistent with an allergic reaction” (27), thus reinforcing the concept. So convinced were these workers that they understood the mechanism of the disease that Woods felt free to inject uveal pigment preparations into patients in a therapeutic attempt to “desensitize” them, and in fact reported favorable results (28). It is now difficult to say what other contaminants may have been present in the crude preparations of uveal pigment then employed, but the results proved quite variable, and an etiology for sympathetic ophthalmia based upon uveal pigment slowly fell out of favor. One of the chief obstacles to progress in understanding the etiology and pathogenesis of sympathetic ophthalmia was the absence of a satisfactory animal model of the disease. Progress was slow, until the Freund’s adjuvant was described in 1942 (29), a technique that advanced the cause of so many autoimmune disease models. In two landmark papers in 1949 and 1953 (30), Collins reported on the production of uveoretinitis in guinea pigs induced by uveal extracts injected in adjuvant. These observations (along with others in autoimmune hemolytic anemias, orchitis, thyroiditis, and encephalomyelitis) helped to ensure the modem revival of interest in autoimmune diseases. It was shown some years later by Wacker and Lipton (31) that retinal extracts are much more efficient in producing autoimmune disease than uveal extracts, and this initiated the search for the organ-specific antigens involved. Three such antigens were found initially, localized by immunofluorescent analysis to the outer segments of the retina (32). Then, simultaneously, two different laboratories isolated and identified a soluble retinal antigen (S-antigen) able to induce autoimmune disease in animals (33). Since then, a number of other organ-specific antigens have been implicated, including an interphotoreceptor retinoid-binding protein (IRBP) (34) and even the visual pigment itself, rhodopsin (35). By varying the dosage and sensitizing regimen, it has been possible to alter the previously observed chronic inflammatory picture to that of a granulomatous form more typical of human sympathetic ophthalmia (36). It is of some interest that experimental autoimmune uveoretinitis induced by S-antigen and IRBP is accompanied by inflammation of the pineal gland, which shares antigens in common with the retina (37). All of the most recent data on mechanisms of host response in this experimental model attest to its autoimmune basis and to its close relationship with human sympathetic ophthalmia (38). Phacoanaphylaxis A new chapter in the history of immunology was opened up by Paul Uhlenhuth when he reported in 1903 that the antigens of the lens of the eye are organ-specific (39). This was the first intimation that unique antigens might exist within a single organ and, further, that they might be shared among widely divergent species. It was then shown by Kraus and co-workers (40) and by Andrejew and Uhlenhuth (41) that these lens (phaco-) antigens could mediate both active and passive anaphylaxis in test

animals. Uhlenhuth and Haendel then showed that a guinea pig could be rendered sensitive to its OMITlens protein and sent into anaphylactic shock with the proteins from any other lens (42). These investigators drew no conclusions from their work that might be applied to clinical problems, although the ophthalmologist Paul Rijmcr had earlier speculated that senile cataract formation might be mediated by autocytotoxic antibodies specific for the lens (43). It was only when F. F. Krusius demonstrated in 19 10 that rupture of the lens capsule in a normal guinea pig would both sensitize the animal and serve also as the disease-producing challenge (44) that the true implications of this system for ocular disease became apparent. In a comprehensive review of the subject in 19 12. Romer and Webb considered the broader implications of these findings in a most interesting way (45). In a section of the review “on the question of the formation of autoanaphylactic antibodies by means of lens proteins.” they asked whether autologous lens is really foreign in the guinea pig, or “whether the ‘law of immunity research,’ which Ehrlich has popularly termed horror autotoxicus, does not rather apply to the lens.” Here. as early as 19 12, was a foretaste of the later concept of the sequestered antigen. If the body cannot respond to self, then all such antigens able to stimulate an immune response JYZLLS~ be foreign, i.e., normally sequestered somehow from contact with the host’s immune system. But as true followers of Ehrlich. they hnally came to the conclusion that lens is indeed self. that it does stimulate an immune response, and that “We are rather convinced that the regulatory mechanism of the organism can and will refuse to serve under special conditions. And the investigation of these situations will further promote OUI understanding of pathological states” (46). Interest in lens-induced immunogenic disease continued, and important con&ibutions were made over the years. The clinical condition was named endophthaltniti, phucoanaphyfactk by Verhoeff and Lemoine in 1922 (47). and these investigators also reported positive skin test responses in patients with this disease (48). Further investigation of antilens responses in patients with cataract was pursued in extensive investigations by Burky and Woods (49). Perhaps the most significant contributions to our understanding of this autoimmune process were made in a series of reports by Marak and co-workers (50). They produced a disease in rats histopathologically similar to that seen in the human. ;dnd were able to transfer the disease adoptively using immune serum: there seems to be little evidence that I- cell mechanisms contribute significantly to the pathogenesis of ‘“phacoantigenic uveitis.” Our story of the immunology of the lens would not be complete without mention of its application to the problem of evolution. As early as 1904. the immunologist Nuttall (5 1) had proposed using the antibody cross-reactions of the numerous protein antigens of different species to measure interspecies relationships, From the 1960s on1 this approach was elegantly pursued by Halbert and Manski (52). using lens antigens and a battery of antilens antisera. Given the evolutionary conservation of these structures, cross-reactions were detectable across the entire vertebrate spectrum, and the results proved to be fascinating.

