Immunological Mechanisms of the Gastrointestinal Tract

Vol. 51, No.6 Printed in U.S.A.

GASTROENTEROLOGY

Copyright © 1966 by The Williams & Wilkins Co.

PROGRESS IN GASTROENTEROLOGY

IMMUNOLOGICAL MECHANISMS OF THE GASTROINTESTINAL TRACT KEITH

B.

TAYLOR,

M.D.

Department of Medicine, Stanford University School of Medicine, Palo Alto, California

Since this is the first review of the topic to appear in the "Progress in Gastroenterology" series, the choice of material has not been restricted to publications appearing in the last 3 years; some earlier references have been incorporated to provide pertinent background. Other recent reviews are available. 1 - 4 Published data and speculation about the role of immune processes in causing or perpetuating, alone or in concert, gastrointestinal diseases in man have accumulated at an increasing rate in the past decade. Interest has not been confined to the gastrointestinal tract. Rapid technical advances in immunology have partly engendered the numerous attempts to elucidate the pathogenesis of chronic inflammatory diseases involving many organs or systems of the body. New concepts of the nature of the immune response have also provided a stimulus. The gastrointestinal tract is a large, composite structure. Gastrointestinal diseases are very prevalent, and they tend to be symptomatically eloquent. Apart from those due to specific and recognized pathogenic organisms, they are of unknown etiology. Early in this century clinical observations tended to focus on alimentary and gastrointestinal allergy to various ingested materials; later, bacterial, dietary, and nutritional factors provided foci of major interest. Most recently, a considerable interAddress requests for reprints to: Dr. Keith B. Taylor, Department of Medicine, Stanford University School of Medicine, Palo Alto California 94304. This work was supported in part by Grant AM 06971 from th e National Institutes of H ealth.

est in autoimmune phenomena has developed, and attempts to implicate exogenous factors have tended to become desultory. The diseases which have been particularly studied with immunological techniques are chronic gastritis, regional enteritis, celiac disease, ulcerative colitis, and chronic active hepatitis. Gastric and duodenal ulceration and acute appendicitis, which together make up a formidable proportion of gastrointestinal diseases in civilized communities, appear to have been little investigated by such techniques in recent years, although the experimental literature of the 1920's abounds with studies by Ivy and others reporting attempts to produce ulceration of the gastrointestinal tract by immunological techniques. Alimentary and Gastrointestinal Allergy

The earlier tendency to ascribe all disturbances of gastrointestinal function associated with specific components of the diet to allergy or immune hypersensitivity has been much modified recently by demonstrations of intolerances to specific foodstuffs due to deficiencies of specific enzymes, particularly of those enzymes normally present in the epithelial cells of the small intestine. Fermentative diarrhea induced by certain carbohydrates was recognized, especially in infants, half a century ago. Later, it was shown that in some subjects displaying intolerance of milk, usually expressed as diarrhea, there is a congenital deficiency of the lactose splitting enzyme lactase in the small intestinal mucosa. 5 More recently there have been

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several demonstrations that the deficiency in adults may be acquired ;5 - 8 the mechanism involved is not clear, although in sprue and in nontropical sprue the inflammatory process itself may be responsible. It must not be overlooked that disaccharidase deficiency may be asymptomatic. Nevertheless, a definite relationship of carbohydrate intolerance with enzyme deficiency does seem fairly well established. Another complication is that various gastrointestinal disturbances, such as vomiting, colic, and diarrhea, associated apparently with the ingestion of certain foodstuffs, may be due to a congenital enzyme deficiency rather than to any disturbance of normal immunological mechanisms; galactosemia is an example of such a condition.9 Tolerance tests performed with appropriate sugars may help to resolve uncertainty, but a recent paper 10 suggests that such tests may sometimes give falsely positive evidence of disaccharidase deficiency. True gastrointestinal and alimentary allergy are difficult to document. The classic demonstrations of food allergenicity by Prausnitz and Klistner 11 have not been extended as widely as they deserve. Heiner 12 has recently reported a patient with extreme sensitivity to wheat protein, whose serum contained specific reagins. In this man even 1 mg of ingested wheat would induce vomiting. In another interesting case reportl 3 of intestinal malabsorption induced by ingestion of cow's milk, carbohydrate intolerance as a cause was excluded, and an immune hypersensitivity to a specific milk protein, ,8-lactoglobulin, was well established as the underlying causative factor. Unfortunately, most of the tests available for establishing an immunological mechanism in food intolerance are unreliable or extremely laborious. Skin tests do not seem to offer a high measure of reliability; earlier reports of the value of injecting suspected antigens directly into the mucosa of the gastrointestinal tract have so far not been amplified. Clinical impressions have too often been adduced as scientific evidence. One uncontrolled study 14 of the effect of milk proteins in ulcerative colitis, in which

