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PubMed2004

Neurological abnormalities associated with celiac disease.

BACKGROUND: Celiac disease (CD) is a gluten-sensitive enteropathy in genetically susceptible individuals. Anecdotal reports suggest that the nervous system might be affected in the disorder, but the severity and prevalence of such an involvement have not been systematically evaluated. MATERIALS AND METHODS: Analysis of files of CD patients diagnosed between 1980 and 1999 for neurological abnormalities. Diagnosis of CD was based on the modified criteria of the European Society for Pediatric Gastroenterology and Nutrition. RESULTS: Of 148 CD patients, 18 (12%) had 21 neurological disorders that could not be attributed to any other condition including muscle abnormality (3), epilepsy (3), psychiatric disease (4), peripheral neuropathy (3), cerebrovascular disease (1), myelopathy (1) and Down syndrome (2). Other disorders probably unrelated to CD were present in 8 patients. CONCLUSION: If this association is not coincidental, both the central and the peripheral nervous systems may be affected in CD by a spectrum of neurological disorders that are either the outcome of CD or share the same pathogenesis with the enteropathy.

Adolescent↗
PubMed2001

The distribution of DQ genes in the Saharawi population provides only a partial explanation for the high celiac disease prevalence.

Celiac disease (CD) is a multifactorial disorder of the small intestine caused by a permanent dietary intolerance to gluten. The combined presence of the HLA class II DQA1*0501 and DQB1*0201 alleles represents the major genetic component for disease predisposition. It has been shown that the Saharawi refugees living in northern Africa have a very high frequency of CD. In the present study we analysed this population to evaluate the degree of association with CD of the haplotypes and genotypes at the main HLA-DQB1 and DQA1 disease loci. We found a strong association of the DR3, DQB1*0201-DQA1*0501-positive haplotypes and genotypes. A very high frequency of DR3, DQB1*0201-DQA1*0501 was also observed in the general Saharawi population. These results indicate that there is a good correlation between disease prevalence and frequency of the main predisposing haplotype in the background population. However, the correlation is incomplete because similar frequencies of DR3 are also observed in populations such as the Sardinians showing a much lower prevalence of CD. We can conclude that the distribution of DQ genes in the Saharawi population only provides a partial explanation for the high prevalence of CD. Other factors, such as rapidly changing dietary habits and/or non-DQ genes, may also play some role.

Adolescent↗
PubMed2002

Monitoring of in vitro deamidation of gliadin peptic fragment by mass spectrometry may reflect one of the molecular mechanisms taking place in celiac disease development.

Celiac disease, a chronic disorder of the small intestine, is caused by dietary gluten and is characterized by villous atrophy and local inflammation associated with infiltration of B and T lymphocytes and/or macrophages into the intestinal wall. In genetically predisposed individuals, the infiltrating cells are activated by gluten, gliadin and their proteolytic fragments and produce chemokines, cytokines and reactive radicals. The sequence of one of the macrophage-stimulatory gliadin peptic fragment was determined by mass spectrometry (MS) as VSFQQPQQQYPSSQ. The role of tissue transglutaminase (tTG) in innate immunity stimulation was studied by mass spectrometric monitoring of sequence changes in this active peptide. Two sites of glutamine deamidation in this peptide were localized by high-resolution scanning in MS/MS mode in an ion trap. A single deamidation in the parent peptide led to the complete loss of its stimulatory effect on macrophages.

Amino Acid Sequence↗
PubMed2004

Neurological manifestations of celiac disease.

UNLABELLED: Celiac disease (CD/ Nontropicalsprue, gluten-sensitive enteropathy) is a malabsortive condition in which an allergic reaction to the cereal grain-protein gluten (present in wheat, rye and barley) causes small intestine mucosal injury. The onset is in the first four decades of life, with a female to male ratio of 2:1. It may be associated with a wide spectrum of neurological manifestations including cerebellar ataxia, epileptic seizures, dementia, neuropathy, myopathy and multifocal leucoencephalopathy. We report three patients with neurological manifestations related with CD: one with cerebellar ataxia, one with epilepsy and one with cognitive impairment. The diagnosis of CD was confirmed by serologic tests (antiendomysial and antigliadin antibodies) and biopsy of the small intestine. In two patients the neurological symptoms preceded the gastrointestinal abnormalities and in all of them gluten restriction failed to improve the neurological disability. CONCLUSION: CD should be ruled out in the differential diagnosis of neurological dysfunction of unknown cause, including ataxia, epilepsy and dementia. A gluten free diet, the mainstay of treatment, failed to improve the neurological disability.

Adult↗
PubMed2005

No genetic association of the human prolyl endopeptidase gene in the Dutch celiac disease population.