Sjogren’s syndrome is a later addition to the list of autoimmune diseases of the eye, and is a product of the recent general interest in this area. It was first described clinically in 1933 (53). and autoantibodies were only described in 1958 (54). It is a disease characterized by an autoimmune attack on the lacrimal and salivary glands. involving

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a chronic inflammatory destruction of acinar cells and ductular epithelium (5 5). This results in the vexing problem of dry eyes and a dry mouth. The history, clinical aspects, and pathophysiology of this disease have been reviewed extensively by Liotet and coworkers (56). Recent experiments appear to confirm the existence of lacrimal glandspecific antigens, able to induce autoimmune dacryoadenitis in the rat without crossreacting involvement of the salivary gland (57). A similar approach has shown that an experimental autoimmune disease specific only for the rat Harderian gland may also be elicited using the appropriate organ-specific antigen (5 8). In these animal models of Sjiigren’s syndrome, T cell-mediated immunity appears to be the dominant mechanism involved (59). The relationship between these animal models and the human disease is presently unclear, given the high degree of organ specificity of the experimental systems. They may, however, be related to a group of apparently chronic inflammatory conditions of the lacrimal gland that bear the nonspecific diagnosis “chronic dacryoadenitis” (60). IMMUNOGENIC

KERATITIS

Cornea1 Arthus Reactions It was Wessely (6 1) who first noticed that the injection of antigen intrastromally in the central cornea of a sensitized rabbit would produce an opaque ring of interstitial keratitis. This observation attracted much attention, especially on the part of Aurel von Szily, who devoted an entire book (62) to the study of this phenomenon. In a model collaboration between immunopathologists and ophthalmologists, Germuth, Maumenee, and co-workers (63), employing modem techniques such as immunofluorescent histochemical staining, proved that the Wessely ring was in fact a true intracornea1 Arthus reaction, i.e., an immune complex deposit with local fixation of complement and the release of pharmacologic agents that attract polymorphonuclear leukocytes to the site. In a similar collaboration, Waksman and Bullington had earlier demonstrated an equivalent Arthus reaction within the uveal tract (64). Tuberculosis Yet another approach to the problem of immunogenic interstitial keratitis stemmed from Robert Koch’s tuberculin test, and from developments in the field of delayed hypersensitivity (later to be called cellular immunology), in which this test played so important a role. During the early period, when many new approaches to the diagnosis of tuberculosis were developed, Calmette proposed his “ophthalmoreaction” (65), in which tuberculin dropped on the eye of a sensitized individual would lead to a moreor-less severe conjunctivitis. While this test proved to be too dangerous, it did stimulate experiments using other ocular tissues, including the cornea. It was quickly found that intracomeal injection of tuberculin into sensitized guinea pigs would yield an interstitial keratitis, whereas intracomeal injection of antigen into an anaphylactically sensitive animal would not lead to cornea1 inflammation. A different mechanism seemed to be involved, one that could operate even within the normally avascular cornea. Indeed, this difference was long used as one of the principal criteria to differentiate these two phenomena. The hypersensitivity that accompanies tuberculosis may also be expressed by the spontaneous development of phlyctenular keratoconjunctivitis. This disease is seen most frequently at the margin between cornea and conjunctiva, and presents as an

inflammatory infiltrate or nodule composed of epithelioid cells surrounded by Iymphocytes, resembling a small tubercle. Descriptions of such nodules appear in the 2nd century in the writings of Paul of .4egina and of Ali ben Isa, and more recently in the 18th century treatise on ocular diseases of St. Yves (66). The condition has been produced experimentally by ophthalmologists Weekers and Riehm in the tuberculinsensitive rabbit, following instillation of tuberculin in the conjunctiva (67). Its association with tuberculosis has been repeatedly confnmed epidemiologically (68) but it may also result from hypersensitivity reactions to other infectious agents and allergens (69).