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cheese was inculpated as a precipitating agent, tended to exclude factors other than protein hypersensitivity. A more recent study 15 of the therapeutic response in ulcerative colitis to partial milk exclusion was not so convincing, since lactose intolerance might have been implicated. Inevitably, a recent report of lactase deficiency in ulcerative colitis has appeared. 16 Further, the "milk-free" diet used by the Oxford group utilized butter, which contains about 0.5% milk protein, an amount presumably sufficient to perpetuate a state of hypersensitivity. Such quantitative factors have yet to be explored. Nevertheless, this study should provide a blueprint for future investigations of a similar sort. Significant increases of incidence in titer of circulating antibodies to milk proteins in suspected allergic conditions and in other gastrointestinal disorders, such as ulcerative colitis, have attracted much attention. In the milk exclusion study it was noteworthy that serum titers to milk proteins did not correlate with clinical responseP An interesting group of infants displaying occult gastrointestinal hemorrhage induced by ingestion of cow's milk is worthy of mention here. This study 18 showed that the sera of these infants contained multiple precipitating antibodies to milk proteins in high incidence and titer. Whether this syndrome has an immunological basis is at present speculative. Infants who die mysterious cot (crib) deaths constitute another interesting group. There have been claims 19 that the sera of such infants contain an abnormally high titer of antibodies to cow's milk, and there certainly seems good evidence that this syndrome occurs in bottle-fed infants and that cow's milk may be found in the lung parenchyma after death. Whether this truly represents an anaphylactic reaction to cow's milk protein is still undetermined. There are also certain special conditions, such as Aldrich's syndrome, in which a high incidence of circulating antibodies to cow's milk is found, but their significance is obscure. 20 - 22 The significance of the presence of circulating antibodies to various dietary proteins remains uncertain. It has been sug-

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gested that they represent a defense ies to proteins in various gastrointestinal against foreign protein, since they occur in diseases should be interpreted accordmany healthy subjects. The differences ob- ingly.29 served in health and in various diseases, Not all published results are in agreethe absence of detectable antibodies in ment. Thus, in ulcerative colitis, some some healthy subjects and some with gas- studies have shown a clear preponderance trointestinal and other diseases are phe- of antibodies to milk proteins compared nomena about which at present there is with healthy matched controls,31-33 whereas much speculation. 23 There is, of course, the other studies have not done so. 34 Another possibility that the antibodies found in the group 35 has confirmed the finding of high sera of healthy subjects differ from those antibody titers to milk in celiac disease but found in some disease states or that the has failed to find antibodies to a gluten antibodies, although the same, are an index fraction in the same sera. Such discrepanof a different type of immune response. A cies may be due to differences in the antirecent study 24 has shown that a positive gens used or to other technical factors. correlation between the incidence of anti- There may also be differences, environmilk antibodies and clinical milk allergy mental or ethnic, between the groups studis obtained only when the passive cutane- ied. ous anaphylaxis technique is applied to Experimental studies in various species demonstrate milk antibodies. Antibodies have provided clear evidence that oral detected by this test are sometimes referred administration of milk or of other antigens may induce anaphylaxis and other states to as sensitizing antibodies. In gluten-induced enteropathy of chil- of immune hypersensitivity 36 -38 or suppress dren and adults many studies25 -30 in recent sensitization.36 · 39 Some experiments in years have shown a significantly higher which bovine serum albumin was fed to incidence and titer of antibodies to various rabbits 40 · 41 suggest that circulating antifractions of wheat gliadin compared with bodies may be formed in the rabbit by imhealthy subjects. One study28 achieved a munocytes in the intestinal tract. The evidegree of immunological differentiation dence is not conclusive, but the implication sufficient to provide the basis for a diagnos- that antibodies to ingested antigens may tic test. However, it has been shown re- be formed locally in the intestinal mucosa peatedly that a high incidence of antibod- is of great interest. There is here an analies to other dietary proteins, particularly ogy with coproantibodies against intestinal to milk proteins, also occurs in celiac dis- pathogenic microorganisms, a subject well ease.26· 27 · 29 · 30 There is some disagreement reviewed fairly recently. 42 Two studies in man have attempted to as to whether such high titers to different antigens show an association26 or a con- explore the problem of antibodies in intestisiderable dissociation. 27 · 29 · 30 Neither is nal mucosa in gluten-induced enteropathy. there apparent a correlation between clini- Both utilized the Coons immunofluorescent cal severity of the disease and the presence technique. The results of one study 43 sugof antibodies. These findings suggest that gested that both the healthy and celiac inthe failure of the diseased bowel to exclude testinal epithelium absorb antigenic deantigenic macromolecules is not in itself an rivatives of gluten or possibly that some adequate explanation for the observed dif- celiac sera contain a humoral autoantibody ferences in circulating antibody formation. to small bowel epithelial cells. The other The factors involved in determining such study 44 did not confirm the presence of cirantibody responses could include proteolytic culating autoantibodies to intestinal epiactivities at all stages on the pathway of thelium in celiac disease. Neither could the absorption, the activity of immunocytes in authors demonstrate synthesis of gliadinthe gut wall, the lymphatic drainage, and specific immunoglobulins in small bowel the predetermined immune responsiveness immunocytes. They did demonstrate in the to specific antigens. The differences illus- lamina propria immunocytes containing trated in one study of circulating antibod- nonspecific immunoglobulins, especially

