Chapter 34
Immunology of Allergic and Multisystem Diseases That Affect the Eye
MITCHELL H. FRIEDLAENDER
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HAY FEVER
DRUG ALLERGY
SERUM SICKNESS
SARCOIDOSIS
BEHÇET'S DISEASE
VOGT-KOYANAGI-HARADA SYNDROME
INFLAMMATORY BOWEL DISEASE
REFERENCES

Immunologic mechanisms are believed to play a major role in the pathogenesis of a wide variety of systemic diseases for which the etiology is uncertain. A host's abnormal immune response to a single disease may be manifest in different organ systems. Because of certain anatomic, physiologic, and antigenic factors, the eye may be incidentally or preferentially affected in many of these systemic diseases that we have come to regard as “immunologic.” This chapter deals with the ocular manifestations of several such diseases and with the possible mechanisms of their pathogenesis.
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HAY FEVER
Hay fever and its ocular manifestation, hay fever conjunctivitis, are allergies to common airborne substances. The pollen of trees, grasses, and weeds and house dust, animal danders, molds, industrial chemicals, and rarely certain foods are responsible for these recurrent and often seasonal allergies. These reactions are a manifestation of type I hypersensitivity and are mediated by immunoglobulin E (IgE). The mucous membranes—nasal or conjunctiva, or both—are affected. Hay fever conjunctivitis is characterized by injection, chemosis, itching, and watery discharge. Conjunctival scrapings contain eosinophils.

IMMUNOPATHOLOGY

Hay fever (allergic rhinitis) is an immediate hypersensitivity reaction to the environmental allergens mentioned previously, most of which are chemically complex substances derived from plants and animals (Table 1). Allergens vary from one geographic area to another, and it is important for the clinician to know which ones are common in his region of the country and the time of year that various trees, grasses, and weeds pollinate. Although the related symptoms may occur year-round, they tend to have seasonal peaks of severity. In many parts of the country, ragweed pollen is the most common and most troublesome allergen, particularly between July and mid-October when the plant is pollinating. Air-sampling devices for identifying and quantitating a currently prevalent pollen are available.

 

Table 1. Allergens That Cause Asthma and Rhinitis

Pollens
  Ragweed, timothy grass, orchard grass, sweet vernal grass, redtopgrass, rye grass, Bermuda grass, elm, oak, birch, maple, poplar,ash, alder, hazel, cedar, cypress, juniper
Molds
  Alternaria, Hormodendrum, Aspergillus, Penicillium, Mucor,Candida, Fusarium, smuts
Indoor allergens
  Dust mites, cat, dog, horse, rabbit, mouse, rat, cattle, guinea pig,gerbil, hamster, feathers, wool, cottonseed, kapokseed
Insects
  Caddis fly, Hymenoptera emanations
Industrial organic dusts
  Green coffee dust, wood dusts, tannic acid, castor bean,cottonseed, flours, grain dust, enzyme detergents, hog trypsin,psyllium powder
Industrial chemicals
  Platinum salts, nickel salts, phenylmercuric compounds, toluenediisocyanate, paraphenylenediamine, piperazine, penicillin
Foods
  Most commonly fish, shellfish, nuts


(Freedman SO, Gold P: Clinical Immunology. Hagerstown, Harper & Row, 1976.)

 

The allergen comes into direct contact with the nasal mucosa or conjunctiva and induces a type I hypersensitivity reaction. It interacts with IgE bound to tissue mast cells and leads to the release of preformed mediators, such as histamine, and synthesized mediators, such as leukotrienes and prostaglandins. These mediators affect blood vessels, smooth muscle, and secretory glands, which in turn are responsible for the clinical manifestations of allergy. The combination of an allergen with a mast cell–bound molecule causes a change in the Fc portion of the molecule attached to the cell membrane. This in turn activates a serine esterase enzyme and initiates a chain of intracellular biochemical events that lead to the physiologic release of mediators. The release of the mediators is inhibited by the elevation of intracellular cyclic adenosine monophosphate (cAMP), the levels of which can be increased by beta-adrenergic stimulation, prostaglandins, and histamine. The release of histamine and other mediators is facilitated by cholinergic stimulation.

The mast cell is structurally and functionally heterogeneous. Different populations of cells may respond differently to physiologic, immunologic and pathologic stimuli. Two main types of mast cells have been identified in ocular allergic disease based on the relative amounts of two neutral proteases in their cytoplasmic granules.1,2 Tryptase-containing (T) mast cells and tryptase/chymase-containing (TC) mast cells) have both been identified in the conjunctiva. In severe allergic conjunctivitis, such as vernal conjunctivitis, both T and TC mast cells increase in numbers and are found throughout the conjunctival stroma and epithelium.3 Most of the mast cells, however, appear to be TC mast cells. Mast cell granules are membrane-bound and contain relatively large amounts of mediators, including histamine, heparin, and tumor necrosis factor alpha (TNF-alpha). They also contain superoxide dismutase, peroxidase, and numerous acid hydrolases, which may act to degrade extracellular matrix.

Inflammatory mediators are secreted by activated cells and serve to trigger or enhance specific aspects of inflammation. Such compounds are said to be pro-inflammatory, meaning that they promote inflammation. Mediators can be arbitrarily divided into four types: (1) those with vasoactive and smooth muscle contracting properties, (2) chemotactic factors, which attract other cells, (3) enzymes, and (4) proteoglycans.4 Vasoactive and smooth muscle-constricting mediators are prominent in ocular allergy. Histamine is a preformed mediator, and a major mediator of allergic inflammation. It exerts its effect by acting on target cell receptors, known as H1, H2, and H3. H1-related effects are most important in allergies because they mediate bronchiolar smooth muscle contraction and increased vascular permeability. Arachidonic acid metabolites include prostaglandins, leukotrienes, thromboxanes and lipoxins. These chemicals have a variety of effects, but generally promote increased vascular permeability and smooth muscle constriction. Platelet activating factor (PAF) and adenosine have similar effects.