Whereas herpesvirus destruction of the cornea1 epithehum (and of the retina m intraocular infections) appears to be the result of direct viral cytopathogenicity. the cornea1 stromal pathology associated with this virus seems to be based upon immunological (hypersensitivity) mechanisms (70). Most investigators have favored a 2‘ cell-mediated pathogenesis (7 l), although immune complex disease has also been suggested (72’). CIORNEAL, TRANSPLANTATION The history of attempts to transplant cornea to restore sight is a long one (73). but it was only around the turn of this century that technical improvements in trephines and sutures permitted the ophthalmic surgeon to begin to realize consistent success in this venture, employing what we now call allogeneic tissue. When, as frequently happened, a graft would fail, it was usually attributed to some unknown physiological factor. Despite the fact that the immunologic “laws of transplantation” were well worked out by tumor transplanters early in this century (74), the information appears to have been unknown outside that field. It remained for Peter Medawar to clarify the immunologic basis of allograft rejection in his elegant series of studies in the 1940s (73, and these immediately caught the attention of transplant surgeons everywhere. It was Maumenee who was chiefly responsible for bringing these immunological hndings to the attention of ophthalmologists, and for bringing to the attention of the transplant immunologists the special characteristics of the cornea that allowed keratoplasty to succeed, while most other tissue and organ grafts failed (76). Again, the important mechanism responsible for the occasional graft rejection was shown to be the cellular immune response mediated by effector lymphocytes, and the high success rate of allokeratoplasty was shown to reside in an immunological privilege of the cornea, involvjng both the afferent and efferent limbs of the immune response. due to the avascularity and lack of lymphatic drainage in the cornea (77). This view is supported by the observation that increased vascularization of the graft predisposes to rejection; the privilege residing mainly in the absence of visiting lymphocytes. IMMUNOGENIC

UVEITIS

From the very outset, it had been demonstrated that the eye shares in the general hypersensitivity of the immunized or infected host (78) and that such sensitization can be induced also by intraocular administration of antigen. But it remained for Sattler (79) to show in 1909 that bland antigen introduced into the vitreous of the rabbit eye would cause in addition a local ocular hypersensitivity, an observation ex-

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tended by the elegant studies of Seegal and Seegal (80). Such a sensitized eye will respond for many months thereafter with an acute anterior uveitis when specific antigen is introduced intravenously or even by feeding. Here was a possible animal model of human recurrent nongranulomatous anterior uveitis that stimulated later workers to investigate its pathogenesis. Among the results of these studies was the finding that the tissues of the eye can support the local formation of antibody, much like a regional lymph node. This understanding emerged initially from studies of equine periodic ophthalmia, an ocular infection due to leptospira. It was shown by Goldmann and Witmer that so efficient is the eye in producing specific antibody that the high serum titers of antileptospiral antibodies found in these infected horses could have originated solely from local formation in that organ (8 1). It was suggested later that the inflammatory response accompanying intraocular antibody formation might be the primary pathogenetic contributor to recurrent anterior uveitis, due to the persistence of specific memory cells within the uveal tract of the sensitized eye (82). In line with developments in the general immunopathology of inflammation, it has been shown that lymphokines play an active role in the mediation of uveal inflammatory responses (83). Intraocular

Infections and the Focal Reaction

With the finding that systemic hypersensitivity accompanies tuberculosis (84) and many other infectious diseases, many investigators wondered whether such immunologic components might not contribute to the pathogenesis of such granulomatous diseases of the eye as tuberculosis, syphilis, toxoplasmosis, and others. This notion received support from the old observation that quiescent tubercles in the eye (and elsewhere) may be reactivated during attempts to desensitize tuberculosis patients with tuberculin, the so-calledfocal reaction (85). For many years, ophthalmologists searched for the trigger of attacks of uveitis (i.e., a source of inciting antigen) at distant sites of infection, including the teeth and appendix (86). The possible role of hypersensitivities in these infectious uveoretinopathies was first advanced by the foremost exponent of this thesis, Alan Woods (87). Anterior Chamber Privilege