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IgA (y1A). Attempts to elucidate the relationship of humoral antibodies against dietary proteins with hypersensitivity states to such proteins and with gastrointestinal disease must provide in the future a fruitful field for study.

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whether enteric organisms, previously designated as normal flora or commensals, can induce immune pathogenic changes by virtue of relative quantitative changes or of factors effecting changes in their access to immune mechanisms in the host.

Bacteria and Immune Reactions

Autoimmune Reactions

The search for specific microorganisms as a cause of gastritis, regional enteritis, ulcerative colitis, and celiac disease has diminished in intensity, despite recent observations in tropical sprue which suggest that it may occur in epidemic form and that it responds to treatment with antibiotics,45 and the interest engendered by the finding of bacilliform bodies in Whipple's disease, which also responds to antibiotic therapy. 46 -48 Attention is now being focused on the potential importance of microorganisms, previously not recognized as pathogenic, in regard to the influence they may have on immunological responsiveness. For instance, many coliforms share a common 0 antigen, an endotoxin, which has been characterized.49 A recent study 50 has demonstrated sharing of antigenic determinants by lipopolysaccharide extracts of germfree colon cells and by a strain of coliform, Escherichia coli 014. This work has provided a link between the observed phenomenon of autoimmunization in ulcerative colitis and immunization to an exogenous antigen. There is a parallel here with the phenomenon of antigenic determinants shared by group A streptococci and the heart. Whether the common 0 antigen of Kunin is the one implicated in the experiments of the Swedish group is not yet clear. An experimental study 51 has shown that rabbits, injected with a wide variety of enteric organisms, such as coliforms, salmonellae, and some other gram-negative bacteria, produce antibodies reactive with gastric, small intestinal, or colonic epithelium or any combination of these. These antibodies display regional specificity. It can be postulated now that, in chronic gastrointestinal diseases, instead of searching for microorganisms of types characterized by traditional criteria as pathogenic, increasing efforts should be made to show

