Autoantibodies to tissue transglutaminase as predictors of celiac disease

Background & Aims: Immunoglobulin A (IgA) autoantibodies to endomysium (EMA) are highly specific and sensitive markers for celiac disease. Recently, we identified tissue transglutaminase (tTG) as the major if not sole endomysial autoantigen. Methods: An enzyme-linked immunosorbent assay (ELISA) was established to measure IgA anti-tTG titers in serum samples from 106 celiac patients with partial or subtotal villous atrophy, 43 celiac patients on a gluten-free diet, and 114 diseased and healthy controls. Results were correlated with clinical and histological data and with EMA titers. Results: In patients with biopsy-proven celiac disease consuming a normal, gluten-containing diet, 98.1% of the serum samples had elevated IgA titers against tTG, whereas 94.7% of the control sera were negative. IgA anti-tTG correlated positively with semiquantitative IgA EMA titers (r = 0.862; P < 0.0001). Conclusions: An ELISA based on tTG allows diagnosis of celiac disease with a high sensitivity and specificity. IgA anti-tTG and IgA EMA show an excellent correlation, further confirming the enzyme as the celiac disease autoantigen. Because the assay is quantitative, not subjected to interobserver variation, and easy to perform, it will be a useful tool for population screening of a hitherto underdiagnosed disease.GASTROENTEROLOGY 1998;115:1317-1321     

Identification of a new coeliac disease subgroup: antiendomysial and anti-transglutaminase antibodies of IgG class in the absence of selective IgA deficiency

OBJECTIVE: The aim of the present study was to increase the sensitivity of the antiendomysial antibody (EMA) test by evaluating also EMAs of IgG1 isotype. DESIGN AND SUBJECTS: Over the last 2 years, serum EMAs IgA and IgG1 were determined in 1399 patients, referred to our gastrointestinal unit due to clinical suspicion of malabsorption. Serum anti-tissue transglutaminase (tTG) antibodies IgA and IgG, as well as total IgA levels, were also investigated. Furthermore, EMAs IgA and IgG1 were evaluated in biopsy culture supernatants. Biopsy specimens were also admitted to histological and immunohistochemical evaluation. Twenty-six patients with gastroenterological disease other than coeliac disease (CD) were used as a disease control group. Ninety-nine blood donors were used as a healthy control group. RESULTS: Diagnosis of CD was based on histological findings in the 110/1399 patients showing EMA IgA positivity, and in a further 56/1399 patients presenting both EMA IgA and IgG1 positivity in sera as well as in culture supernatants. Of the remaining 1233 EMA IgA-negative patients, 60 showed only EMA IgG1 positivity both in sera and in culture supernatants. It is noteworthy that anti-tissue transglutaminase antibodies IgG (anti-tTG) were positive in all 60 EMA IgG1-positive patients as well. By contrast, a selective IgA deficiency was found in only 11 out of the 60 EMA IgG1-positive patients. Villous height/crypt depth ratio was < 3:1 in 38 of the 60 EMA IgG1-positive patients (63.3%), whilst overexpression of ICAM-1 and CD25 was observed in all these patients. CONCLUSIONS: In this study, we observed a group of CD patients who were EMA IgG1-positive even in the absence of EMA IgA positivity and IgA deficiency. The diagnosis was based on the finding of the gluten-dependent clinical and histological features typical of CD. Data emerging from the present investigation thus suggest that the prevalence of CD should be reassessed and that the determination of EMA IgG1 could offer a new tool in the diagnostic armamentarium of CD.     

Coeliac disease characteristics, compliance to a gluten free diet and risk of lymphoma by subtype

Objective

Coeliac disease is associated with an increased risk of malignant lymphomas. We investigated the importance of coeliac disease characteristics and diet compliance for risk of lymphoma.

Methods

In a nested case–control design, we identified 59 patients with lymphoma and 137 matched controls from a population-based cohort of 11,650 inpatients with coeliac disease. We assessed coeliac disease characteristics at diagnosis and dietary compliance collected prospectively from medical records during follow-up.

Results

Poor compliance was not significantly associated with risk of lymphoma overall (odds ratio 1.83, 95% confidence interval 0.78–4.31) nor of lymphoma subtypes. Risk estimates differed by subtype; risk of T-cell lymphoma (odds ratio 1.01, confidence interval 0.32–3.15) or intestinal lymphoma (odds ratio 0.66, confidence interval 0.17–2.56) was unelevated, whereas there was an indication of a risk increase of B-cell lymphoma (odds ratio 4.74, confidence interval 0.89–25.3) or extraintestinal lymphoma (odds ratio 3.00, confidence interval 0.73–12.3) following poor compliance. History of weight loss (odds ratio 2.89, confidence interval 1.00–8.29) at coeliac disease diagnosis was associated with an increased risk of lymphoma when excluding tumours occurring with short latency (<3 years).

Conclusions

Compliance to a gluten-free diet did not significantly alter lymphoma risk, but a moderate effect cannot be excluded. Weight loss, a potential marker of coeliac disease severity, may be associated with lymphoma risk.     

Lymphocyte-filled villi: Comparison with other lymphoid aggregations in the mucosa of the human small intestine

Background & Aims: Solitary lymphoid structures that may be sites of primary extrathymic T-cell differentiation have been described recently in murine (cryptopatches) and rat (lymphocyte-filled villi) small intestine. This study tests the hypothesis that similar structures occur in human small intestine. Methods: Normal small intestine was obtained during surgery. Fixed tissue was examined histologically, and frozen sections were examined by an indirect immunoperoxidase technique using a panel of mouse monoclonal antibodies. Results: A new isolated lymphoid structure, with epithelium resembling follicle-associated epithelium of Peyer's patches, is described as a lymphocyte-filled villus. These structures contain major histocompatibility complex (MHC) class II–positive dendritic cells, a majority of memory T cells, a variable B-cell component, and no evidence of immature lymphocytes that express either c-kit or CD1a. Two previously described lymphoid aggregations (isolated lymphoid follicles and submucosal lymphoid aggregations) are components of a single structure. The complete structure contains a B-cell follicle, T cells with mainly memory (CD45RO-positive) phenotype, high endothelial venules, and no detectable population of immature lymphocytes. Conclusions: A new solitary lymphoid structure is described in the human small intestine. Neither these structures nor isolated lymphoid follicles appear to be similar to solitary primary lymphoid structures in rodent intestine.GASTROENTEROLOGY 1998;115:1414-1425     

Cholesteryl ester transfer protein genetic polymorphisms, HDL cholesterol, and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis

The cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, −629C/A, Taq1B, and −2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, carotid intimal-medial thickness (IMT), and carotid artery plaque measured by ultrasonography. Carriers of the 451Q and 373P alleles have a significantly higher CETP concentration (22.4% and 19.5%, respectively; p < 0.001) and activity (13.1% and 9.4%, respectively; p < 0.01) and lower HDL-C (5.6% and 6.0%, respectively; p < 0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p = 0.006 and p = 0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p = 0.036). Polymorphism is associated with neither common nor internal carotid IMT. We confirmed that the −629A, Taq1B B2, and −2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p < 0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p < 0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p < 0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.