Celiac disease (CD) is a complex genetic disorder of the small intestine. The DQ2/DQ8 human leucocyte antigen (HLA) genes explain approximately 40% of the genetic component of the disease, but the remaining non-HLA genes have not yet been identified. The key environmental factor known to be involved in the disease is gluten, a major protein present in wheat, barley, and rye. Integrating microarray data and linkage data from chromosome 6q21-22 revealed the prolyl endopeptidase (PREP) gene as a potential CD candidate in the Dutch population. Interestingly, this gene encodes for the only enzyme that is able to cleave the proline-rich gluten peptides. To investigate the role of the human PREP gene as a primary genetic factor in CD, we conducted gene expression, sequence analysis, and genetic association studies of the PREP gene and determined PREP enzyme activity in biopsies from CD patients and controls. Sequence analysis of the coding region of the PREP gene revealed two novel polymorphisms. Genetic association studies using two novel polymorphisms and three known PREP variants excluded a genetic association between PREP and CD. Determination of PREP activity revealed weak but significant differences between treated and untreated CD biopsies (P < 0.05). Our results from the association study indicate that PREP is not a causative gene for CD in the Dutch population. These are further supported by the activity determinations in which we observed no differences in PREP activity between CD patients and controls.

Adolescent↗
PubMed1993

Gliadin-specific, HLA-DQ(alpha 1*0501,beta 1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients.

Celiac disease (CD) is most probably an immunological disease, precipitated in susceptible individuals by ingestion of wheat gliadin and related proteins from other cereals. The disease shows a strong human HLA association predominantly to the cis or trans encoded HLA-DQ(alpha 1*0501,beta 1*0201) (DQ2) heterodimer. T cell recognition of gliadin presented by this DQ heterodimer may thus be of immunopathogenic importance in CD. We therefore challenged small intestinal biopsies from adult CD patients on a gluten-free diet in vitro with gluten (containing both gliadin and other wheat proteins), and isolated activated CD25+ T cells. Polyclonal T cell lines and a panel of T cell clones recognizing gluten were established. They recognized the gliadin moiety of gluten, but not proteins from other cereals. Inhibition studies with anti-HLA antibodies demonstrated predominant antigen presentation by HLA-DQ molecules. The main antigen-presenting molecule was established to be the CD-associated DQ(alpha 1*0501, beta 1*0201) heterodimer. The gluten-reactive T cell clones were CD4+, CD8-, and carried diverse combinations of T cell receptor (TCR) V alpha and V beta chains. The findings suggest preferential mucosal presentation of gluten-derived peptides by HLA-DQ(alpha 1*0501, beta 1*0201) in CD, which may explain the HLA association.

Amino Acid Sequence↗
PubMed1999

Autoantibodies predicting diabetes mellitus type I in celiac disease.

UNLABELLED: Celiac disease (CD) and diabetes mellitus type I (DM-I) are both autoimmune diseases. Abnormal first-phase insulin response (FPIR) is associated with the prediabetic phase. Glutamic acid decarboxylase (GAD) and islet cell antibodies (ICAs) - especially the tyrosine phosphatase-like protein IA-2 antibodies - are considered to be serological markers of DM-I future development. The aim of this study is to investigate the presence of autoantibodies (GAD, IA-2) in individuals with CD, on a gluten-free diet, who have normal intestinal morphology. Thirty patients with CD (4-22, mean 15 years), 30 newly diagnosed diabetic children (2.5-16, mean 10 years) and 30 healthy subjects (7-35, mean 18 years) were investigated. Serum GAD and IA-2 autoantibodies were assessed by a quantitative enzyme-linked immunosorbent assay (ELISA) method in all patients and controls. Seven CD patients (23%), 28 diabetic children (93%) and none in the control group had positive GAD and IA-2 antibodies. The FPIR was normal in CD patients (>/=46 mU/l). CONCLUSIONS: GAD and IA-2 antibodies are detected in 23% of patients with CD. These patients may be at risk to develop DM-I. Regular follow-up and determination of FPIR for the early diagnosis of the prediabetic phase in patients with CD having circulating autoantibodies is recommended.

Adolescent↗
PubMed2004

Serologic assay based on gliadin-related nonapeptides as a highly sensitive and specific diagnostic aid in celiac disease.

