Diagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines.

OBJECTIVES: This guideline provides recommendations for the diagnosis and management of suspected cow's-milk protein allergy (CMPA) in Europe. It presents a practical approach with a diagnostic algorithm and is based on recently published evidence-based guidelines on CMPA. DIAGNOSIS: If CMPA is suspected by history and examination, then strict allergen avoidance is initiated. In certain circumstances (eg, a clear history of immediate symptoms, a life-threatening reaction with a positive test for CMP-specific IgE), the diagnosis can be made without a milk challenge. In all other circumstances, a controlled oral food challenge (open or blind) under medical supervision is required to confirm or exclude the diagnosis of CMPA. TREATMENT: In breast-fed infants, the mother should start a strict CMP-free diet. Non-breast-fed infants with confirmed CMPA should receive an extensively hydrolyzed protein-based formula with proven efficacy in appropriate clinical trials; amino acids-based formulae are reserved for certain situations. Soy protein formula, if tolerated, is an option beyond 6 months of age. Nutritional counseling and regular monitoring of growth are mandatory in all age groups requiring CMP exclusion. REEVALUATION: Patients should be reevaluated every 6 to 12 months to assess whether they have developed tolerance to CMP. This is achieved in >75% by 3 years of age and >90% by 6 years of age. Inappropriate or overly long dietary eliminations should be avoided. Such restrictions may impair the quality of life of both child and family, induce improper growth, and incur unnecessary health care costs.

Frequencies of genetic polymorphisms of TLR4 and CD14 and of HLA-DQ genotypes in children with celiac disease, type 1 diabetes mellitus, or both.

OBJECTIVES: Besides the central role of the adaptive immune system, a disturbance of innate immunity is also involved in the pathogenesis of celiac disease (CD). Inasmuch as CD and type 1 diabetes mellitus (T1DM) frequently coexist because of a common genetic predisposition, our aim was to study the frequency of CD14 C-260T and TLR4 A+896G single nucleotide polymorphisms (SNPs) and the distribution of HLA-DQ genotypes in children affected by CD, T1DM, or both. PATIENTS AND METHODS: TLR4 and CD14 SNPs were tested by polymerase chain reaction, followed by restriction fragment length polymorphism analysis in 80 children with T1DM, 100 children with CD, and 47 children with both CD and T1DM. Determination of HLA-DQ alleles was done by sequence-specific polymerase chain reaction. Frequencies were compared with those of healthy control children. RESULTS: The prevalence of the homozygous CD14 C-260TT genotype was significantly (P = 0.0081) lower in children with T1DM but not in those with CD and T1DM, compared with control children. No difference was found in the genotype and allele frequencies of TLR4 between the studied groups. In patients with T1DM, the frequency of the homozygous HLA-DQ8 genotype was significantly higher than in CD, whereas the frequency of homozygous or heterozygous HLA-DQ2 genotypes did not differ from that in control children. In patients with CD, both homozygous and heterozygous HLA-DQ2 genotypes were significantly more frequent than in the control and T1DM groups, and no elevation in the frequency of the HLA-DQ8 genotypes was observed. In patients with T1DM and those with CD and T1DM, the occurrence of HLA-DQ2/8 heterozygosity was significantly higher than in children with CD only and in control children. CONCLUSIONS: Our results suggest that in patients with T1DM, the CD14 C-260TT homozygous genotype increases the risk for the development of CD. The distribution of HLA-DQ genotype is different in children with CD and T1DM than in children with CD or T1DM only. Determination of the HLA-DQ genotype in children with T1DM may help in estimating the risk for the development of CD.

Increased expression of Toll-like receptor (TLR) 2 and TLR4 in the colonic mucosa of children with inflammatory bowel disease.

Inflammatory bowel disease (IBD) may result from exaggerated stimulation of the mucosal immune system by luminal bacterial flora. Bacterial products are recognized by pattern recognition receptors such as Toll-like receptors (TLRs), which are key regulators of the innate immune system. Therefore, the expression of TLR2, TLR3 and TLR4 in colonic biopsy samples taken from children with active IBD were studied and compared to controls. Colonic biopsy samples were collected from macroscopically inflamed and non-inflamed regions of the mucosa of 12 children with freshly diagnosed IBD (fdIBD) and 23 children with relapsed IBD (rIBD). Specimens were also obtained from eight controls. TLR2, TLR3 and TLR4 mRNA expression and protein levels were determined by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot. We found higher TLR2 and TLR4 mRNA and protein levels in the inflamed colonic mucosa of children with fdIBD and rIBD compared to controls. In the non-inflamed colonic mucosa of children with fdIBD and rIBD, TLR2 and TLR4 mRNA and protein levels were similar to controls. TLR2 and TLR4 mRNA and protein levels also did not differ between children with fdIBD or rIBD in either inflamed or non-inflamed colonic mucosa. TLR3 mRNA expression and protein levels were similar in all groups studied. Our results of increased levels of TLR2 and TLR4 in the inflamed colonic mucosa of children with IBD confirm the hypothesis that innate immunity has an important role in the pathogenesis of this disease.