A plethora of publications has been devoted to various aspects of so-called autoimmunization in recent years, and in gastrointestinal diseases such studies have uncovered some interesting associations and lacks of associations. Evidence of autoimmunization has been adduced in aphthous ulceration of the mouth, chronic gastritis, and gastric atrophy, chronic pancreatitis, primary biliary cirrhosis, chronic hepatitis, and ulcerative colitis. Studies of sera taken from patients with recurrent aphthous ulceration have shown that 75% contained autoantibodies to extracts of glossal mucosa. 52 Sera from other subjects with other types of ulcerating and nonulcerating oral diseases were negative, and the antibodies in the aphthous ulcer sera were specific for oral mucosa. In chronic gastritis, with or without the lesion of pernicious anemia, many recent studies have endorsed the presence of humoral antibodies directed against two antigenic components of the human gastric parietal cell. One of these is intrinsic factor (IF), the other is a cytoplasmic antigen which is associated with an insoluble lipoprotein microsomal element. 53 The latter has not yet been characterized biologically or chemically. In addition, in the sera of many patients with pernicious anemia, antibodies against thyroglobulin and the cytoplasm of the thyroid acinar cell have been detected in a higher than normal incidence. Parietal Cell (non-IF) Antibody

The results of earlier studies54-5 7 in pernicious anemia have been confirmed more recently. 58 -61 The antibody is of the 7S type and is both IgG and IgA, the former probably predominating. 59 · 62 There seems to be general agreement that the complement fixing antibody to gastric mu-

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cosal "microsomal" extracts is the same as the parietal cell antibody demonstrated by immunofluorescent techniques, but proof of this is lacking and may remain so until the antigen has been isolated. There is fair correlation between complement-fixing gastric antibody and positive immunofluorescent results, but the latter in one series was positive in 86% of all cases compared with 62% using complement fixation. 55 This could be an index of the greater sensitivity of the immunofluorescent technique, or it could be that in at least some of the sera positive by immunofluorescence the technique was demonstrating an IF antibody (which is not complement fixing), since it has been shown63 that, if pernicious anemia sera containing both the IF and complement-fixing gastric antibodies are treated with a preparation of parietal cells which do not contain IF (hog gastric mucosa), such treatment does not abolish antibody uptake by human parietal cells detected by immunofluorescence. There is still doubt whether parietal cell cytoplasmic antibody is ever present in the sera of subjects without inflammatory disease of the gastric mucosa. If it is, the incidence must be very low. Recently, anumber of studies have provided some information on this point. In one such study64 there was 1 patient out of 47 whose gastric biopsies were normal, who had parietal cell antibody present in the serum; in another,65 there were 2 out of 20 such subjects; in a third, 66 the gastric biopsies from 20 relatives of pernicious anemia patients with parietal cell antibodies were found to be normal in 4; the fourth study 67 showed that of 20 patients with parietal cell antibody all had gastritis, and similar results have been obtained by others. In keeping with these findings are those in which the presence of gastric parietal cell antibody in the serum has been associated with some reduction in the secretion of gastric acid. 68 · 69 It must not be overlooked that in many of these studies only single gastric biopsies have been taken, and thus in those cases where they have appeared to be normal there may have been gastric mucosal disease elsewhere. It is probably fair to state that, so far, parietal cell antibod-

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ies have not been found to be associated unequivocally with normal gastric mucosa. The incidence of parietal cell antibodies in apparently healthy subjects is about 10%, being lower in those under the ages of 60 than in those above 60 years of age. 55 This age difference may be an expression of an increased incidence of chronic gastritis with age. Since progressive disappearance of parietal cells is a constant feature of pernicious anemia it was possible that the incidence or titer of parietal cell antibodies would fall with duration of the disease, but two studies suggest that this is not the case. 55 · 59 One paper70 deserves special comment, in view of the very high incidence (38.5%) of parietal cell antibodies observed in a "control" group of Welsh women. Unfortunately, no gastric mucosal studies were done. Although these women were not significantly anemic, it is quite possible that they had been iron deficient prior to the study. Much clearer evidence of an increased incidence of parietal cell antibodies associated with chronic iron deficiency has been presentedY These findings are of considerable interest in view of the possible association between iron deficiency and gastritis, which has been claimed by some. 72 · 73 In an excellent discussion of gastritis the evidence has been carefully scrutinized.74 Observations of impaired acid and IF secretion in animals long maintained in a state of iron deficiency may have some relevance here, 75 · 76 although gastritic changes were not found. A point which requires examination is that there may be widely different incidences of autoantibodies in people of different ethnic groups and in different environments. Such a possibility should be entertained when results obtained in different centers are compared. Parietal cell antibodies have also been found to be raised in chronic gastritis without pernicious anemia. 58, 67, 68, 77-79 Further, there is another rather poorly defined group of patients with atrophic gastritis in whom vitamin B 12 absorption is impaired but who do not have a marked megaloblastic anemia or neurological lesions; they have been described as having latent pernicious anemia, but the term has little to commend it. These patients have