BACKGROUND: Celiac disease (CD) is induced by wheat gliadins and related cereal proteins. Anti-gliadin antibodies (AGAs) are present in the serum of CD patients, but these antibodies have lower diagnostic specificity and sensitivity than autoantibodies [anti-endomysium antibodies (AEmAs) and anti-tissue transglutaminase antibodies (AtTGAs)]. Recently, AGAs from CD patients were found to recognize deamidated gliadin peptides, probably formed by the action of tissue transglutaminase. METHODS: We synthesized several gliadin peptides and their glutamine-glutamic acid-substituted counterparts on cellulose membranes and tested their recognition by IgA in sera of 52 AEmA-positive CD patients and 76 AEmA-negative controls in a luminescence assay. For comparison, we assayed IgA concentrations of AGAs, AtTGAs, and AEmAs. For measurement of AtTGAs, we used the human recombinant antigen. RESULTS: We identified several nonapeptides that were detected with high specificity by IgA in CD patients. Diagnostic accuracy of the peptide antibody assay was highest when peptide PLQPEQPFP was used in combination with peptide PEQLPQFEE within one assay. AGAs were above the cutoff in 14 of the controls, but only 5 of the controls were positive for peptide antibodies. For comparison, 82% and 94% of samples were correctly classified by AGAs and the combination nonapeptide assay, respectively (P = 0.007), and the AtTGAs correctly classified 98%. CONCLUSION: The peptide antibody assay has higher diagnostic accuracy than AGAs for distinguishing patients with CD from controls, and has diagnostic accuracy similar to that of AtTGAs.

Adolescent↗
PubMed2005

Gliadin as a stimulator of innate responses in celiac disease.

In celiac disease (CD) we have the prototype of an immune mediated response dominated by the activation of the adaptive immune system and in particular of CD4+ HLA class II restricted T cells. Various seminal studies have established the precise mechanism of how antigen (prolamine) specific activation of CD4+ mucosal T cells occurs. Thus, CD is a condition in which T cells and their activation is the essential hinge in the pathogenic process. These functional studies have provided the explanation for the genetic association between CD and certain HLA alleles (HLA DQ2 and DQ8). These genetic, molecular and functional studies have permitted the clarification of a powerful Th1 dominated pro-inflammatory response that characterises the small intestine of active CD patients. Despite this unassailable set of information and reports there are some intriguing points that have been raised by a series of studies which have indicated that CD is not only defined by an aberrant prolamine-induced activation of the adaptive immune system. New evidence and re-assessments of old studies, point to a more complex pathogenic cascade, which may help to unravel some of the residual obscure points of CD pathogenesis. Here, we outline the current concepts that indicate a direct involvement of the adaptive immune system and we discuss all the evidence supporting a direct activation of the innate immune system by fragments of prolamines, which are not recognized T cell epitopes and how they could influence CD. The gliadin-induced activation of the 'innate' immune system might also have a significant role in the induction and persistence of many CD complications and most definitively for the most aggressive one, namely mucosal T cell lymphomas. We further suggest a novel way to harness the unwanted immune response to toxic prolamine, and thus indicate new potential therapeutic strategies to treat or at least control CD.

Animals↗
PubMed2006

Screening for celiac disease in Down's syndrome patients revealed cases of subtotal villous atrophy without typical for celiac disease HLA-DQ and tissue transglutaminase antibodies.

AIM: To investigate the prevalence of celiac disease (CD) as well as CD marker antibodies and susceptibility HLA-DQ haplotypes in 134 karyotyped Down's syndrome (DS) patients. METHODS: Immunoglobulin A (IgA) and G (IgG) type anti-gliadin antibodies (AGA), IgA type anti-tissue transglutaminase (tTG) antibodies (anti-tTG) with antigen of guinea pig and human source were determined by enzyme-linked immunosorbent assay and endomysium antibodies (EMA) by indirect immunofluorescence test. HLA-DQA1*0501/DQB1*0201 (DQ2) was revealed by polymerase chain reaction. Celiac disease was diagnosed by revised ESPGHAN criteria. RESULTS: 41% of DS patients had AGA, 6.0% IgA anti-tTG with guinea pig antigen, and 3.0% IgA EMA (all positive for anti-tTG with human tTG). Subtotal villous atrophy was found in 5 out of 9 DS patients who had agreed to small bowel biopsy. One of them had DQA1*0501/DQB1*0201 and anti-tTG and EMA i.e. typical for CD markers (this case also fulfilled the ESPGHAN diagnostic criteria),but other four lacked these markers. Three non-biopsied DS patients had also most probably CD because DQA1*0501/DQB1*0201 and IgA anti-tTG (EMA) were detected. Thus, the prevalence of CD among our DS patients population is 3.0% (95 % of confidence interval [CI]: 0.1-5.9%). CONCLUSION: We confirm the increased frequency of CD among DS patients. In addition, we have revealed a subgroup of patients with subtotal villous atrophy but without characteristic for CD immunological and genetic markers. Whether these cases represent CD (with atypical immunopathogenesis) or some other immune enteropathy, requires further investigations.

Adolescent↗
PubMed1999

High prevalence of celiac disease in apparently healthy blood donors suggests a high prevalence of undiagnosed celiac disease in the Dutch population.

