Coeliac disease (CoD) is a small intestinal disorder characterized by villous atrophy, crypt cell hyperplasia and an increased production of T helper cell type 1 (Th1) cytokines. Interleukin (IL)-18 is a pro-inflammatory cytokine that has a crucial role in maintaining the Th1 response. In this study, the serum levels of IL-18 were measured in children with CoD or other gastrointestinal diseases in order to evaluate the possibility of using IL-18 as a disease activity marker. IL-18 levels were higher in samples from CoD patients [median 443 pg/ml (148-885)] compared to healthy controls [median 205 pg/ml (11-379)], P <0.05. In contrast, the levels of IL-18 were not enhanced significantly in the serum from patients with inflammatory bowel disease (IBD) [median 324 pg/ml (207-546)] or in the disease control group [median 303 pg/ml (2-689)]. In CoD patients, after 2 weeks of gluten challenge (GC), serum IL-18 was unchanged [median 268 pg/ml (59-458)] compared to patients on a gluten-free diet [median 220 pg/ml (53-600)], while IL-18 was increased after 12 weeks of GC [median 551 pg/ml (94-952)], P <0.01. The IL-18 levels correlated with IgA anti-transglutaminase antibody levels (rs=0.59, P=0.016) in serum from untreated CoD patients, and IL-18 also followed the degree of small intestinal villous atrophy in 12 out of 19 CoD patients. Our results support the view that serum IL-18 concentrations in children with CoD follow disease activity, suggesting a role for IL-18 in the induction of an inflammatory Th1-response after gluten exposure.

OBJECTIVES:We measured circulating autoantibodies and evaluated the potential of circulating antitissue transglutaminase (tTG) antibodies to determine the presence of celiac disease (CD) in children with Down syndrome.METHODS:An ELISA based on recombinant human tTG was used to measure the levels of immunoglobulin A and immunoglobulin G antibodies in serum samples from 72 children with Down syndrome, 52 children with biopsy-verified CD, 21 disease controls with a normal small intestinal mucosa and 23 healthy controls. Of the 72 Down syndrome children, 11 under-went a small intestinal biopsy.RESULTS:Four of 72 children with Down syndrome were diagnosed as having CD and three of them had serum levels of immunoglobulin A tTG antibodies greater than 6 U/mL (668, 147 and 7 U/mL). One Down syndrome child with biopsyproven CD had normal levels of immunoglobulin A tTG. Two Down syndrome children had increased levels of immunoglobulin A tTG (13 and 7 U/mL) but none of these children had an intestinal biopsy performed. Of the 52 CD subjects (median 664 U/mL) one was negative for immunoglobulin A tTG (5 U/mL) and all healthy controls (median 1.2 U/mL) and disease controls (median 0.9 U/mL) had immunoglobulin A tTG antibody levels less than 6 U/mL. Two of four Down syndrome children with CD and 36 of 52 celiac children had increased serum levels of immunoglobulin G tTG antibodies. There was no correlation between the serum levels of tTG and antithyroid autoantibodies.CONCLUSIONS:Although the diagnosis of CD depends on histologic evaluation of intestinal biopsies, detection of anti-tTG antibodies provides a useful complementary diagnostic method for CD in children with Down syndrome.

The production of cytokines from T cells and macrophages is of potential importance for the histological changes apparent in coeliac disease (CoD). Small intestinal biopsy specimens from children with CoD and disease control subjects were investigated for their content of cytokines and tissue transglutaminase (tTG). The transforming growth factor-beta1 (TGF-beta1) expression was increased in the lamina propria of children with villous atrophy. In contrast, TGF-beta3 was expressed at a higher level in the epithelium and the lamina propria of the disease control subjects. The tTG expression was increased in the small intestine of CoD patients as compared with that in subjects. Interleukin-4 (IL-4) was detected in the lamina propria of both CoD patients and controls, and some of the investigated biopsy specimens also showed IL-4 expression in the epithelium. We conclude that children with active CoD could have an altered expression of TGF-beta and tTG in the small intestine and that a disturbed regulation of TGF-beta may be of importance in the immune pathogenesis of CoD.