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the basic lesion of pernicious anemia and should be classified accordingly. In such subjects a high incidence of parietal cell antibodies has been described. 58, 77, 78, 80 In disease of certain endocrine glands an abnormally high incidence of parietal cell antibodies has been recorded. They are present in about one-third of all patients with Hashimoto's thyroiditis, primary myxedema, and thyrotoxicosis. 54 · 81 These findings may provide a clue to the possible clinical and pathological associations of thyroid disease and pernicious anemia. It has been found that the presence of these antibodies shows some positive correlation with hypochlorhydria. 69 Conversely, in pernicious anemia it has been shown that the incidence of thyroid autoantibodies is abnormally high, both to thyroglobulin and to thyroid acinar cell cytoplasm. 54 · 81, 82 Studies of the sera of first order relatives of subjects with pernicious anemia and with chronic thyroid disease have also shown an increased incidence of parietal cell antibodies66· 83 and of thyroid antibodies 83 in both groups. Parietal cell antibodies have also been detected in a number of other diseases, such as idiopathic Addison's disease 68 · 84 in females. 84 In ulcerative colitis, in which gastritis seems frequently to be present, 85 there may be an increase in parietal cell antibodies. 68 · 86 · 87 In another study no abnormal incidence of parietal cell antibodies was found in ulcerative colitis. 88 In diabetes mellitus an increased incidence has also been recorded. 89 Recent studies 59 · 62 have shown the presence of antibodies to gastric parietal cells in gastric juice of subjects who have circulating parietal cell antibodies. Whether these have any special function has not yet been elucidated. In summary, the significance of parietal cell anti bodies remains uncertain; they are not present in a large proportion of certain groups with advanced chronic gastritis, yet in pernicious anemia they show a high incidence. So far their presence has never been demonstrated in the presence of an unequivocally normal gastric mucosa. One view held by many is that they are an expression of an underlying immune dis-

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turbance which may be itself pathogenic via other intermediaries. The abnormal incidence in some conditions other than pernicious anemia tends to mitigate the diagnostic value of the test. 90 Antibody to IF Earlier reports92 -94 of spontaneously occurring circulating autoantibodies to IF in pernicious anemia have been amplified recently by studies in which more sensitive methods of detection have been applied.94· 95 No IF antibodies haYe been detected in sera from healthy subjects. Two recent studies suggest that the antibody may only be present in adult pernicious anemia and is not found in atrophic gastritis without the lesion of pernicious anemia. 77 • 78 It seems occasionally to occur in thyroid disease. 80 · 98 In juvenile pernicious anemia, in which the gastric mucosa is only slightly if at all abnormal, neither gastric complement fixing nor IF antibodies are present. 83· 97 However, true Addisonian pernicious anemia sometimes occurs at an early age, and the serological findings in these cases may be positive. Recent circumstantial evidence has been provided for the presence of antibodies to IF in the gastric juice of some patients with pernicious anemia ;98 this strengthens the hypothesis that an important factor in the development of pernicious anemia may be the development of such antibodies, which would inhibit the action of IF when its secretion was already impaired by gastric mucosal disease. Inadequate B 12 absorp tion would then ensue. It has become recognized that circulating antibodies to IF per se may not impose inhibition of orally administered IF. Thus, in the earliest observations of circulating antibodies to IF following administration of heterologous intrinsic factor to patients with pernicious anemia, it was found that antibodies might be present in such patients, not all of whom had an intestinal block to hog IF.92 Further, 2 subjects with pernicious anemia were inj ected with hog IF and produced circulating antibodies, yet responded to hog IF when it was given to them by mouth together with labeled vitamin B 12 .99 No information is available as to whether these