Chemotactic factors attract various kinds of cells to the inflammatory reaction. Over 35 of these factors have been identified. Enzymatic mediators, including tryptase and chymase, are released during mast cell degranulation. They may have an effect on host tissues or interact with the complement and clotting systems. Mast cells are rich in proteoglycans, protein-polysaccharide complexes that form much of the structural matrix of the granules and serve as binding sites for heparin and other mediators.

Eosinophils are a hallmark of the allergic reaction. While their exact role remains unknown, they have a number of observed actions which are presumed to be important in the allergic response.55 They may limit the allergic response through the secretion of histaminase, which inactivates histamine, and aryl sulfatase, which inactivates certain leukotrienes. They also contain a number of toxic substances that may contribute to the pathology and morbidity of the allergic reaction. Pro-inflammatory mediators derived from eosinophils include major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neuroprotein (EDN), and Charcot-Leyden crystal (CLC) protein.

Although everyone in a particular environment may be exposed to the same allergens, only atopic subjects develop clinical allergy. The reasons for individual variations in the response to allergens are not entirely clear. It has been suggested that in allergic subjects the nasal mucosa may be more permeable to allergens than in normal subjects, probably because of local edema, vasodilatation, and epithelial hyperplasia.6 In children, there is a striking association between IgA deficiency and allergic disease, possibly because the absence of IgA at the mucosal surface reduces the opsonization and phagocytosis of the allergens.7 These allergens can then stimulate IgG-producing lymphoid tissues.8 There is evidence that genetic factors also play a role in allergic sensitization.9 For example, there is an association between human leukocyte antigen B7 (HLA-B7) and the IgE response to ragweed antigen Ra5; immune-response genes govern antigen recognition at the T-cell level and may account for impaired IgA production. Absence of local defense mechanisms can increase the penetration of allergenic substances and trigger the overproduction that is probably due to excessive T-helper cell activity and a reduced T-suppressor-cell population.10,11

Locally synthesized IgE concentrates on mast cells and basophils in numbers ranging from 10,000 to 40,000. The percentage of occupied receptors per cell is higher in the allergic than in nonallergic individuals. The interaction of antigen and cell-bound IgE results in the release of histamine, eosinophil chemotactic factor A (ECF-A), leukotrienes, and PAF. These mediators, which affect local blood vessels and smooth muscle, lead to the typical signs of allergic rhinitis and conjunctivitis.

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DRUG ALLERGY
Drug reactions are too common in medical practice and specifically in ophthalmology. When drugs are used topically, it is often difficult to distinguish between their toxic and allergic side effects. Drug allergy may be caused by any one of four hypersensitivity mechanisms, but type IV (delayed) hypersensitivity reactions are the most common.

IMMUNOPATHOLOGY

Type I (anaphylactic) hypersensitivity reactions are the most serious and are potentially fatal. They occur within moments after the administration of a drug and are mediated by IgE. The typical clinical manifestations are urticaria and morbilliform eruptions that affect the skin, including the skin of the lids. Other manifestations are hypotension, shock, asthma, and laryngeal edema. Anaphylactic reactions may occur in response to such antibiotics as penicillin and streptomycin. (Penicillin also can cause adverse side effects as a result of types II, III, and IV hypersensitivity reactions.)

Type II (cytotoxic) hypersensitivity occurs when antibody reacts with antigen attached to a target cell. These reactions are complement dependent. Usually a complex that contains drug, antibody, and complement becomes fixed to the cell membrane, and this leads to lysis of target cells (leukocytes or platelets). Type II reactions can be induced by penicillin, methyldopa, sulfonamides, quinidine, or incompatible blood transfusions.

Type III (immune-complex) hypersensitivity drug reactions may lead to urticaria, serum sickness, or a multisystem, complement-dependent vasculitis. Immune complexes are deposited within tissues, especially blood vessels, and the complement pathways are activated, resulting in local inflammatory foci. Bilateral iritis has been described in a patient who developed serum sickness after a series of injections of antipneumococcal horse serum for pneumonia, and a similar type of uveitis has been produced experimentally in the rabbit.12

Type IV (delayed) hypersensitivity drug reactions are commonly encountered as contact allergies to topical medications. In ophthalmology, allergies of this type often are reactions to topical antibiotics, anesthetics, dilating agents, and certain drug preservatives.

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SERUM SICKNESS
Serum sickness is a type III hypersensitivity reaction in which immune complexes are deposited in various tissues. It usually follows the injection of heterologous proteins.13 Antitoxins, such as those prepared for the treatment of diphtheria, rabies, snake venom, and clostridial infections, may produce this type of reaction, and certain drugs, such as penicillin and the sulfonamides, also have been implicated. The signs and symptoms appear 1 or 2 weeks after the injection of a foreign protein and include arthritis, fever, urticaria, lymphadenopathy, splenomegaly, occasionally glomerulonephritis and laryngeal edema, and a number of ocular lesions.12,14 Immune complexes are thought to be deposited in the uveal tract (as in the kidney and synovial membranes), where they fix complement and attract inflammatory cells. Bilateral anterior chamber and keratic precipitates may be seen. Serum sickness iritis has been reported after an injection of antipneumococcal horse serum (for pneumococcal pneumonia) or an injection of tetanus antiserum.

Laboratory studies demonstrate an elevated sedimentation rate, leukocytosis, hematuria, proteinuria, and low levels of serum complement. The disease is usually self-limited and free of complications. Urticaria can be treated with epinephrine and antihistamines. Arthritis usually responds well to salicylates. If the patient is severely ill, a short course of systemic corticosteroids can be given. Uveitis responds well to topical corticosteroids and dilating drops. A patient described by Theodore and Lewson developed bilateral iritis in association with generalized serum sickness on two occasions, 9 days and 30 days after a series of inoculations with antipneumococcal horse serum for pneumonia.12 Wong produced in a rabbit experimental uveitis similar to the uveitis described in serum sickness.15

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SARCOIDOSIS
Sarcoidosis is a multisystem disease of unknown cause but with a number of immunologic defects. It can affect almost any organ, but the principal targets are the lungs and lymph nodes. Ocular lesions—most commonly iridocyclitis, but also eyelid and conjunctival nodules, keratitis, and retinal, optic nerve, and orbital lesions—occur in approximately 26% of cases (Figs. 1, 2, 3, 4, and 5). An ocular syndrome with the characteristics of sarcoidosis but lacking systemic disease also has been seen.