The extensive studies of H. S. N. Greene on the transplantation of tumors and endocrine tissues into the anterior chamber of the eye (88) had implied that this site might enjoy a degree of immunological privilege, although this privilege appears not to be absolute (89). The basis of this phenomenon has been examined in detail in the immunology laboratories of Streilein and his collaborators, who suggest that an anterior chamber-associated immune deviation (ACAID) results from the induction of suppressor T cells when antigens are presented to the immune system by this route (90). This peculiarity of the anterior chamber has led to several curious experimental findings. In addition to the survival of otherwise immunogenic tumors in the anterior chamber (9 l), infection of the mouse eye with herpesvirus results in T cell-mediated prevention of ipsilateral retinal destruction, while destruction of the contralateral retina proceeds unchecked (92). Ocular Immunopathology

and Systemic Disease

Recent developments, especially in immunogenetics, have led to increasing collaboration between ophthalmologists and internists, endocrinologists, geneticists, and

immunologists. A significant group of systemic diseases known or suspected to involve immunopathogenetic mechanisms have been shown to manifest ocular complications. most usually uveitis or uveoretinitis. Among those with demonstrable genetic predispositions are: ankylosing spondylitis, associated with HLA-B27; Behget’s syndrome. associated with HLA-B5; and Vogt-Koyanagi-Harada’s disease, associated with HLA-, DRw54. Even sympathetic ophthalmia has been associated with HLA-DR4 and HLADRw53 among Japanese, although apparently not among Caucasians (93). Ocular complications in other systemic diseases where HLA association has not yet been demonstrated include lupus erythematosis, periarteritis nodosa, sarcoidosis, myasthenia gravis, and Grave’s disease. The presence in the vitreous of type II collagen has also excited the interest of rheumatologists seeking to explain the ocular involvement in this group of diseases. The clinical and pathogenetic factors involved in the ocular components of these systemic diseases are reviewed in detail by Faure and col leagues (94). ALLERGlC

CONJUNCTIVlTlS

We have already seen that the conjunctiva may become inflamed by instillation of tuberculin in the sensitized individual. With the finding that hayfever and asthma are also immunologic (“anaphylactic”) reactions, it became apparent that immunogenic conjunctivitis was a more general phenomenon, and ophthalmic clinicians became more interested in its pathogenesis and treatment (95). This stimulated research on the possible immunopathogenesis of such diseasesas vernal catarrh, a seasonal papillary conjunctivitis most often associated with pollen allergy (96). Perhaps the most interesting development along these lines was the suggestion that a chronic immune response to the antigens of Chlamydia trachomatis might account for the primary lesions seen in trachoma (97) and in other follicular conjunctivitides. Trachoma is characterized by the exuberant development of germinal centers beneath the conjunctival epithelium, leading Barrie Jones to liken the conjunctival sac to a lymph node cut open. where antigenic stimuli enter through an overlying epithelium (98). Recent studies have implicated the chlamydial heat-shock protein as the stimulus for conjunctival delayed-type hypersensitivity responses in this disease (99)

Due to the widespread use of ophthalmic medications, and especially of cosmetics. contact allergy has become an increasingly important problem in industrialized societies. While the conjunctiva may be involved in the process, it is more often as a secondary complication of an allergic reaction of the skin of the eyelids. The mechanisms involved, and the many agents that may elicit this disease, are reviewed in detail by Theodore and Schlossman (100). 1NSTITUTIONALIZATlON

OF THE DISCIPLINE

It is always difficult to assign an exact date to the formal establishment of a scientific discipline. In the case of ocular immunology/immunopathology: the components of a specific research program (involving sympathetic ophthalmia, lens-induced disease. anaphylactic keratitis and conjunctivitis. etc.) had already been identified by 1912. and an interacting community of clinical and laboratory researchers had formed. The first special monograph devoted to ocular immunopathology appeared in 19 14 ( 10 1)