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antibodies reached the gastrointestinal tract; in any event it is possible that the doses of heterologous IF by mouth were more than sufficient to overcome any inhibition imposed by antibody activity. Another study emphasized this point. 100 Yet another has purported to show that human IF is less effective than hog IF in potentiating vitamin B 12 absorption in patients with pernicious anemia. 101 This effect was independent of whether the subjects tested had circulating IF autoantibodies or not, and no attempt was made to determine whether the doses of IF of either human or hog origin were maximal, so that the significance of these studies is not yet established; the hypothesis of the authors that the probable explanation is due to the presence of an antibody to human IF acting at small gut level must at present be regarded with caution. In the in vivo tests of IF antibody activity there has so far not been any satisfactory demonstration that human IF is more easily inhibited than hog material. Earlier observations of improvement of vitamin B 12 absorption in patient with pernicious anemia treated with steroids 102 -105 and the disappearance of IF antibodies93 have recently been extended by observations106-108 of some response of the atrophic gastric mucosa to steroids with an increase in number of parietal cells and, in some patients, evidence of increased acid production by the gastric mucosa. At present it does not appear that the goal suggested in an earlier review/ 09 that attempts be made to reverse the pathological process in gastritis, has been attained; nevertheless, the observations may be important in t erms of our understanding of the underlying lesion. Two recent papers are recommended for further reading. 96 · 110 Ulcerative Colitis and Regional Enteritis

Examination of the significance of immunological mechanisms in the etiology of ulcerative colitis and regional enteritis has produced a spate of papers, some concerned with studies of the human disease, some with attempts to produce experimen-

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tal models of the human disease. Reports have appeared of the occurrence of ulcerative colitis and other disorders thought to be of an immune nature, in the same patient. These disorders include systemic lupus erythematosus/ 11· 112· lupoid hepatitis,113 gastritis and pernicious anemia, 114 autoimmune hemolytic anemia, 115 · 116 thyroiditis,117 and myasthenia gravis.U 8 Though of some interest , such reports do not represent valid evidence of significant associations of these diseases. A review by Broberger119 provides a good account of all but the most recent immunological work. Colon antibodies have been detected in the serum of some patients with ulcerative colitis by various techniques, using as antigen extracts of human fetal colon. 120 Some positive reactions have also been obtained using sera from patients with rheumatoid arthritis, systemic lupus erythematosus, some liver diseases, and the nephrotic syndrome, but in much lower incidences than in ulcerative colitis. 120 -121 Conversely, extracts of kidney and fetal liver may also give reactions with some sera. When extracts of normal, bacterially contaminated colon are used, most sera give positive reactions, whether from patients with ulcerative colitis or healthy subjects. 50 So far it has not been determined whether the colon antibodies in ulcerative colitis are true autoantibodies. Further, the results of studies involving the use of bacterially contaminated colon should be interpreted with reserve. Similarly reacting antibodies can be extracted from lymph nodes draining the colon. 123 It has been demonstrated by the Coons immunofluorescent technique that the antibodies are directed against the cytoplasm of colonic epithelial cells, including sterile fetal colonic cells. 87 · 123 -127 Hemagglutination tests are more sensitive than immunofluorescent tests. Eighty per cent of sera of children with ulcerative colitis were positive by the former, about 50% by the latter.119 Absorption of sera with fetal colon inhibited positive results with both techniques. Extracts of colon from germ-free rats can be substituted for those of human fetal colon, with minor loss of disease

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specificity. 50 The antigen is probably a lipopolysaccharide, but its nature remains uncertain. Positive sera have not been shown to be cytotoxic to colon cells, though such cells grown in culture will fix antibody. 124 However, the circulating leukocytes from some ulcerative colitis patients have been found to be cytotoxic in vitro,1 28 · 129 though in one other study the results were negative.127 Cells from about one-third of ulcerative colitis patients may also produce autologous skin reactions. 130 Another study has been reported of an unidentified precipitate coating human amniotic cells to which serum from rabbits immunized with ulcerative colitis colon has been added. 131 Both bacterial and allogeneic factors might account for this. It has already been mentioned that, recently, antigenic cross-reactivity between lipopolysaccharide extracts of coliform bacteria and of fetal colon has been demonstrated50 and that r abbits injected with various enteric organisms produce antibodies which react with their own colonic, small intestinal, and gastric mucosa. 51 Thus, a recent hypothesis of the course of events in the evolution of ulcerative colitis is that subjects may become immunologically sensitized to components of normal, or at any rate nonpathogenic, bacteria. Such an immune response might then be directed against colonic mucosa, immunocytes serving as the mediator, circulating antibodies having no demonstrable role (though some recent experimental work suggests that they may be protective and not injurious 132· 133 ). A number of studies of the prevalence of other circulating autoantibodies in ulcerative colitis have been published. There have been 3 reports of an increased incidence of gastric parietal cell antibody (different from the antibody sometimes present in ulcerative colitis serum which reacts with gastric epithelial cells) in ulcerative colitis68 · 86 · 87 and one report in which no increase was found above the incidence in controls. 88 It is possible that these findings may relate to the reported association of ulcerative colitis with gastritis, 85 or possi-

