We investigated the presence of IgA anti-tissue transglutaminase (tTG) antibodies in untreated coeliac disease (CD) and other gastrointestinal diseases, and compared IgA tTG concentrations with anti-endomysium (EMA) immunofluorescent findings. The study included 116 untreated CD patients (74 female, 42 male, age range 15-78 years, median 47 years), 82 treated CD patients, 65 patients with normal duodenal histology, 260 disease control samples and 29 healthy volunteers. IgA anti-tTG, EMA, and anti-gliadin (AGA) antibodies were measured. Serum total IgA was measured in the CD patients. Two IgA-deficient untreated CD patients were excluded. IgA EMA and IgA AGA were positive in 99 (87%) and 69 (61%), respectively, of the 114 untreated CD patients. Elevated IgA anti-tTG were found in 92/114 (81%) untreated coeliacs, 1/82 (1%) treated coeliacs, 2/65 (3%) non-coeliacs, 10/260 (4%) disease controls and 2/29 (7%) volunteers. Four of the untreated CD patients, with a normal serum total IgA concentration, were negative for all the serological tests. IgA anti-tTG concentrations were significantly higher in untreated coeliacs (median 10200 units/ml) than in other groups (Mann-Whitney, p<0.00001) and compared well with IgA EMA titres (r(2)=0.54; p<0.0001).
SUMMARYClinical investigation of gut immunity is difficult because of the need to study intestinal tissues or secretions directly. Others have reported that immunoglobulins, antibodies and cytokines can be detected in saline extracts of faeces. We have assessed the validity of this approach by measuring immunoglobulins, albumin, a|-antitrypsin and isotype-specific antibodies in matched samples of faeces and whole gut lavage fluid. Results were compared as estimated output per day, and by using haemoglobin as a common reference substance. Samples were obtained from 10 patients with active infiammatory bowel disease and 10 with other benign Gl diseases. For immunoglobulins, albumin and antibodies, the amount detected in faeces varied from < 0 01% to 355% (based on estimated daily output) and < 0 01 % to 18 5% (based on haemoglobin) of the amount known to be produced in the gut from results of assays on whole gut lavage fluid (WGLF); there were significantly higher rates of recovery in faecal specimens from patients with active gut inflammation than from other patients. Detection rates and titres of specific antibody in faeces were even lower than those for immunoreactive IgA. These data indicate that immunological tests on saline extracts of faeces do not represent the true status of the gut humoral immune system, and such studies should be strongly discouraged.
In this paper we consider recent new data on the pathological features of gluten sensitivity and on the disease-associated antigens, in the context of a multistage hypothesis that we have been developing for the last five years. This incorporates concepts of oral tolerance induction, mucosal T-cell and antibody-mediated injury, and genetic contributions. Until now, there has been complete agreement that the diagnosis of celiac disease must be based on small bowel histology. There are patients with low-grade gluten-sensitive enteropathy, in whom the only morphological abnormality is a high count of intraepithelial lymphocytes (IEL). Some, but not all, also have positive serum IgA anti-endomysium antibody (AEA). With good techniques, in a properly accredited laboratory, in a patient suspected on clinical grounds to have celiac disease, a positive serum IgA AEA test (perhaps, alternatively, high-titer anti-transglutaminase by ELISA), is virtually diagnostic of the condition. Our hypothesis of a stepwise pathogenesis of severe gluten-sensitive enteropathy is re-examined in the light of these new data. It is evident that there are at least five different levels at which genetic influences may operate.
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