Fig. 1. Skin nodules of eyelid in sarcoidosis. (Courtesy of F.I. Proctor Foundation.)

Fig. 2. Conjunctival involvement in sarcoidosis. (Courtesy of F.I. Proctor Foundation.)

Fig. 3. Granuloma of iris in sarcoidosis. (Courtesy of Dr. R. Weinberg.)

Fig. 4. Candle wax exudates in sarcoidosis. (Courtesy of Dr. R. Weinberg.)

Fig. 5. Conjunctival biopsy in sarcoidosis showing granuloma formation. (Courtesy of Dr. R.Weinberg.)

IMMUNOPATHOLOGY

Although a number of agents, includingmycobacteria, pine pollen, organic dusts, beryllium, fungi, and viruses, have been linked with sarcoidosis, its cause remains unknown. It is often classified as an immunologic disorder because of the characteristic alterations in cell-mediated immunity associated with it.16–18 It still is not known, however, whether sarcoidosis is the result of an immunologic disturbance or whether the immunologic disturbances are secondary to widespread lymph node inflammation from another cause or causes. A slow virus remains an etiologic possibility, but viral isolation attempts have been unsuccessful.19 Recently a transmissible agent, possibly mycobacterial or viral, that was isolated from human sarcoid tissue homogenates has produced epithelioid and giant cell granulomas in the footpads of mice. The ability to produce granulomas is destroyed when the homogenates are autoclaved.

Immunologic features of sarcoidosis include (1) accumulation of T cells and monocyte-macrophage populations, (2) activated CD4 T cells, (3) polyclonal gammopathy, and (4) depressed cellular immunity. Activated CD4 T cells spontaneously release interferon gamma, interleukin-2, and other cytokines producing a large number of T cells through chemotaxis and mitogenesis at the site of disease.20

There are three types of immunologic abnormalities in sarcoidosis: (1) depression of delayed hypersensitivity, (2) lymphoproliferation with increased serum gamma globulins, and (3) granulomatous reactions. Depression of delayed hypersensitivity is a well-known feature of sarcoidosis. The reactivity of the skin to a variety of antigens—mumps, tuberculin, DNCB, pertussis, and KLH—is depressed or absent.16 This suggests a T-lymphocyte—mediated anergy and impaired cellular immunity. The tuberculin skin test is negative in two thirds of patients with sarcoidosis (although it may become positive when the disease resolves), and most patients cannot be sensitized to either DNCB or KLH.16 Whether this impaired delayed hypersensitivity in sarcoidosis is due to an abnormality of circulating T lymphocytes or to circulating serum inhibitors is still unknown.

Most in vitro studies of sarcoidosis show depressed T-cell function and overactive B-cell function.16,21 When the lymph nodes are affected, the circulation of T lymphocytes may be impaired, and this may contribute to the lowering of the T-cell counts.22 Lymphocytes from patients with sarcoidosis respond less actively to the mitogen phytohemagglutinin than do the lymphocytes of other subjects, but during remission this response is re stored.23 The lymphocytes also show a greater spontaneous blastogenic response in vitro, especially after they have been cultivated for 5 to 7 days. This phenomenon is associated with the release of lymphokines, and recently serum migration inhibition factor (MIF) was detected in affected patients. As a result, attempts have been made to establish an in vitro test for sarcoidosis based on MIF production.24 However, although inhibition takes place when sarcoid spleen is used as an antigen, the lymphocytes of some of the controls also are positive. The results of other attempts to produce MIF with Kveim antigens and lymphocytes from sarcoid patients also have been mixed, and the fact that lymphocytes from patients with Hodgkin's disease and tuberculosis also respond positively may limit the usefulness of MIF production as a test for sarcoidosis.

In contrast to the depressed cellular immunity in sarcoidosis, antibody production is overly active. During active disease the levels of IgG, IgA, and IgM are elevated. As soon as there is clinical improvement, the levels of IgG and IgM drop back to normal, but the IgA level usually remains elevated. High levels of circulating antibody to Epstein-Barr virus and the viruses of herpes simplex, rubella, measles, and parainfluenza have been reported.25,26

False-positive results in other serologic tests and abnormally severe antibody reactions to mismatched blood also have been described.27 Serum IgD levels are either normal or elevated (although in middle-aged patients they may be depressed), and serum IgE levels are significantly elevated.28,30 Elevated immunoglobulin levels are the rule in the bronchial secretions of sarcoidosis patients but also have been noted in various other diseases. There is no evidence that patients with sarcoidosis have any particular HLA type.

Immune complexes and increased complement activity have been detected in the sera of patients with sarcoidosis. Some of the patients with immune complexes in their sera had erythema nodosum, and one had acute iritis.31–33

Circulating immune complexes are considered responsible for some of the clinical symptoms of sarcoidosis. They may attach nonspecifically to lymphocytes by means of their Fc receptors and lead to inaccurate quantitation of T and B cells. Lymphocytes bearing complement receptors (B cells) are increased in sarcoid patients, but the frequency of autoantibodies seems to be the same as in the general population.

The Kveim test for sarcoidosis is positive in 80% of patients and in only 2% of controls. The test is performed by injecting intradermally an extract of human spleen from a patient with active sarcoidosis. The site is watched for 6 weeks for the development of a nodule. If one appears, a biopsy is examined for a sarcoid granuloma. The disadvantages of the Kveim test should be borne in mind. In atypical cases, for example, in which a specific test would be particularly useful, the Kveim reaction may be negative. The Kveim antigen is not readily available, moreover, and some authors feel that the test is so complicated and difficult to perform that it is impractical for diagnostic purposes.16

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BEHÇET'S DISEASE
Behçet's disease is a chronic inflammatory disease with widespread clinical manifestations. It affects adults of both sexes, especially in Mediterranean countries and Japan. Classically it consists of a triad of recurrent lesions: iritis, oral ulcers, and genital ulcers (Fig. 6).34 Other common features are vasculitis, skin lesions, optic papillitis (Fig. 7), arthritis, meningomyelitis, and inflammatory bowel disease. Loss of vision is one of its most frequent and serious manifestations. In Japan, the disease is said to be responsible for one-third of all cases of uveitis. Ocular disease occurs in 75% of affected patients, usually in the form of hypopyon, uveitis, occlusive retinal vasculitis, and optic nerve lesions. The cause of Behçet's disease is unknown, but viral, immunologic, and hereditary factors have been suspected.