Short-term omeprazole treatment does not influence biochemical parameters of bone turnover in children.

Gastric proton pump inhibitors are widely used in the treatment of dyspeptic problems and for the eradication of H. pylori infection. Data are not available on whether omeprazole, a representative of proton pump inhibitors, influences the function of osteoclastic H+-pump in children. We studied the impact of short-term omeprazole administration on the biochemical parameters of bone turnover in pediatric patients. Urinary calcium excretion, serum total alkaline phosphatase activity, collagen type 1 crosslinked C-telopeptide, and osteocalcin levels were determined in 34 children [20 girls (9 prepubertal) and 14 boys (6 prepubertal)] before and after 2 weeks of omeprazole treatment at a dose of 20 mg/day. The measured parameters were within the healthy reference range in each patient. None of them altered during the study in any age or in any gender. We conclude that omeprazole, at a dose of 20 mg/day, does not significantly influence the investigated biochemical parameters of osteoclast and osteoblast function in pediatric patients.

Higher serum eosinophil cationic protein levels in children with cow's milk allergy.

BACKGROUND: In the pathogenesis of cow's milk allergy, abnormal immunologically mediated reactions play a basic role. Eosinophil activation also participates in the development of several allergies. The purpose of this study was to characterize the degree of this activation by measuring the serum level of eosinophil cationic protein (sECP) and establishing whether it is a useful parameter in monitoring oral cow's milk allergy. METHODS: The sECP level of 35 patients with previously confirmed cow's milk allergy (mean age, 16 months) was evaluated using a fluoroimmunoassay before the cow's milk rechallenge test and at 2 hours and 24 hours after cow's milk challenge. RESULTS: Of the 35 children with previously confirmed cow's milk allergy, 10 had positive clinical reactions after the milk rechallenge test, whereas 25 children had no reaction. The median sECP level of all the patients before the challenge test was significantly higher (12.4 microg/L) than that of the control group (4.3 microg/L) (P < 0.05). Two hours after the challenge, the median sECP of all patients (9.4 microg/L) was lower than the starting values. The median sECP levels were higher in children with positive challenge test results at all time points. However, this difference was not statistically significant. CONCLUSIONS: The normalization of sECP level may indicate the cessation of the cow's milk allergy. Therefore, the measurement of sECP may be helpful in determining the optimal time in which to repeat the challenge test, when the result will more likely be negative. The significant decrease of the sECP level 2 hours after the beginning of milk challenge test may be explained by the fact that this protein is excreted into the intestinal lumen.

Bone mineral content and density in asymptomatic children with coeliac disease on a gluten-free diet.

OBJECTIVES: Osteoporosis is a complication of coeliac disease. A gluten-free diet improves but does not normalize bone mineral density in adult patients. Only limited data are available regarding the influence of the disease and diet on bone mineralization in children. The aim of this study was to evaluate the radial bone mineral content and density in children and adolescents who are asymptomatic on a gluten-free diet. SUBJECTS AND METHODS: The bone mineral content (BMC) and density (BMD) values of the non-dominant radius midshaft in 91 children (53 girls, 38 boys, mean age 11.7 years, mean duration of disease 8.7 years) were determined by single-photon absorptiometry. At the diagnosis and at least three years after commencement of a gluten-free diet, serum calcium, phosphorus, albumin concentrations and alkaline phosphatase activities were measured in all patients, and intact parathormone concentrations in 16 patients. RESULTS: The mean BMC Z-score value in the female adolescent group only was significantly lower than normal (mean Z-score -1.04, P < 0.01). In contrast, the mean BMD Z-score was significantly higher compared to a healthy population both in girls (mean Z-score +1.36, P < 0.001) and in boys (mean Z-score +0.53, P < 0.02), as well as in the total patient group (mean Z-score +1.01, P < 0.001). The radial diameter was significantly smaller than normal in both pre-pubertal and adolescent groups. Serum laboratory parameters of asymptomatic patients were in the normal range. The parathormone mean value was significantly lower after at least three years of gluten-free diet than at diagnosis (mean +/- SD 3.77 +/- 1.07 versus 7.89 +/- 2.54 pmol/l, P < 0.01), but significantly higher compared to controls (2.89 +/- 0.90 pmol/l, P < 0.05). CONCLUSIONS: These data indicate that treated, asymptomatic coeliac children and adolescents have normal or even higher radius mineral density values than controls, but the bone size remains reduced. Although there is no direct evidence of calcium malabsorption in this cohort of coeliac patients, the slightly higher parathormone levels, together with some other factors, particularly delayed puberty, may result in reduced bone size.