BACKGROUND: In the last few years the prevalence of celiac disease (CD) seems to have increased. It is clear that subclinical and silent CD exist in a large subgroup of the celiac population. METHODS: The aim of this study was to evaluate the prevalence of CD in an apparently healthy population. Blood samples were obtained from 1000 apparently healthy blood donors at Arnhem and Nijmegen Blood Donation Centers from January 1997 through April 1998. Sera from 660 blood donors were assayed for total IgA. By means of immunofluorescence, antibodies, including those to endomysium (EMA), were determined. Serum immunoglobulin levels (IgA) were assayed by means of nephelometry. All donors who had positive serology for EMA underwent small-intestinal biopsy. RESULTS: Of the 1000 healthy blood donors 3 had positive EMA. Small-intestinal biopsy of two of these showed subtotal villous atrophy (Marsh IIIb), and the third had intraepithelial lymphocytosis and crypt hyperplasia (Marsh II). The prevalence of gluten sensitivity was 1 of 330. Low IgA (0.60-0.23 g/l) in our study group was found in 9 of 660 (1%), but no one showed an IgA < or = 0.02 g/l. CONCLUSION: Our study shows that the prevalence of gluten-sensitivity in apparently healthy blood donors is 3 of 1000, which suggests a high prevalence of CD in the Dutch population, in contrast to the results of the last published Dutch epidemiologic studies. The recorded prevalence will increase further with greater recognition of subclinical and asymptomatic forms detected by screening tests.

Adult↗
PubMed2001

[Occurrence of celiac disease in siblings and offspring of patients with celiac disease].

BACKGROUND: Incidence of the coeliac disease in our population is 0.3 to 0.5%, however, in direct relatives of patients with coeliac disease incidence rises up to 5-15%. Though the disease in not always clinically manifested, it can be identified by serologic screening. METHODS AND RESULTS: 96 patients treated for active coeliac disease and their 130 siblings were examined. In four of 130 siblings the disease clinically manifested and was confirmed with finding of enteropathy of jejunal mucosa. In 14 out of 126 asymptomatic siblings endomysial antibodies were identified and in 11 of them enteropathy was diagnosed. Coeliac disease was diagnosed in 15 (11.5%) persons from 130 siblings. Also 74 offsprings of 43 parent patients were examined. In four of them the coeliac disease manifested clinically and was later confirmed with finding of enteropathy. Antiglidin antibodies were tested in 45 asymptomatic offsprings with 6 positive results. Endomysial antibodies were tested in 25 asymptomatic offsprings with one positive result. Villous atrophy of jejunal mucosa was found in four asymptomatic offsprings. Coeliac disease was diagnosed in 8 (11.5%) persons from 74 offsprings. CONCLUSIONS: Coeliac disease represent a major risk for the patient's direct relatives. Goal-directed examination and the early diagnosis of the disease in childhood may help to prevent impairments in the development of the child and possible complications later.

Adolescent↗
PubMed1993

Value of endoscopic markers in celiac disease.

Duodenoscopy in celiac disease has identified several markers of the disease. Our aim was to evaluate, in a prospective study, the usefulness of the different endoscopic features in 100 consecutive cases referred to endoscopy for intestinal biopsy. Histological examination of duodenal samples showed severe villous atrophy (grade III/IV) in 36 patients. Of these patients, 34 had endoscopic markers suggestive of celiac disease. These were reduction in number or loss of Kerkring's folds (in 27), mosaic pattern (14), scalloped folds (12), and visibility of the underlying blood vessels (5). Endoscopic visualization of these markers had a sensitivity of 94%, a specificity of 92%, and a positive predictive value of 84%. Reduction in number, or loss of, Kerkring's folds was the most sensitive (76%) and specific (98%) single endoscopic change indicating celiac disease. Duodenoscopy permitted diagnosis in three of four asymptomatic patients in a group of 24 first-degree relatives of celiac disease patients. We conclude that endoscopy of distal duodenum is a sensitive and specific indicator of celiac disease.

Adult↗
PubMed2006

Increased risk of papillary thyroid cancer in celiac disease.

Patients with celiac disease have an increased rate of malignancies that are not limited to lymphomas. Thyroid carcinoma has not previously been associated with celiac disease. However, among a cohort of patients with celiac disease, we identified an increased risk of papillary carcinoma of the thyroid, standard morbidity ratio of 22.52 (95% confidence interval 14.90-34.04; P < .001), compared to United States national surveillance data. These patients were on a gluten-free diet. Only 1 had Hashimoto's thyroiditis, suggesting that mechanisms apart from autoimmune thyroiditis contribute to the increased risk of carcinoma of the thyroid in celiac disease.

Adult↗
PubMed2002

The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease.

BACKGROUND & AIMS: Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease. METHODS: Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis. RESULTS: HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation. CONCLUSIONS: In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.

Adult↗