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and other texts and monographs followed (102). Departments of ophthalmology throughout the world added immunological research laboratories to their facilities ( 103). These ocular immunology units soon began to hire basic science faculty members, a trend that accelerated after the Second World War with the expansion of interest in all biomedical specialties (104). The establishment of the National Eye Institute at the U.S. National Institutes of Health in Bethesda, Maryland in 1968 testifies to the growing scientific and political strength of ophthalmic and vision research, from the fruits of which research in ocular immunology also benefited immeasurably. One of the hallmarks of disciplinary institutionalization is the development of first informal and then formal networks of individuals with common scientific interests. In the mid- 1940s ophthalmologists Phillips Thygeson, James Allen, and Fred Theodore organized an informal group to discuss epidemic keratitis and other problems in ocular microbiology. Immunological discussions quickly entered, and in 1966 Thygeson formalized the meeting at the Proctor Foundation in San Francisco as the Ocular Immunology and Microbiology Group. This group served as the model for the Section on Ocular Immunology and Microbiology, when the Association for Research in Vision and Ophthalmology (ARVO) was reorganized into disciplinary sections in 1968 (105). Both the Group and the ARVO Section continue to meet annually, and the latter has grown from a few dozen persons at the start to a current membership of over 400. Whereas the earlier investigators were almost all clinicians with a bent for research, more than 50% of the current members are basic scientists with formal training in such fields as immunology, molecular biology, bacteriology, and virology. Another prerequisite for the formation of a new discipline is the definition of its scope. A significant step in this direction was the organization in the late 1950s of a series of Macy Foundation meetings by Alan Woods and A. E. Maumenee. Prominent basic immunologists were invited to interact with clinicians in highly productive exchanges (106). A similar set of meetings, involving ophthalmic scientists and a broad spectrum of basic immunologists, was assembled in a series of workshops sponsored by the National Eye Institute (107). Immunology had been identified by the Eye Institute as one of the principal research areas for future exploitation, and these meetings were designed to define the current status of the field and to identify new and fruitful approaches. Perhaps the most significant organizational development in this field was the founding in 1974 of a series of quadrennial International Symposia on the Immunology and Immunopathology of the Eye by W. Bake of Germany, R. Campinchi and E. Bloch-Michel of France, and M. Luntz of South Africa. Five such symposia have been held, whose sessions and resulting publications (108) have consolidated this specialized community of scientists, recorded the progress in the field, and stimulated new interest and activity by promoting the exchange of information with other scientific disciplines. CONCLUSIONS In the first 20 years of its existence (after 1880), most of the exciting reports emanating from immunological laboratories concerned the prevention, diagnosis, or cure of injktious diseases. While these advances attracted worldwide attention, they were translated into laboratory and clinical activity only by those interested in infection. Indeed, those who founded the discipline of immunology (e.g., Pasteur, Koch, Roux, Behring, Pfeiffer, and Wassermann) were primarily bacteriologists. Even the zoologist Metch-