Increased expression of intercellular adhesion molecule-1 and mucosal adhesion molecule alpha4beta7 integrin in small intestinal mucosa of adult patients with food allergy.

The mechanisms of adverse reactions to foods in the gastrointestinal tract are poorly understood. Previous studies of other atopic diseases and animal models suggest that adhesion molecules and mucosal lymphocytes may be implicated in the pathogenesis of food allergy (FA). The aim of our study was to investigate the expression of adhesion molecules and mucosal lymphocytes in duodena of patients with food allergies and of controls. Ten patients with FA to cereals (wheat, oats, and rye) or cow's milk and 9 control patients were included in the study. Quantitative analysis and immunohistochemical stainings for two pairs of adhesion molecules (intercellular adhesion molecule-1 (ICAM-1), lymphocyte function-associated antigen-1 (LFA-1), alpha4beta7 integrin, and mucosal addressin cell adhesion molecule (MAdCAM-1) and lymphocyte markers on endoscopic duodenal biopsy specimens were performed. The villous structure and density of LFA-1-positive cells were normal in every biopsy specimen, but the patients had significantly more alpha4beta7+ cells in the intraepithelial space (P = 0.01). The expression of ICAM-1 in the lamina propria of patients with FA was also substantially increased (P = 0.003); however, staining with MAdCAM showed no intergroup difference. Moreover, we found significantly increased CD4+ and HLA-DR+ cells in the lamina propria of patients, in comparison to the controls, P = 0.05 and P = 0.04, respectively. The densities of CD3, CD8, HLA-DP, T cell receptor alphabeta+ and gammadelta+ cells and IgA-, IgA1-, and IgA2-containing cells did not differ in the two groups studied. Our results suggest that the increased expression of ICAM-1 and alpha4beta7 integrin may play an important role in the pathogenesis of food hypersensitivity and with the elevation of CD4- and HLA-DR-positive cells reflect a stage of inflammation in the structurally normal intestines.

[Treatment of infants with acute diarrhea in Hungary]. / A csecsemókori akut hasmenés kezelésének hazai gyakorlata.

In the treatment of infants with acute diarrhoea complicated by mild to moderate dehydration, there is a great importance of rapid rehydration over 3-4 hours with oral rehydration solution containing 60 mmol/l sodium and then the rapid reintroduction of normal diet or breast feeding which should be continued all the time if possible. The pharmacological treatment of diarrhoea is not justified. In the present study which was part of a European multicentre survey using questionnaires the authors analysed how the recommendation of European Society of Pediatric Gastroenterology, Hepatology and Nutrition are followed in Hungary. It was evaluated 131 returned questionnaires, 80 of primary care and 51 of hospital-based pediatricians. The overwhelming majority of pediatricians (92%) recommended the oral rehydration at the beginning of treatment. The four fifth of them use the ORS with recommended composition. Only 31% of them use rapid oral rehydration over 3-4 hours. Merely 10% of them suggest the early reintroduction of normal feeding after the oral rehydration, while more than half of the respondent pediatricians (52%) think that temporarily the use of lactose free formula is justified. It is a very favourable fact that 84% of doctors recommend the continuation of breast feeding. Some kind of drugs for the treatment of diarrhoea is suggested by 15% of repliers. On the base of results it is obvious that the guidelines for the treatment of acute diarrhoea in infancy is complied only partially in Hungary and the reintroduction of normal feeding is delayed.

[Helicobacter infection in children]. / Gyermekkori Helicobacter pylori-infekció.