Fig. 6. Hypopyon iritis in Behçet's disease. (Courtesy of Dr. K. Yamaguchi.)

Fig. 7. Optic papillitis in Behçet's disease. (Courtesy of Dr. G. Mintsioulis.)

IMMUNOPATHOLOGY

Behçet described inclusion bodies in the smears of ulcer exudates from patients with the disease and was the first to suggest that it was caused by a virus.34 Others claim to have isolated a virus from the blood of patients with aphthae and to have produced the disease in mice and rabbits by inoculation.35,36 In addition to isolating a virus, Evans and co-workers found neutralizing antibodies in the sera of affected patients.37 Because the validity of these various observations has been questioned by some investigators, however, and because recent attempts to isolate a virus from body fluids have been unsuccessful, it still is not known whether a virus is involved in the etiology of this predominantly Mediterranean disease.38,39

The role of autoimmune mechanisms in the pathogenesis of Behçet's disease also has been investigated.40,41 Serum globulin, especially the alpha-2 fraction, is elevated, and autoantibodies to oral mucosa have been detected.40,42–44 However, some authors believe that these antibodies are the result of nonspecific destruction of the mucosa, especially because there is no correlation between antibody titer and the activity of the disease.45 The same antibodies, moreover, have been found with the same frequency in patients suffering from aphthous stomatitis.46 It has been suggested that the characteristic skin hyperreactivity seen in Behçet's disease is an Arthus reaction; no local immunoglobulin or complement deposits have been found, however, and this suggests that local humoral factors may not be relevant.40,47

Elevated levels of total hemolytic-complement activity and a marked increase in C9 levels have been reported in Behçet's disease, but their pathogenetic significance is still unclear. Normal C3 levels also have been reported.45,48,49

Cell-mediated immune mechanisms have been studied in patients with Behçet's disease. Lymphocyte transformation to mucosal antigens occurs, and the lymphocytes produce cytotoxic effects on the oral mucosa.50–52 Delayed hypersensitivity reactions to skin homogenates have been observed, and the skin reactions are characterized histologically by intense lymphocytic infiltration.53 None of these findings proves a cellular immune etiology for Behçet's disease, however. Lymphocytic sensitization after tissue injury may explain some of these reactions, and lymphocytic skin reactions can certainly be caused by such nonimmunologic factors as trauma. Cell-mediated immunity has been correlated with the activity of Behçet's disease, and a possible impairment of the regulatory mechanisms that control T-cell proliferation has been suggested.45,54

Abnormally large numbers of mast cells have been reported in the cellular infiltrates of the recurrent ulcers and in the skin lesions of Behçet's disease.45,55 Because the numbers of mast cells are usually reduced in nonspecific ulcers of the mouth, they may conceivably play a role in the skin and mucosal lesions of Behçet's disease.

A number of patients with Behçet's disease have reported exacerbations of their symptoms after the ingestion of certain foods, especially walnuts, chocolate, and tomatoes. When extracts of English walnuts were cultured with the lymphocytes of normal patients and of those with Behçet's disease, the incorporation of tritiated thymidine in the DNA of the lymphocytes was increased.56 Within 2 days of the ingestion of walnuts by these two groups of patients, their in vitro lymphocyte reactivity to walnut extract and to Candida antigens was significantly reduced. This depression lasted longer in the lymphocytes from the patients with Behçet's disease than in those from the normal subjects. The mitogenic effect and the subsequent depressive effect of English walnuts in patients with Behçet's disease, although nonspecific, may affect the course of the disease adversely.

A greater than normal prevalence of HLA-B5 and antigen 4c has been found in Japanese patients with Behçet's disease.57 Antigen 4c is known to be closely related to HLA-B5, HLA-BW35, and HLA-B18. Other studies have shown no significantly greater prevalence of any HLA antigen.58 A report of Behçet's disease found in four generations of one family has strengthened the view that susceptibility to the disease is genetically transmitted.59 Behçet's disease is strongly associated with HLA-B51.60 Microbial infection induced stress may up-regulate certain gene products, which in turn stimulate gamma delta and alpha beta T-cell receptor-positive cells to generate effector and suppressor T cells. These activated T cells, antibodies and neutrophils induce cytokines to modulate the immune response. The end result of these complex cellular and cytokine immune interactions in HLA-B51 or genetically related subjects is to induce pathologic changes consistent with Behçet's disease.

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VOGT-KOYANAGI-HARADA SYNDROME
The Vogt-Koyanagi-Harada syndrome (VKHS) is a chronic, bilateral, exudative uveitis associated with whitening of the hair and eyelashes (Fig. 8), vitiligo, and meningeal irritation. It is a combination of two overlapping disease entities. VKHS is a severe anterior-segment inflammation associated with dysacousia, vitiligo, alopecia, and poliosis. Harada's disease is limited largely to posterior uveal inflammation with serous retinal detachments, disc involvement, meningeal inflammation, and sometimes skin and hair changes (Figs. 9 and 10). Because the symptoms of the two diseases overlap significantly and their histopathologic features are similar, the two are now regarded as a single disease entity.

Fig. 8. Poliosis in Vogt-Koyanagi-Harada syndrome. (Courtesy of F.I. Proctor Foundation.)

Fig. 9. Optic nerve involvement in Vogt-Koyanagi-Harada syndrome. (Courtesy of Dr. R. Weinberg.)

Fig. 10. Posterior involvement in Vogt-Koyanagi-Harada syndrome with pigmentary changes and scarring. (Courtesy of Dr. R. Weinberg.)