Coeliac disease has emerged as a public health problem. The aim of the present study was to analyse trends in the occurrence of symptomatic coeliac disease in Swedish children from 1973 to 1997, and to explore any temporal relationship to changes in infant dietary patterns. We established a population‐based prospective incidence register of coeliac disease in 1991, and, in addition, retrospective data from 1973 were collected. A total of 2151 cases fulfilled the diagnostic criteria. Furthermore, we collected national data on a yearly basis on duration of breastfeeding, intake of gluten‐containing cereals and recommendations on when and how to introduce gluten into the diet of infants. From 1985 to 1987 the annual incidence rate in children below 2 y of age increased fourfold to 200‐240 cases per 100 000 person years, followed from 1995 by a sharp decline to the previous level of 50‐60 cases per 100 000 person years. This epidemic pattern is quite unique for a chronic disease of immunological pathogenesis, suggesting that prevention could be possible. The ecological observations made in this study are compatible with the epidemic being the result, at least in part, of a change in and an interplay among three factors within the area of infant feeding, i.e. amount of gluten given, age at introduction of gluten, and whether breastfeeding was ongoing or not when gluten was introduced. Other factor(s) may also have contributed, and the search for these should be intensified.

BACKGROUND:Highly discriminatory markers for celiac disease are needed to identify children with early mucosal lesions. The purposes of this study were to evaluate the clinical potential of circulating anti-tissue transglutaminase (tTG) immunoglobulin (Ig)A antibodies in the diagnosis of childhood celiac disease and to investigate the extent of autoreactivity of these antibodies.METHODS:Included in this retrospective study were samples from 22 children with biopsy-verified celiac disease, 23 control subjects with disease, and 22 healthy control subjects without any known gastrointestinal or inflammatory disorders. An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of IgA antibodies specific for human and guinea pig tTGs. All samples were also analyzed for antibodies to gliadin and endomysium (EMA).RESULTS:The concentrations of IgA specific for human and guinea pig tTGs correlated with the small intestinal villous structure and the serum levels of IgA EMA. The tTG ELISAs exhibited a high specificity and sensitivity for detection of untreated celiac disease. The human erythrocyte IgA tTG ELISA had the highest sensitivity (100%) and a specificity of 98%. The IgA EMA method had a sensitivity of 95% and the highest specificity (100%) of all tests.CONCLUSIONS:Our results provide additional support to the concept that anti-tTG IgA antibodies can be used as a highly discriminatory serologic marker for celiac disease and that measurements of these autoreactive antibodies may in the future be used as an alternative to the EMA test.

Coeliac disease (CoD) is a small intestinal disorder characterized by crypt cell hyperplasia and villous atrophy, and the production of cytokines from T cells and macrophages are of importance for the histological changes seen in CoD. A peroral immunization with an antigen, which gives rise to a mucosal immune response, may increase the levels of circulating cytokine-producing cells, and we wanted to obtain a better picture of an eventual emergence of activated circulating T cells in the peripheral blood in children with CoD. The cytokine expression of interferon-gamma (IFN-gamma), IL-4, IL-6 and IL-10 was measured at the single-cell level by an ELISPOT method in 38 children with CoD. The numbers of IFN-gamma-producing cells in the peripheral blood was increased in children with untreated CoD (P < 0.01) and after gluten challenge (P < 0.05) compared with healthy controls. Also, the numbers of IL-6-producing cells were increased (P < 0.05) after gluten challenge compared with the healthy controls. A paired comparison showed that the numbers of IFN-gamma-producing cells increased after gluten challenge (P < 0.05), whereas no such change was seen for IL-4- or IL-10-producing cells. There were no differences in the numbers of IFN-gamma-producing cells between the group of children with treated CoD and the groups of untreated or challenged CoD children. IL-4 production correlated with serum levels of total IgE. These results show that circulating mononuclear cells in children with active CoD secrete cytokines compatible with a type 1 response.

