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

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.

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.

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

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

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.

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

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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