IMMUNOPATHOLOGY

That VKHS is caused by a virus has been suggested but not satisfactorily confirmed. Vitreous from a patient with VKHS lesions of the posterior segment produced uveitis and optic neuritis when injected into the cerebrospinal fluid of rabbits.61 Others have injected cerebrospinal fluid from affected patients into the eyes of experimental animals to show the transmissibility of the disease.62,63 Viral cultures have been negative, but inclusion bodies have been found in phagocytic cells.64,65

VKHS appears to be a T cell-mediated autoimmune response to retinal antigens.66 HLA-DR4 appears to be statistically related to the disease.67 Autoreactive T cells against tyrosinase and/or tyrosinase-related protein may contribute to the development of the disease.68

Antibodies and delayed hypersensitivity skin reactions to uveal pigment have been found in patients with VKHS.69,70 Lymphocytes sensitized to melanin have been identified in the peripheral blood of patients with the disease, and leukocyte migration is inhibited when lymphocytes from affected patients are cultured in the presence of uveal pigment.71,72 Cellular hypersensitivity to uveal pigment also has been found in sympathetic ophthalmia by means of lymphocyte transformation and leukocyte migration inhibition assays, and bovine uveal antigen inhibited leukocyte migration in eight of 12 patients with Harada's disease.71–73 Circulating anti-melanin antibodies are associated with vitiligo, one of the clinical signs of VKHS.

The significance of heightened cellular and humoral reactivity to uveal antigens is unclear. Whether they indicate that pigment hypersensitivity is important in the development of the disease or whether cellular reactivity to uveal antigens is secondary to the uveal inflammation is unknown. Recently, by using two types of rosette assays, Char and colleagues found fewer than the usual number of peripheral-blood T lymphocytes in patients with VKHS.74 Whether the missing T lymphocytes were suppressor cells or other subpopulations of lymphocytes is not clear, but their reduced number strengthens the concept that immune factors are important in the development of VKHS. Increased levels of complement, especially C3, have been detected during the early course of the disease. The frequency of HLA-Bw22J in Japanese patients with VKHS has been found to be greater than in healthy Japanese patients, occurring in 43% of VKHS patients and in only 13% of controls.75 In another series, however, none of nine patients with VKHS had HLA-Bw22J, although several of the nine were Asian.76

Histopathologic examination shows a granulomatous uveitis in tissue from VKH. It resembles the uveitis of sympathetic ophthalmia, although a greater amount of chorioretinal scarring usually is seen in preparations from VKHS. Occasionally, the uveitis is nongranulomatous.77 As in sympathetic ophthalmia, plasma cell infiltration of the uveal tract, hyperplasia of the retinal pigment epithelium, and pigment phagocytosis have been seen in VKHS. T lymphocytes account for 70% of the infiltrative cells, whereas B lymphocytes may aggregate centrally.78 Scattered macrophages may be seen, but choroidal melanocytes are notably decreased.79

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INFLAMMATORY BOWEL DISEASE
Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory diseases of unknown etiology affecting primarily the gastrointestinal tract, but with some extraintestinal manifestations as well. Because of their many similarities and the recent strongly held view that they represent polar ends of a spectrum of disease, these two disorders are sometimes included in the term inflammatory bowel disease (IBD). The suggested causal factors are infectious, autoimmune, psychogenic, and toxic. Ocular manifestations, most commonly uveitis, may accompany IBD. Other ocular lesions are keratopathy (with white opacities just inside the limbus) recurrent conjunctivitis, marginal corneal ulcers, scleritis, episcleritis, and optic neuritis. There also is a high incidence of arthritis and sacroiliitis associated with IBD.

IMMUNOPATHOLOGY

The possibility that IBD is infectious has received much attention. Using filtrates of human ileum from patients with CD, a condition similar to CD has been transmitted to mice and rabbits.80,81 This transmissible agent may be a virus or an aberrant bacterium.82,83 Similar lesions have been induced in mice with homogenates from the colons of UC patients.

A dietary allergy to milk has been suggested as a possible cause of UC.84 Although dietary exclusion of cow's milk or other proteins may be beneficial in some patients, milk allergy is no longer thought to be a cause of IBD. There is some indirect evidence favoring a type I hypersensitivity reaction in UC, however. Some patients with UC have increased numbers of eosinophils in their blood and rectal mucosa, increased circulating basophils, increased numbers of mast cells in the lamina propria, and a large amount of histamine in their rectal tissues.85 Patients with CD, on the other hand, usually do not have these features.

Humoral immune mechanisms have been investigated in some depth in patients with IBD. There are no consistent differences in circulating immunoglobulins, but autoantibodies have been found in the sera of children with UC, suggesting the possibility of an autoimmune disease.86,87 These antibodies to colonic tissue are true autoantibodies, because they react with autologous and heterologous rectal biopsy tissue. They may belong to any of the three major immunoglobulin classes but do not seem to be related to the extent or severity of clinical disease. They persist after colectomy, are not cytotoxic for colon cells in tissue culture, and are probably not pathogenic in IBD. It has been suggested that bacterial antigens, particularly Escherichia coli (E. coli), may stimulate the production of antibody, which then cross-reacts with endogenous colonic tissue.87 However, antibody titers to E. coli are the same in IBD patients and control patients; therefore, although this is an attractive hypothesis, it has yet to be proved.

Other circulating autoantibodies also have been found in patients with IBD. Among them are antinuclear factors, rheumatoid factor, antierythrocyte and adrenal antibodies; antibodies to gastric and small intestinal mucosa, gastric parietal cells, thyroglobulin, liver and kidney extracts, and reticulin; and precipitins to pancreatic homogenates.88 Autoimmune disorders—systemic lupus erythematosus, chronic active hepatitis, autoimmune hemolytic anemia, Hashimoto's thyroiditis, myasthenia gravis, and pernicious anemia—have often been associated with UC and less often with CD. These associations may be coincidental, and there is no convincing evidence that autoantibody levels are elevated in IBD.

Immune complexes have been found in the sera of some patients with UC and may account for some of the extraintestinal manifestations of IBD. Although the nature of the antigen in UC is still a mystery, the antibody appears to be IgG.89 Serum complement levels usually are normal.

Skin testing and in vitro assays have been used to study cellular immunity. In some studies, anergy to tuberculin and DNCB has been demonstrated, and in another study fewer than the normal number of circulating T lymphocytes have been found in UC and CD.90,91 One third of patients with UC have delayed cutaneous responses to DNA, and patients with CD have positive Kveim tests. Whether these findings are significant and whether there is a relationship between IBD and sarcoidosis awaits further investigation.