nikoff, when he advanced his phagocytic theory of immunity, did so in the context of the pathology of infection. But very rapidly, immune reactions were generalized far beyond the response to pathogenic organisms. Paul Ehrlich’s side-chain theory of antibody formation (I 897) linked the “receptors” of the immune response to the physiological functions of nu trition and drug action, and attracted the attention of academics in many branches of medicine. The findings in the late 1890s that an immune response could be engendered against bland proteins and even against bodily tissues and organs further reinforced this generalization. Finally, the observations that the immune response might UZUSEdisease (autoimmune paroxysmal cold hemoglobinuria, anaphylactic shock. hay fever, asthma, etc.) offered to medical specialists of all types a possible explanation for the pathogenesis of their least well-understood diseases. Perhaps in no other medical specialty did these immunological findings strike a more responsive chord than in ophthalmology, and in no other did they stimulate activity for so long. Clinical ophthalmologists rapidly seized upon these immunological concepts and utilized them to explain the pathogenesis of such diseases as uveitis. keratitis, and sympathetic ophthalmia. They adapted also the experimental approaches of the immunologists to test their theories in laboratory animals. Each new advance by the immunologists was immediately translated into ophthalmic terms and ocular experiments. Thus, by the end of the first decade of this century it may be said that a new subdiscipline, ocular immunology/immunopathology, had been born, based entirely upon the content of the immunological research program. Even when immunologists lost interest in disease problems during the Era of Immunochemistry (from about the First World War to the late 1950s) the ophthalmologists, almost alone among medical specialties, persisted in their application of immunology to ophthalmic problems.. Then, with the advent of the immunobiomedical revolution of the 1960s ophthalmology reinforced its collaboration with immunology. and ocular immunology expanded its activities, joined now by many other medical specialties. The many inter-, disciplinary interactions of immunology with other fields led to a profusion of new disciplines and subdisciplines., in which the prefix immuntr or the suffix -immunology defines these interactions. NOTES AND REFERENCES I. See. for example. Shapere, D., Iri “Reason and the Search for Knowledge” (D. Shapere, Ed.). R&et. Dordrecht, 1984; Lemaine. G.. Macleod, R.. Mulkay. M.. and Weingard, P.. Eds., “Perspectives on the Emergence of Scientific Disciplines.” Aldine. Chicago, 1976: Darden, L., and Maull, N.. P/zi(o$ Sci. 45, 43. 1979: and Hull. D.. Phibs Sri. 45. 335. 1978. See also Rosen. G.. “The Specialization of Medicine. with Particular Reference to Ophthalmology” (Thesis, Columbia IJniversity), Froben. New York. 1944. 2. A major transition in immunology, tiom an mterest in biomedical problems (infectious diseases and the general pathology of inflammation) to chemical approaches, occurre~I about the time of the First World War. The reasons for and implications of this gestalt shift are discussed in Silverstein, A. M.. C’eU.Immunol. 132, 5 15. 199 I. See also Moulin. A.-M.. “Le Dernier Langage de la Medicine: Im. munologie de Pasteur au SIDA,” Paris, 1991. in press. 3. W. Bake. “Immunpathologie des Auges.‘~ Karger. Basel, 196X; Rahi. A. H. S., and tiarner. A.. -‘lm.munopathology of the Eye,” Blackwell. Oxford, 1976; Fame, J.-P., Bloch-Michel, E.. IR Hoang, P and Vadot, E.. “Immunopathologie de I’Oeil.” Masson, Paris. 1988. 4. Pasteur. I-... C’ R. .4d. Sci 90, 239, 952, 1880. 5. von Behring. E., and Kitasato. S.. /Xsch Med. U’&mschr. 16, 11 13. 1890; von Behring. E.. and Wernicke. E.. %. If.vg. 12, IO. 45. IPU2. 6. Hirschberg, J., “Geschichte der Augenheilkunde,” Cc;.Ohm, Hildesheim, 1977. English version, The History of Ophthalmology’” (F. C. Blodi, transl.). Wayenborgh, Bonn. 1982-.