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bly be due to iron deficiency associated with ulcerative colitis, or possibly to some interplay of all these factors. Whether such a finding strengthens the concept of ulcerative colitis being due to a basic immune disturbance will not be clarified until proper studies have been done, similar to those being conducted into the problem of pernicious anemia. The presence of antinuclear factor in the sera of ulcerative colitis patients has been reported. Results are conflicting; a higher incidence than in a control group has been reported, 126, 1 34 whereas others have reported no difference.85-88 Techniques have varied. Conventional methods have given negative results, and controls have not been matched for age or sex, which is probably essential in such studies. There may be environmental or ethnic differences. The lupus erythematosus (LE) cell phenomenon is apparently rare in ulcerative colitis and when present is associated with extraintestinal manifestation of systemic LE,113 lupus declaring itself after the onset of ulcerative colitis. Since there have been some rather tentative reports of reduced serum complement activity in the active phase of certain connective tissue and other diseases in which autoimmunization is currently held to be involved,l 35 · 136 assays of complement have been made in ulcerative colitis. By contrast, normal or high activity has been found in two groups of patients ;137· 138 the rise has been more apparent in the active disease. These findings do not support the idea of a continuing complement-fixing antigenantibody reaction, but there are too many factors other than complement fixation which might introduce variation:::, and no useful conclusions can be drawn from this work. Regional Enteritis

This disease displays no demonstrated abnormally high incidence of any organspecific or non-organ-specific circulating autoantibodies.126 A significant ly lower incidence of circulating antibodies to some dietary proteins than in healthy controls has been described. 29 Some observations of impaired delayed type skin sensitization, as

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for instance the tuberculin reaction, 139 have been reported, but only when focal granulomatous disease is present. 140 Even then the differences are not very great. The analogy with sarcoidosis 141 is perhaps a little strained, and attempts to develop a test equivalent to the Kveim test, using extracts of Crohn's tissue, have so far not been successful. 140· 142 Liver and Pancreas

There is some evidence for involvement of immune mechanisms in various types of hepatitis. The presence of antibodies to liver extracts in the sera of patients with various kinds of liver diseases has been described.U3-145 In primary biliary cirrhosis the incidence is high; in viral hepatitis there are divergent reports. Antibodies reactive with liver have been found in postnecrotic cirrhosis, and the hepatic antigen involved is apparently different from that in primary biliary cirrhosis.14 4 In the latter, 73% of sera were found to contain an antibody to a component of the cells of the bile ductules ;146 in sera from patients with other liver disease this antibody was rarely found. Another recent study has shown a 100% incidence of an antimitochondrial antibody in primary biliary cirrhosis, using the Coons indirect immunofluorescent technique ;147 again this was present only at a much lower incidence in active chronic hepatitis, acute viral hepatitis, and some nonhepatic connective tissue diseases. In obstructive jaundice this antibody was not present. The mitochondrial antigen is not organ specific. In chronic active hepatitis, which may include so-called plasma-cell hepatitis, lupoid hepatitis, and juvenile cirrhosis, infiltration of the liver parenchyma with plasma cells and lymphocytes, hypergammaglobulinemia, and the prevalence of circulating antinuclear factors suggest an immune basis for the liver damage; the disease (or group of diseases) is quite often characterized by rashes, arthralgias, and even attacks of pleurisy. Positive latex, sheep-cell agglutination, and antinuclear factor tests are common in this condition . Some sera produce the LE cell phenomenon. Recently the presence of an antibody against smooth muscle has been