Because efforts to transform lymphocytes by plant mitogens and assays for MIF have been inconclusive, it is not yet known whether there is a cellular immune component in IBD. Normal and below-normal responses have been seen with phytohemagglutinin; however, when extracts of gastrointestinal tissue were used, leukocyte migration inhibition was demonstrated in UC and CD.92

Leukocytes from patients with UC are cytotoxic for human fetal colon cells, and cytotoxicity for autologous and allogeneic adult human colon cells has been shown in both UC and CD.93,94 Normal lymphocytes also can be made cytotoxic by incubating them for 4 days with sera from patients with UC or CD, but the effect is lost 10 days after colectomy. This cytotoxic factor, which seems to be contained in lymphocytes from patients with IBD, suggests lymphotoxin-mediated target-cell destruction. Cytotoxicity may be conferred on lymphocytes from healthy subjects by preincubation with E. coli lipopolysaccharide and sera from patients with UC or CD. This effect is due to IgM in the sera. It would seem that sensitized T cells bind to epithelial cells through specific surface receptors or that killer cells coated with immune complexes recognize target colonic epithelial cells. Target-cell destruction seems to depend largely on the production of lymphotoxin.95 This suggests that IBD is the result of a lymphocyte-mediated hypersensitivity reaction to bacterial antigens normally present in the lower gastrointestinal tract.

In one study there were more IBD patients than normal subjects with HLA-11 and HLA-7; in another study there were more IBD patients than normal subjects with HLA-A2, HLA-BW35, and HLA-BW40 and fewer IBD patients with HLA-A10.96,97 Other studies have reported no significant differences between patients and controls in the prevalence of these antigens, but more IBD patients who also had ankylosing spondylitis or sacroiliitis had HLA-B27.98

There is a striking overlap of IBD with rheumatologic disease (especially ankylosing spondylitis), and uveitis. There is evidence of a shared gene hypothesis.99 Often, a diagnosis of uveitis precedes the development of IBD.100

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REFERENCE

1. Morgan SJ, Williams JH, Walls AF et al: Mast cell number and staining characteristics in the normal and allergic conjunctiva. J Allergy Clin Immunol; 87:111, 1991.

2. Irani AM, Butrus S, Tabbara KF et al: Human conjunctival mast cell: Distribution of MCT and MCTC in vernal and giant papillary conjunctivitis. J Allergy Clin Immunol 86:34, 1990.

3. Graziano FM, Stahl JL, Cook EB et al: Conjunctival mast cells in ocular allergic disease. Allergy Asthma Proc 3:121, 2001.

4. Terr AI: Inflammation. In: Parslow TC, Stites DP, Terr AI, Imboden JB (eds): Medical Immunology, pp 189–203. New York: Lange, 2001.

5. Gleich GJ: Mechanisms of eosinophil-associated inflammation. J Allergy Clin Immunol 105:651, 2000.

6. Buckley CF, Cohen AB: Nasal mucosal hyperpermeability to macromolecules in atopic rhinitis and extrinsic asthma. J Allergy Clin Immunol 55:213, 1975.

7. Kaufmann HS, Hobbs JR: Immunoglobulin deficiencies in an atopic population. Lancet 2:1061, 1970.

8. Hubscher TT: Immune and biochemical mechanisms in the allergic disease of the upper respiratory tract: Role of antibodies, target cells, mediators, and eosinophils. Ann Allergy 38:83, 1977.

9. Cooke RA, Veer VA: Human sensitization. J Immunol 1:201, 1916.

10. Marsh DG, Bias WB, Hsu SH et al: Association of an HLA-7 cross-reacting group with a specific reaginic antibody response in allergic man. Science 179:691, 1973.

11. Kisimoto T, Ishizaka K: Regulation of antibody response in vitro: 6. Carrier-specific helper cells for IgG and IgE antibody response. J Immunol 111:720, 1973.

12. Theodore FH, Lewson AS: Bilateral iritis complicating serum sickness. Arch Ophthalmol 21:828, 1939.

13. Erffmeyer JE: Serum sickness. Ann Allergy 56:105–109, 1986.

14. Hoover RE: Nongranulomatous uveitis: A complication of serum sickness. Am J Ophthalmol 41:534, 1956.

15. Wong VG, Anderson RR, McMaster PRB: Endogenous immune uveitis. Arch Ophthalmol 85:93, 1971.

16. James DG, Neville E, Walker A: Immunology of sarcoidosis. Am J Med 59:388, 1975.

17. Kataria VP: Sarcoidosis: An overview. Clin Notes Respir Dis 14:2, 1975.

18. Mitchell DN, Scadding JG: Sarcoidosis. Am Rev Respir Dis 110:774, 1974.

19. Steplewski Z, Israel HL: The search for viruses in sarcoidosis. Proceedings of the Seventh International Conference on Sarcoidosis. Ann N Y Acad Sci 278:260, 1976.

20. Mueller-Quernheim J: Sarcoidosis: Immunopathogenetic concepts and their application. Eur Respir J 12:716, 1998.

21. Cummiskey JM, McLaughlin H, Keelan P: T and B lymphocytes in sarcoidosis: A clinical correlation. Thorax 31:665, 1976.

22. Ramachandar K, Douglas DS, Siltzbach LE: Peripheral blood lymphocyte subpopulations in sarcoidosis. Cell Immunol 16:442, 1975.

23. Hirschorn K, Schriebman RR, Bach FH et al: In vitro studies of lymphocytes from patients with sarcoidosis and lymphoproliferative disease. Lancet 2:842, 1964.

24. Becker FW, Krul P, Deicher H et al: The leukocyte migration test in sarcoidosis. Lancet 1:120, 1972.

25. Byrne EB, Evans AS, Fouts DW et al: A seroepidemiological study of Epstein-Barr virus and other viral antigens in sarcoidosis. Am J Epidemiol 97:355, 1973.

26. Wahren B, Carlens E, Espmark A et al: Antibodies to various herpes viruses in sera from patients with sarcoidosis. J Natl Cancer Inst 47:747, 1971.