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‘7. The six principal components of the early immunological research program are discussed by Silverstein, note 2. These were: preventive immunization, cellular (phagocytic) immunity, serotherapy, cytotoxic antibodies, serodiagnosis, and anaphylaxis and related phenomena. 8. Metchnikoff, E., “L’Immunite dam les Maladies Infectieuses,” Masson, Paris, 1901. 9. Ehrlich, P., Klin. Jahrb. 6,299, 1897; Proc. R. Sot. London B 66, 424, 1900. 10. Bordet, J., Ann. Inst. Pasteur 12, 688, 1899. 11. See, e.g., Ann. Inst. Pasteur 14, 1900. 12. Ehrlich, P., and Morgenroth, J., Berl. klin. Wochenschr. 28, 25 1, 1901. 13. Ehrlich, P., Verh. 73 Ges. Dtsch. Naturjorsch. Aerzte, 190 1. Reprinted In “The Collected Papers of Paul Ehrlich,” Vol. 2, p. 298. Pergamon, New York, 1957. 14. Metalnikoff, S., Ann. Inst. Pasteur 14, 577, 1900. 15. Donath, J., and Landsteiner, K., Munch. med. Wochenschr. 51, 1590, 1904. 16. The background to this hiatus is discussed in Silverstein, A. M., “A History of Immunology,” pp. 160189. Academic Press, New York, 1989. 17. Portier, P., and Richet, C., C. R. Sot. Biol. 54, 170, 1902. 18. At-thus, M., C. R. Sot. Biol. 55, 817, 1903. 19. von Pirquet, C., and Schick, B., “Die Serumkrankheit,” Deuticke, Vienna, 1906. 20. Wolff-Eisner, A., “Das Heufieber,” Munich, 1906; S. Meltzer, J. Am. Med. Assoc. 55, 1021, 1910. 2 1. Santucci, S., Riv. Ital. Ottal. Roma 2, 2 13, 1906. A similar suggestion was made for the pathogenesis of syphilis, involving the participation of “autoantibodies” directed against the tissue breakdown products associated with this disease, Weil, E., and Braun, H., Wien. klin. Wochenschr. 20, 527, 1907; 22,372, 1909. 22. Golowin, S., Klin. Monatsbl. Augenheilk. 47, 150, 1909. 23. Golowin, S., Russky Vratch, No. 22, May 29, 1904. 24. Elschnig, A., von Graefes Arch. Ophthalmol. 75, 459, 1910; 76, 509, 1910; 78, 549, 1911; 79, 428, 1911. 25. Woods, A. C., Arch. Ophthalmol. 45, 557, 1916; 46, 8, 503, 1917; 47, 161, 1918. 26. Woods, A. C., Trans. Ophth. Sot. U. K. 45 (part 1), 208, 1925. 27. Friedenwald, J. S., Am. J. Ophthalmol. 17, 1008, 1934. 28. Woods, A. C., “Allergy and Immunity in Ophthalmology,” pp. 76-77. Johns Hopkins Press, Baltimore, 1933. 29. Freund, J., and McDermott, K., Proc. Sot. Exp. Biol. Med. 49, 548, 1942. 30. Collins, R. C., Am. J. Ophthalmol. 32, 1687, 1949; 36, 150, 1953. 31. Wacker, W. B., and Lipton, M. M., Nature 206, 253, 1965; J. Immunol. 101, 151, 1968. 32. Kalsow, C. M., and Wacker, W. B., Int. Arch. Allergy Appl. Immunol. 44, 11, 1973; 48,287, 1975. 33. Wacker, W. B., Donoso, L. A., KaIsow, C. M., Yankeelov, J. A., and Organisciak, D. T., J. Immunol. 119, 1949, 1977; Dorey, C., and Faure, J.-P., Ann. Immunol. (Inst. Pasteur) 128, 229, 1977. 34. Gery, I., Mochizuki, M., and Nussenblatt, R. B., Prog. Retinal Res. 5, 75, 1986. 35. Marak, G. E., Shichi, H., Rao, N. A., and Wacker, W. B., Ophthalmic Res. 12, 165, 1980; MeyersElliot, R. H., Gammon, R. A., Somner, H. L., and Shimizu, I., Clin. Immunol. Immunopathol. 27, 81, 1983. 36. Rao, N. A., Wacker, W. B., and Marak, G. E., Arch. Ophthalmol. 97, 1954, 1979. 37. Kalsow, C. M., and Wacker, W. B., Invest. Ophthalmol. Vis. Sci. 17, 774, 1978; Broekhuyse, R. M., Winkens, H. J., and Kuhlmann, E. D., Curr. Eye Res. 5,23 1, 1986; Gery, I., Wiggert, B., Redmond, T. M., Kuwabara, T., Crawford, M. A., Vistica, B. P., and Chader, G. J., Invest. Ophthalmol. Vis. Sci. 27, 1296, 1986. 38. The most recent comprehensive review of progress in this field may be found in “Immunopathologie de I’Oeil,” note 3, pp. 241-281. 39. Uhlenhuth, P., In “Festschrift zum 60 Geburtstag von Robert Koch,” pp. 49-74. Fischer, Jena, 1903. 40. Kraus, R., Doerr, R., and Sohma, M., Wien. klin. Wochenschr. 21, 1084, 1908. 4 1. Andrejew, P., and Uhlenhuth, P., Arb. Kaiser/. Gesundheitsamte 30, 450, 1908. 42. Uhlenhuth, P., and Haendel, Z. Immunitiitsforsch. 4, 761, 1910. 43. Romer, P., and Gebb, H., von Graefes Arch. Ophthalmol. 60, 175, 1905. 44. Krusius, F. F., Arch. Augenheilk. 67, 6, 1910. 45. Romer, P., and Gebb, H., von Graefes Arch. Ophthalmol. 81, 367, 387, 1912. 46. It will be recalled that Paul Ehrlich did not mean by Horror Autotoxicus that autoantibodies could not be formed under any circumstances. Rather, he suggested that some type of immunoregulatory mechanism prevented them from causing disease. The consequences of the misinterpretation of

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47. 4X. 4Y.

50.

5I 52.

S3. 54. 55. 56. 57.

ARTHliR

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