BACKGROUND:An association between Down syndrome and celiac disease has been reported. This study was conducted to determine the association between childhood celiac disease and Down syndrome in the county of Uppsala, Sweden.METHODS:All 76 children with Down syndrome (1-18 years) were screened for the occurrence of anti-gliadin antibodies (AGA) and anti-endomysium antibodies (EMA). Twelve children with suspected celiac disease were investigated further.RESULTS:Increased levels of both IgA and IgG AGA were found in 26% of the children and of EMA in and 5 of 76. Celiac disease was diagnosed in at least three of the children (3.9%; 95% confidence interval 0%-8.3%), and it could have been present in as many as eight. Three of the five EMA-positive children with suspected celiac disease had the HLA phenotype DR3, DQ2.CONCLUSIONS:The results show that determination of EMA is more useful as a screening test for celiac disease and for follow-up than is AGA in children with Down syndrome. The present study also confirms that celiac disease is overrepresented among Swedish children with Down syndrome and that celiac disease should be considered in all persons with Down syndrome.

At a seminar arranged in September 1997 by the Swedish Paediatric Working Group for Coeliac Disease, a diagnostic protocol proposed by the working group was approved by a majority of the paediatricians present, representing almost all paediatric units in Sweden. Briefly, a small bowel biopsy is called for in all children, both at presentation and as a control during gluten-free dieting. Subsequent gluten challenge and biopsy are mandatory only in cases of atypical presentation or if the diagnosis is questioned at some future date. Serum antigliadin and anti-endomysial antibody tests are complementary tools. Agreement was also reached regarding the institution of a national coeliac disease registry.

[Gluten intolerance in children--diagnostic routines in Sweden 1996. Great variations in celiac disease studies]

BACKGROUND:Mast cells and eosinophils are key cells in the development of active symptoms in allergic diseases and other inflammatory conditions, and they mediate their action through the release of very potent granule constituents.METHODS:Five patients with milk-related gastrointestinal symptoms diagnosed by double-blind placebo-controlled milk challenges, but with negative responses to skin prick tests and RASTs with milk, and eight healthy control subjects were investigated. Repeated perfusion studies were performed with a two-balloon, six-channel tube by using milk, casein, and whey as antigens. Luminal eosinophil cationic protein, histamine, and albumin were measured by radioimmunoassay.RESULTS:Luminal cow's milk induced a pronounced increase in intestinal secretion of histamine and eosinophil cationic protein in patients, but not control subjects, during the first 20 minutes after challenge (histamine from 123 +/- 12 to 543 +/- 175 ng/cm, hr; eosinophil cationic protein from 80 +/- 23 to 686 +/- 262 ng/cm, hr). Albumin, as a marker of plasma leakage, was also significantly increased.CONCLUSION:These data indicate that mast cells and eosinophils are effector cells not only in patients with allergic disease but also in patients intolerant to foods and lacking circulating antibodies. The underlying mechanisms may be a reaction mediated by locally appearing antibodies or an immunologic activation resembling that found in intestinal disorders such as celiac disease.

BACKGROUND: Increased luminal transport of proteins and fluid is part of the inflammatory reaction in inflammatory disease of the bowel and of the airways in allergic diseases and asthma. The objective of this study was to determine intestinal appearance rates of albumin and hyaluronan in vivo in atopic patients allergic to birch, as well as changes in net jejunal transport of monovalent ions and water induced by the antigen. METHODS: Secretion studies were performed with the use of a segmental jejunal perfusion system with a small two-balloon, six-channel tube. The intestinal mucosa was challenged with birch allergen in patients allergic to birch and in matched control subjects (n = 12 in both groups). RESULTS: In patients, but not in control subjects, the luminal antigen induced a net increase in albumin of 2689 ± 567 μg/cm/hr and in hyaluronan of 2609 ± 737 ng/cm/hr (p < 0.01 vs control subjects in both cases). Furthermore, basal net absorption of Cl- ions, Na+ ions, and water was converted to a net secretion after antigen challenge. CONCLUSION: Exposure to antigen normally acting on the respiratory tract induced increased permeability of the gastrointestinal mucosa. This would suggest less organ specificity and more general allergic recognition shared by several immunocompetent tissues in the body, probably mediated by circulating IgE antibodies. (J ALLERGY CLIN IMMUNOL 1996;97:1225-32.)