27. Sands JH, Palmer PP, Maycock RL: Evidence for serological hyperreactivity in sarcoidosis. Am J Med 19:401, 1955.

28. Goldstein RA, Israel HA, Janicki BW et al: Serum immunoglobulin D levels in sarcoidosis. Proceedings of the Sixth International Conference on Sarcoidosis. Tokyo: Tokyo University Press, 196, 1974.

29. Buckley CE, Trayer HR: Serum IgD concentrations in sarcoidosis and tuberculosis. Clin Exp Immunol 10:257, 1972.

30. Von Bergmann K-C, Zausmmell I, Lachmann B: IgE konzentratione im serum von patienten mit sarkoidose und lungentuberkulose. Dtsch Geisindheitsw 27:1774, 1972.

31. Buckley CE, Nagaya H, Sieker HO: Altered immunologic activity in sarcoidosis. Ann Intern Med 64:508, 1966.

32. Agnello V, Winchester RJ, Kunkel HG: Precipitin reaction of the C1q component of complement with aggregated gamma-globulin and immune complexes in gel diffusion. Immunology 19:909, 1970.

33. Hedfors E, Norberg R: Evidence for circulating immune complexes in sarcoidosis. Clin Exp Immunol 16:493, 1974.

34. Behçet H: Uber die rezidivierende, Aphthose, durch ein Virus verursachte Geschwure am Mund, am Auge und an den Genitalien. Dermatol Wochenschr 105:1152, 1937.

35. Noyan B, Gursky G, Aktiu E: Inoculation of cerebrospinal fluid of a neuro-Behçet patient into mice. Acta Neuropathol (Berl) 12:195, 1969.

36. Sezer N: Further investigations on the virus of Behçet's disease. Am J Ophthalmol 41:41, 1956.

37. Evans AD, Pallis CA, Spillane JD: Involvement of the nervous system in Behçet's syndrome: Report of three cases and isolation of virus. Lancet 2:349, 1957.

38. Dowling GB: Behçet's disease. Proc R Soc Med 54:101, 1961.

39. Sigel N, Larson R: Behçet's syndrome: A case with benign pericarditis and recurrent neurologic involvement treated with adrenal steroids. Arch Intern Med 115:203, 1965.

40. Oshima Y, Shimizu T, Yokohari et al: Clinical studies on Behçet's syndrome. Ann Rheum Dis 22:36, 1963.

41. Shimizu T, Katsuta Y, Oshima Y: Immunological studies on Behçet's syndrome. Ann Rheum Dis 24:494, 1965.

42. Cooper DA, Penny R: Behçet's syndrome: Clinical, immunological, and therapeutic evaluation of 17 patients. Aust N Z J Med 4:585, 1974.

43. Lehner T: Behçet's syndrome and autoimmunity. Br Med J 1:465, 1967.

44. O'Duffey JD, Carney JA: Behçet's disease: Report of 10 cases, 3 with new manifestations. Ann Intern Med 75:561, 1971.

45. Haim S, Sobel JD, Friedman-Birnbaum R et al: Histological and direct immunofluorescence study of cutaneous hyperactivity in Behçet's disease. Br J Dermatol 95:631, 1976.

46. Lehner T: Immunological aspects of recurrent oral ulcers. Lancet 2:80, 1964.

47. Cooper D, Penny R, Fiddes P: Autologous-plasma sensitization in Behçet's disease. Lancet 1:910, 1971.

48. Kogure M, Shimada K, Hara HG: Complement titer in patients with Behçet's disease. Acta Soc Ophthalmol Jpn 75:1260, 1971.

49. Kawachi-Takahashi S, Takahashi M, Kogure M et al:. Evaluation of C9 level associated with Behçet's disease. Jpn J Exp Med 44:488, 1974.

50. Lehner T: Stimulation of lymphocyte transformation by tissue homogenate in recurrent oral ulceration. Immunology 13:159, 1967.

51. Dolby AE: Recurrent aphthous ulceration: Effect of sera and peripheral blood lymphocytes upon oral epithelial tissue culture cells. Immunology 17:709, 1967.

52. Rogers RS, Sams WM, Shorter EG: Lymphocytotoxicity in recurrent aphthous stomatitis: Lymphotoxicity for oral epithelial cells in recurrent aphthous stomatitis and Behçet's syndrome. Arch Dermatol 109:361, 1974.

53. Coe JE, Feldman JD, Lee S: Immunologic competence of thoracic duct cells: I. Delayed hypersensitivity. J Exp Med 123:267, 1966.

54. Lehner T: Characterization of mucosal antibodies in recurrent aphthous ulceration and Behçet's syndrome. Arch Oral Biol 14:843, 1969.

55. Lehner T: Pathology of recurrent oral ulceration and oral ulceration in Behçet's syndrome: Light, electron, and fluorescence microscopy. J Pathol 97:481,1969.

56. Marquardt JL, Snyderman R, Oppenheim JJ: Depression of lymphocyte transformation and exacerbation of Behçet's syndrome by ingestion of English walnuts. Cell Immunol 9:263, 1973.

57. Ohno S, Nakayama E, Suguira S et al: Specific histocompatibility antigens associated with Behçet's disease. Am J Ophthalmol; 80:636, 1975.

58. O'Duffy JD, Taswell HF, Elvebeck LR: HLA antigens in Behçet's disease. J Rheumatol 3:1, 1976.

59. Goolamli SK, Comaish JS, Hassanyeh F: Familial Bench's syndrome. Br J Dermatol 95:637, 1976.

60. Meador R, Ehrlich G, Von Feldt JM: Behçet's disease: Immunopathologic and therapeutic aspects. Curr Rheumatol Rep 4:47, 2002.

61. Takahashi M: Clinical and experimental studies on the nature of idiopathic, bilateral, severe uveitis. Acta Soc Ophthalmol Jpn 34:506, 1930.

62. Friedenwald JS, McKee EM: A filter-pasing agent as a cause in endophthalmitis. Am J Ophthalmol 21:723, 1938.

63. Remky H: Beitrag zur Kenntnis schwerer Foremen der Uveoencephalitis. Klin Monatsbl Augenheilkd 123:166, 1953.

64. Morris RW, Schlaegel TF: Virus-like inclusion bodies in subretinal fluid in uveoencephalitis. Am J Ophthalmol 58:940, 1964.