Consensus was achieved on the following issues: in children H. pylori infection causes chronic gastritis, but rarely gastric and duodenal ulcer disease. Eradication of H. pylori leads to healing of these conditions. To-date, there is no evidence demonstrating a link between H. pylori gastritis and abdominal pain except in those children where a gastric or duodenal ulcer is present. Children should be investigated for H. pylori infection only if their symptoms are suggestive of organic disease rather than functional abdominal pain. Endoscopy with biopsies is the optimal method to investigate a child with upper gastrointestinal symptoms suggestive of organic disease but this should only be carried out when a diagnostic work up using non-invasive methods has excluded other causes such as lactose maldigestion, constipation, coeliac disease, liver or biliary tact disease. If H. pylori is identified through investigations carried out during endoscopy the infection should be treated. Treatment should be monitored with a reliable non-invasive test and the 13C-urea breath test is the preferred method. H. pylori eradication in such children will cure gastritis but there is no data to support a relationship between a cure of H. pylori gastritis and symptom relief except in patients with ulcer disease. Further studies are needed to establish whether there are any specific symptoms associated with H. pylori gastritis alone and whether infected children without ulcer disease benefit from anti-H. pylori therapy regarding their symptoms. This consensus meeting did not deal with the optimal therapy for H. pylori infection as there are insufficient studies concerned the best treatment in children.

[Serum eosinophil cationic protein (sECP) level after cow's milk challenge test in allergic children]. / A szérum eosinophil kationos protein szintjének változása tehéntejterhelést követóen allergiás gyermekekben.

The eosinophil cationic protein (ECP) level in the sera is higher in allergic diseases. The change of the ECP level in the sera of patients with cow milk allergy was examined during the cow's milk challenge test after a long cow's milk free diet period. The sECP level of 35 milk sensitive patients was determined by a fluoroimmunoassay (Pharmacia CAP System ECP FEIA) before the milk challenge test, as well as 2 and 24 hours after it. The average age of the patients was 16 (6-49) months. The basic sECP level of cow's milk allergic patients was significantly higher (12.2 micrograms/l vs. 7.0 micrograms/l, p < 0.05) than that of the control group (n = 20). The sECP level significantly decreased 2 hours after the milk challenge test (12.2 micrograms/l vs. 9.2 micrograms/l, p = 0.01), 24 hours after the challenge it was again on the basic level (11.2 micrograms/l, p = 0.26). Out of the 35 allergic children ten had positive clinical reactions after the milk challenge test (positive group), while 25 had no reaction after it (negative group). Comparing the sECP level of these two groups, no significant difference was found in the sECP level either before the milk challenge test or after it. The significant decrease of the sECP level 2 hours after the beginning of milk challenge test might be explained by the fact that this toxic protein is secreted into the bowel.

Jejuna of patients with insulin-dependent diabetes mellitus (IDDM) show signs of immune activation.

The roles of enteric viruses and food antigens as possible triggers in human insulin-dependent diabetes mellitus and the evidence that mucosal-associated homing receptors are important in both human and experimental diabetes prompted us to undertake an immunohistochemical study of intestinal specimens from patients with IDDM. We studied jejunal morphology and immunohistochemistry in 26 patients with IDDM, 13 of whom had the HLA-DQB1*0201 gene and therefore a higher risk of coeliac disease. The findings were compared with those in specimens from age-matched controls. Villous structure and the density of the intraepithelial lymphocytes were normal in every biopsy specimen. The extent of positivity with anti-DR and -DP antibodies in the villous epithelium was significantly greater in the specimens from patients than in those from controls (P = 0.0002 in both comparisons). The crypts were also more positive: for DR P = 0.0001, and for DP P = 0.002. The densities of T cells, CD4+, CD8+, and T cell receptor alpha/beta+ and gamma/delta+ cells in the epithelium and lamina propria were similar in patients and controls, but the patients had significantly more alpha 4/beta 7 integrin+ cells in the lamina propria (P = 0.006). No difference was seen between HLA-DQB1*0201-positive and -negative patients. These findings reflect a stage of inflammation in the structurally normal intestines of patients with IDDM and suggest secretion of inflammatory Th1-type cytokines in the intestine.

Immunohistochemical findings in the jejunal mucosa of patients with coeliac disease.