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demonstrated in this condition. This appears to be tissue specific, is dissimilar from the striated muscle antibodies found in myasthenia gravis, and is not found in systemic lupus erythematosus or in conditions so far studied.148 Its significance is quite unclear. A recent study suggests that it may be a valuable means of diagnosing chronic active hepatitis. 149 Many of the positive sera react also with renal glomerular tissue. The pericholangitis found in association with ulcerative colitis may be self perpetuating, suggesting the possibility of an autoimmune reaction; 150 the demonstration of the presence of y-globulin on both colonic and biliary epithelium in ulcerative colitis may be pertinent. 151 Positive precipitin reactions with saline extracts of human pancreas have been reported in cases of chronic pancreatitis and pancreatic carcinoma. 152 -154 The antigen may be associated with the endoplasmic reticulum of the acinar cell rather than with pancreatic enzyme activity. 155 It seems to have a high degree of species specificity. Other studies have not demonstrated circulating iso- or autoantibodies specific for pancreas.156-159 Experimental Studies

A good review of the literature up to

1960 is available. 1 Repeated attempts to

produce models of chronic inflammatory disease of the gastrointestinal tract have been rather unsuccessful. The Auer phenomenon produces acute, but not chronic, lesions in the colon of animals. 160 -163 Preliminary reports of the successful application of the Masugi technique to produce acute colitis in dogs require amplification.164· 165 As has been mentioned earlier, recent work in the case of other organs suggests that organ-specific heterologous antibodies do not produce damage in the appropriate organ, and may indeed protect that organ from the induction of autoimmune inflammation. 132· 133 It is very possible that bacterial factors may obscure any phenomena directly related to tissue antigens. Of interest are reports of the induction of colitis by direct application of dinitrochlorobenzene to the rectal mucosa of guinea pigs previously sensitized by skin

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contact,l 66 • 167 Interesting speculations have also been initiated by the report of the intestinal lesions seen in "runt" disease in mice. 168 Site of Production and Nature of Immunoglobulins

Attempts have been made recently to characterize and quantify the products of plasma cells or lymphocytes in the lamina propria of the gastrointestinal mucosal surfaces. The presence of cells producing the three main species of human immunoglobulins, namely IgG, IgA, and IgM, has been demonstrated in the small intestine in celiac disease 44 and in the stomach in pernicious anemia. 169 The relative distribution of these cells in normal tissues in the human small intestine has been quantified.170 The IgA producers seem to predominate. What contribution such cells make to circulating serum globulin fractions is at present unknown, and it is not clear whether antibodies demonstrated in gastric juice are produced locally in the wall of the stomach or not. A recent paper discusses some of the special features of immunoglobulins in external secretions.l 71 Recent reports of specific reduction of immunoglobulins associated with steatorrhea172-175 (and in two groups with Giardia infestation173· 174 ) have appeared which suggest that the dysgammaglobulinemia may be due to failure of synthesis in the intestinal wall. An interesting association in these studies has been of hyperplasia of lymphoid nodules in the lamina propria of the small intestine. Response to Therapy

The concept that certain chronic inflammatory diseases of the gastrointestinal tract in man might be due to abnormal immunological response has intruded into therapeutics. Apart from treatment with corticosteroids in ulcerative colitis, however, no properly designed controlled therapeutic trials involving either corticosteroids or immunosuppressive agents have been reported. It has been mentioned already that corticosteroids restore vitamin B12 absorption in a proportion of patients with atrophic gastritis-this may be due to

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increased intrinsic factor activity. Restoration of acid production is minimal, but the results reported are intriguing. In most patients with pernicious anemia experience has so far been r ather barren as regards restoration of acid production and of parietal cells; it may be that in these subjects the capacity for proper gastric mucosal repair has been irrevocably lost. So far, there are no practicable means of early detection of gastritis, when the institution of therapy might reverse the process, but this is a field in which practical application may perhaps prove fruitful in future. The use of mercaptopurine, 6-thioguanine, and busulphan in ulcerative colitis has been reported,H 7 as has that of azathioprine.l77 No series has been reported in which proper evaluation is possible. The same is true of chronic active hepatitis. It is to be hoped that in the future therapeutic trials will be performed which will not only lead to real advances in the treatment of the various gastrointestinal diseases under consideration but may also illuminate some of the factors involved in their causation. REFERENCES 1. Kirsner, J. B., and M. D. Goldgraber. 1960.

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