65. Wilczek M, Feltynowski A: Study of sympathetic ophthalmia by electron microscopy. Klin Oczna 25:11, 1956.

66. Rao NA: Mechanisms of inflammatory response in sympathetic ophthalmia and VKH syndrome. Eye 11:213, 1997.

67. Pivetti-Pezzi P, Accorinti M, Colabelli-Gisoldi RA et al: Vogt-Koyanagi-Harada disease and HLA type in Italian patients. Am J Ophthalmol 122:889, 1996.

68. Gocho K, Kondo I, Yamaki K: Identification of autoreactive T cells in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci 42:2004, 2001.

69. Kahan A, Sztanojevits A, Szabados T et al: Pigment-autoagression in der Pathogenese des Vogt-Koyanagi-Harada syndrome. Graefes Arch Ophthalmol 167:246, 1964.

70. McPherson SD, Woods AC: The significance of the intracutaneous test for hypersensitivity to uveal pigment. Am J Ophthalmol 31:35, 1948.

71. Hammer H: Lymphocyte transformation test in sympathetic ophthalmitis and Vogt-Koyanagi-Harada syndrome. Br J Ophthalmol 55:850, 1971.

72. Hammer H: Cellular hypersensitivity to uveal pigment confirmed by leukocyte migration tests in sympathetic ophthalmitis and the Vogt-Koyanagi-Harada syndrome. Br J Ophthalmol 58:773, 1974.

73. Sanefuji M: Cell-mediated immunity in uveitis: II. Leukocyte migration inhibition test in Harada disease. Acta Soc Ophthalmol Jpn 78:306, 1974.

74. Char DH, Brunn J, West W: Thymus-derived lymphocytes in the Vogt-Koyanagi-Harada syndrome. Invest Ophthalmol 16:179, 1977.

75. Tagawa Y, Sugiura S, Yakura H et al: HLA and Vogt-Koyanagi-Harada syndrome. N Engl J Med 295:173, 1976.

76. Ohno S, Char DH, Kimura SJ et al: HLA and Vogt-Koyanagi-Harada syndrome. N Engl J Med 295:788, 1976.

77. Perry HD, Font RL: Clinical and histopathologic observations in severe Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 83:242, 1977.

78. Chan CC, Palestine AG, Kuwabara T et al: Immunohistologic studies of Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 105:607, 1988.

79. Inomata L, Sakamoto T: Immunohistochemical studies of Vogt-Koyanagi-Harada disease with sunset sky fundus. Curr Eye Res 924, 1990.

80. Mitchell DN, Rees RJW: Agent transmissible from Crohn's disease tissue. Lancet 2:168, 1970.

81. Cave DR, Mitchell DN, Kane SP et al: Further animal evidence of a transmissible agent in Crohn's disease. Lancet 192:1120, 1973.

82. Gitnick GL, Rosen VJ: Electron microscopic studies of viral agents in Crohn's disease. Lancet 2:217, 1976.

83. Parent K, Mitchell P: Cultivation of viral agents from Crohn's disease. Lancet 2:576, 1976.

84. Anderson AFR: Gastrointestinal manifestations in food allergy. Med J Rec 122:271, 1925.

85. Binder V, Hvidberg E: Histamine content of rectal mucosa in ulcerative colitis. Gut 8:24, 1967.

86. Broberger O, Perlmann P: Autoantibodies in human ulcerative colitis. J Exp Med 110:657, 1959.

87. Weinstein L: Bacterial aspects of ulcerative colitis. Gastroenterology 40:323, 1961.

88. Kraft SC, Kirsner JB: The immunology of ulcerative colitis and Crohn's disease: Clinical and humoral aspects. In: Kirsner JB, Shorter RG (eds): Inflammatory Bowel Disease, pp 72–73. Philadelphia: Lea & Febiger, 1975.

89. Ballard J, Shiner M: Evidence of cytotoxicity in ulcerative colitis from immunofluorescent staining of the rectal mucosa. Lancet 1:1014, 1974.

90. Jones JV, Housley J, Ashurst PM et al: Development of delayed hypersensitivity to dinitrochlorobenzene in patients with Crohn's disease. Gut 10:52, 1969.

91. Meyers S, Sachar DB, Taub RN et al: Anergy to dinitrochlorobenzene and depression of T-lymphocytes in Crohn's disease and ulcerative colitis. Gut 17:911, 1976.

92. Whorwell PJ, Wright R: Immunological aspects of inflammatory bowel disease. Clin Gastroenterol 5:303, 1976.

93. Perlmann P, Broberger O: In vitro studies of ulcerative colitis: Cytotoxic action of white blood cells from patients on human fetal colon cells. J Exp Med 117:717, 1963.

94. Shorter EG, Cardoza M, Spencer RJ et al: Further studies of in vitro cytotoxicity of lymphocytes from patients with ulcerative and granulomatous colitis for allogeneic colonic epithelial cells including the effects of colectomy. Gastroenterology 56:304, 1969.

95. Watson DW, Shorter EG: The immunology of ulcerative colitis and Crohn's disease: Cell-mediated immunity responses. In: Kirsner JB, Shorter EG (eds): Inflammatory Bowel Disease, p 61. Philadelphia: Lea & Febiger, 1975.

96. Asquith P, Mackintosh P, Stokes PL et al: Histocompatibility antigens in patients with inflammatory bowel disease. Lancet 1:113, 1974.

97. Nahir M, Gideoni O, Eidelman S et al: HLA antigens in ulcerative colitis. Lancet 1:573, 1976.

98. Mallas EG, Mackintosh P, Asquith P et al: Histocompatibility antigens in inflammatory bowel disease. Gut 17:906, 1976.

99. Brophy S, Pavy S, Lewis P et al: Inflammatory eye, skin, and bowel disease in spondyloarthritis: Genetic, phenotypic, and environmental factors. J Rheumatol 28:2667, 2001.

100. Lyons JL, Rosenbaum JT: Uveitis associated with inflammatory bowel disease compared with uveitis associated with spondyloarthropathy. Arch Ophthalmol 115:61, 1997.

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