In the pathogenesis of coeliac disease, disturbed immunological processes play a basic role. This is also proved by immunohistochemical findings in the jejunal mucosa of patients with this disorder, which are discussed in this review. Intraepithelial lymphocytes are increased in number in active coeliac disease, most being of the CD8 subpopulation. The counts of lamina propria lymphocytes and the relative numbers of their subsets are comparable to those in healthy controls, but several studies have indicated that the densities of IgA, IgM and IgG immunoglobulin-containing cells in the lamina propria are increased in untreated coeliac disease. Activated T cells can also be found in the lamina propria of patients on gluten-containing diets. In the crypt epithelial cells of coeliac patients on normal diets, strong expression of HLA Class II antigens can be observed. All of these changes are normalized on a gluten-free diet. It was recently discovered by the authors and others that one of the hallmarks of coeliac disease, both active and treated, is an increase in number and proportion of gamma/delta intraepithelial T lymphocytes. The permanent increase of gamma/delta T cells may facilitate identification of a coeliac patient also when an intestinal biopsy is taken on a gluten-free diet and other morphologic signs are normalized. The detection of elevated numbers of intraepithelial gamma/delta T cells is also an indispensable help in the diagnosis of latent coeliac disease.

Density of gamma/delta+ T cells in the jejunal epithelium of patients with coeliac disease and dermatitis herpetiformis is increased with age.

Increased density of gamma/delta T cell receptor (TCR)+ intraepithelial lymphocytes is the only characteristic in the jejunum of patients with coeliac disease and dermatitis herpetiformis which is not normalized on a gluten-free diet. We explored the age-dependent changes in intraepithelial gamma/delta and alpha/beta TCR+ cells from 137 biopsies from patients with coeliac disease and dermatitis herpetiformis and from controls. Biopsy specimens from 100 patients with coeliac disease and dermatitis herpetiformis and from 37 controls were studied with an immunohistochemical method using MoAbs to T cell receptors and peroxidase staining. An increase in the density of intraepithelial gamma/delta T cells above the mean +2 s.d. of the density in controls was present in 97 of 100 specimens from patients with coeliac disease and dermatitis herpetiformis. The density of gamma/delta+ cells of patients with coeliac disease and dermatitis herpetiformis on a normal gluten-containing diet showed a positive correlation with age (r = 0.45, P < 0.0001). In controls, the density of gamma/delta+ cells remained low throughout the age-range studies, from age 0.6-57 years. In controls, alpha/beta+ cells increased with age (r = 0.57, P < 0.001). The increase in density of intraepithelial lymphocytes with age is in agreement with their thymus-independent character and local proliferation.

[Mineral content in bones of children with symptomless celiac disease and gluten-free diet]. / Glutenmentes diétán tünetmentes coeliakiás gyermekek csont ásványianyag-tartalmának vizsgálata.

Osteoporosis is a complication of adult celiac disease. The gluten-free diet improves but does not normalize bone mineral density. Only few and conflicting data are known about the influence of the disease and diet on bone mineralization in children. The aim of this study was to evaluate the radial bone mineral content (BMC) and density (BMD) in children and adolescents who are asymptomatic on gluten-free diet. The BMD and BMC values of non-dominant radius midshaft in ninety-one children (53 girls and 38 boys, mean age: 11.7 years, mean duration of disease: 8.7 years) were determined by single photon absorptiometry. At the diagnosis and at least three years after gluten-free diet, serum calcium, phosphorous and albumin concentrations and alkaline phosphatase activities were determined in all, and additionally intact parathormone concentrations in 16 patients. The mean BMC Z-score value in the entire study population did not differ from the value of normal age-matched population (mean Z-score: -0.27), but in female adolescent group was significantly lower than the normal value (mean Z-score: -1.04, p < 0.01). In contrast, the mean BMC Z-score value was significantly higher than in normal value in girls (mean Z-score: +1.36, p < 0.001), in boys (mean Z-score: +0.53, p < 0.02) as well as in the total patients group (mean Z-score: +1.01, p < 0.001). The diameter of radius midshaft was significantly smaller in all age group than the normal mean value. Serum laboratory parameters of asymptomatic patients were in the normal range. The serum parathormone value in treated patients was significantly lower than in untreated celiac children (mean +/- SD: 3.77 +/- 1.07 versus 7.89 +/- 2.54, p < 0.01), but significantly higher compared to controls (2.89 +/- 0.9, p < 0.05). The data indicate that the gluten-free diet alone is not able to normalize bone mineralization in children. The significant increase of serum parathormone level in treated asymptomatic patients may be explained by the lower calcium content of gluten-free diet. The authors suppose that low calcium supply in children similarly to adult patients can lead to increased parathormone secretion, which can cause the retardation of bone growth even in treated patients with celiac disease.