The capsule technique for small bowel biopsy performed at Swedish paediatric clinics was evaluated using two questionnaires in 1990 and 1993, respectively. Replies were received from all 45 centres which together perform approximately 2300 biopsies per year. Clotting function tests prior to biopsy were carried out in 42% of the centres. The biopsies were performed under intubation anaesthesia in 13% of the centres. The most striking difference between the answers to the two questionnaires was the mode of sedation. The use of intravenous sedatives increased from 40% of the centres in the first questionnaire to 59% in the second one. The use of the oral, rectal and intramuscular routes decreased correspondingly. The most frequently used drugs for intravenous sedation were benzodiazepines, in the first questionnaire diazepam and in the second one midazolam. The failure rate was approximately 5%. In the first questionnaire, no complication was encountered. In the second questionnaire, three cases of intramural duodenal haematoma were reported, one of which led to pancreatitis. We conclude that by focusing on questions of sedation these rather simple questionnaires may have resulted in more effective sedation of children undergoing small bowel biopsy.

Background The mechanisms for adverse reactions to foods in the gastrointestinal tract are poorly understood. Presently, only limited possibilities are available for identification of adverse immunological reactions to different foods.Objective The intestinal inflammatory reactions in adult patients with a history of milk-related gastrointestinal symptoms were studied after intestinal challenges by a jejunal perfusion technique and compared with the reactions in a control group.Methods Five skin-prick test and radioallergosorbent test negative and lactose tolerant patients with a history of milk-related gastrointestinal symptoms, verified by double-blind placebo-controlled challenge, and eight healthy controls were investigated. Perfusions were performed allowing analyses of a well-defined 'closed' jejunal segment. Milk perfusions were performed in patients and controls after an overnight fast. Ten millilitres of milk were administered to the segment at 3 mL/min. The jejunal fluid levels of hyaluronan (hyaluronic acid) and albumin were measured.Results In the five patients the milk challenges induced as a mean fivefold increased levels of hyaluronan compared with prestimulation values, whereas no such increases were seen in the control subjects. Albumin, as a marker of plasma leakage, was also increased in the patients but not in the control subjects.Conclusion The underlying mechanisms for locally increased levels of hyaluronan and also albumin in the intestinal lumen may be secretion of lymph rich in hyaluronan and reflect the mucosal oedema. This capacity of the intestinal mucosa to react with lymph leakage towards a locally infused allergen may be a possible way to delineate gastrointestinal reactions in food-related disorders.

Pediatric Allergy and ImmunologyVolume 4, Issue S3 p. 21-24 Age-related antibody response to food antigens A. Dannaeus, Department of Pediatrics, University Hospital, Uppsala, Sweden A. Dannaeus, Department of Pediatrics, University Hospital, S-000 00 Uppsala, SwedenSearch for more papers by this author A. Dannaeus, Department of Pediatrics, University Hospital, Uppsala, Sweden A. Dannaeus, Department of Pediatrics, University Hospital, S-000 00 Uppsala, SwedenSearch for more papers by this author First published: June 1993 https://doi.org/10.1111/j.1399-3038.1993.tb00327.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Citing Literature Volume4, IssueS3June 1993Pages 21-24 RelatedInformation

Acta PaediatricaVolume 82, Issue s385 p. 1056-1056 Is the incidence of childhood coeliac disease in Sweden still rising? L Stenhammar, L Stenhammar Departments of Paediatrics1Search for more papers by this authorH Ascher, H Ascher Norköping Hospital, University Hospitals of Göteborg, SwedenSearch for more papers by this authorB Catell, B Catell Lund, SwedenSearch for more papers by this authorL Danielsson, L Danielsson Danderyd Hospital, SwedenSearch for more papers by this authorA Dannaeus, A Dannaeus University Hospitals of Uppsala, SwedenSearch for more papers by this authorA Ivarsson, A Ivarsson Umeå, SwedenSearch for more papers by this authorB Lindquist, B Lindquist örebro Medical Centre, SwedenSearch for more papers by this author L Stenhammar, L Stenhammar Departments of Paediatrics1Search for more papers by this authorH Ascher, H Ascher Norköping Hospital, University Hospitals of Göteborg, SwedenSearch for more papers by this authorB Catell, B Catell Lund, SwedenSearch for more papers by this authorL Danielsson, L Danielsson Danderyd Hospital, SwedenSearch for more papers by this authorA Dannaeus, A Dannaeus University Hospitals of Uppsala, SwedenSearch for more papers by this authorA Ivarsson, A Ivarsson Umeå, SwedenSearch for more papers by this authorB Lindquist, B Lindquist örebro Medical Centre, SwedenSearch for more papers by this author First published: January 1993 https://doi.org/10.1111/j.1651-2227.1993.tb12810.xCitations: 9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Cavell B, Stenhammar L, Ascher H, Danielsson L, Dannaeus A, Lindberg T, Lindquist B. Increasing incidence of childhood coeliac disease in Sweden. Results of a national study. Acta Paediatr 1992; 81: 589–92. 2 Meeuwisse GW. Diagnostic criteria in coeliac disease. Actd Paediatr Scand 1970; 59: 461–3. 3 Walker-Smith JA, Guandalini S, Schmitz J, Shmerling DH, Visakorpi J. Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society for Paediatric Gastroenterology and Nutrition. Arch Dis Child 1990; 65: 909–11. 4 Hed J, Lieden G, Ottosson E, et al. IgA anti-gliadin antibodies and jejunal mucosal lesions in healthy blood donors. Lancet 1986; 11: 215. 5 Grodzinsky E, Franzén L, Hed J, Ström M. High prevalence of coeliac disease in healthy adults revealed by antigliadin antibodies. Ann Allergy 1992; 69: 66–70. Citing Literature Volume82, Issues385January 1993Pages 1056-1056 ReferencesRelatedInformation

Background: To determine whether inflammatory markers and mediators were released in response to different intestinal antigens, studies were performed in atopic patients allergic to birch, patients allergic to psyllium powder (ispaghula), and patients intolerant to milk.Methods: Allergy to birch and psyllium powder was documented by the presence of circulating IgE antibodies and positive skin tests. Patients intolerant to milk had negative outcomes Of radioallergosorbent tests and skin tests but positive results of double-blind, placebo-controlled tests. Challenge of the intestine with different antigens was achieved by perfusion of a jejunal segment occluded between balloons. Basal and antigen-activated release of mast cell/basophil and eosinophil products and of substances emanating from the plasma and interstitial fluid was compared in perfusate fluid from patients (n = 8) and matched healthy controls (n = 8).Results: Perfusate levels of albumin and hyaluronan (previous name hyaluronic acid) were increased threefold to fivefold by antigen in all patients, but not in controls. Eosinophilic cationic protein increased in patients but also in ispaghula controls. Histamine was released in response to milk, but not in patients allergic to birch or ispaghula. Prostaglandin E2 increased in milk- and birch-sensitive patients. In response to ispaghula, however, it was released in both patients and controls.Conclusions: We conclude that subclinical intestinal challenge with antigen induces an increase in the appearance rate of albumin and hyaluronan in the intestinal lumen both in atopic patients (with target organs such as the lungs or nose and eves) and in patients with intestinal intolerance to milk. These changes in permeation are similar to those reported from other organs such as the lung. They may reflect a common response in early phase I reactions that are either IgE-mediated or occur in response to food antigens without any obvious involvement of an IgE-mediated mechanism. Subclinical provocation with intestinal antigens should prove useful for further elucidation of mechanisms underlying intestinal mucosal reactions to exogenous stimuli.