Increased frequency of IgM antibodies to cow's milk proteins in Hungarian children with newly diagnosed insulin-dependent diabetes mellitus.

UNLABELLED: We investigated the association between serum antibodies to cow's milk proteins and insulin-dependent diabetes mellitus (IDDM) in Hungarian children. Forty-eight children 1.0-17.1 years of age with newly diagnosed IDDM and 74 control children 1.0-16.0 years of age were studied for serum IgG, IgA and IgM antibodies to cow's milk, beta-lactoglobulin, bovine serum albumin and ovalbumin by enzyme-linked immunosorbent assays. The specificity of IgM antibodies to beta-lactoglobulin and bovine serum albumin was controlled by Western blot. The levels of IgG and IgA antibodies to cow's milk proteins were similar in children with and without IDDM, with the exception of slightly increased levels of IgA antibodies to beta-lactoglobulin in diabetic children (P = 0.05). The levels of IgM antibodies to cow's milk were significantly higher in IDDM patients than in control children (P = 0.0002). Children with IDDM more often had IgM antibodies to beta-lactoglobulin (46.3% vs 18.8%; P = 0.002) and bovine serum albumin (87.8% vs 49.3%, P < 0.0001) than control children. Neither the levels of IgG or IgA antibodies to ovalbumin nor the frequency of IgM antibodies to ovalbumin differed between diabetic and control children. CONCLUSION: In Hungarian children, clinical manifestation of IDDM is often associated with IgM antibody response to cow's milk protein and its fractions, beta-lactoglobulin and bovine serum albumin, indicating a loss of immunological tolerance to these proteins. IgG and IgA antibodies to cow's milk proteins, associated with an early introduction of cow's milk in diet, seem to play a minor role in the development of childhood IDDM in Hungary.

[Favorable effect of breast feeding and late introduction of cow's milk on the prevention of suspected allergic symptoms in infancy]. / Az anyatejes táplálás és a késöi tehéntejfehérje-bevitel kedvezö hatása a csecsemökori allergiára utaló tünetek megelözésében.

The authors studied in Káposztásmegyer belonging to the IVth district of Budapest the way of feeding and the frequency of skin, respiratory and gastrointestinal symptoms suggesting allergic disease in the first year of life of 405 infants born in 1993. It was analyzed whether the frequency of symptoms was related to the duration of breast feeding and the first introduction of cow's milk protein. In the 53 infants with symptoms the duration of breast feeding was significantly shorter (mean 12.5 weeks) than in the symptomless ones (20.2 weeks, p < 0.01). The first introduction of cow's milk was also significantly earlier in the infants with symptoms (mean 6.2 weeks) than in the healthy ones (11.8 weeks, p < 0.01). Cow's milk protein was more frequently introduced before the age of one months in infants with suspected cow's milk protein allergy (56%), than in the symptomless infants (34%, p < 0.01). It can be concluded that the shorter duration of breast feeding and the earlier exposure of cow's milk protein may increase the prevalence of allergic symptoms in infancy.

Immunohistochemical findings in jejunal specimens from patients with IgA deficiency.

Jejunal biopsy specimens from 25 patients with IgA deficiency (IgAd) were studied immunohistochemically to find markers of inflammation. Five of the 25 patients had coeliac disease (CD): they were on a gluten free diet and had normal jejunal morphology. Only two of 15 specimens from control subjects had CD25+ cells in the surface epithelium, while this was seen in 19 out of 20 specimens from IgAd patients (p < 0.0001). A significant increase of CD25+ cells was also noted in the lamina propria of IgAd patients. The median percentage of crypt cells in mitosis (Ki67+ cells) was higher in the specimens from IgAd patients (26%) than in those from controls (13%, p < 0.001). The densities of gamma delta T cell receptor positive cells in the surface epithelium and lamina propria did not differ in the specimens from IgAd patients and those of controls nor was the expression of HLA class II antigens augmented in the surface epithelium. These findings were similar for the IgAd patients whether or not the patient had DQB 0201 allele, a genetic marker which is strongly associated with CD. The inadequacy of the local immunoglobulins in patients with IgAd may lead to increased T cell activation, which is accompanied by the appearance of intraepithelial CD25+ cells and with an increase in the mitotic rate in the crypts.