David J. Unsworth

Linear IgA disease in adults

A multi‐centre study is described in which thirty‐five adult patients with papillary IgA dermatitis herpetiformis (DH) were compared with forty‐two patients with linear IgA deposits, of whom thirty‐four had homogeneous‐linear (HL) and eight had granular‐linear (GL) IgA deposits.

IgA anti-tissue transglutaminase as a diagnostic marker of gluten sensitive enteropathy.

AIMS: To compare and contrast the sensitivity, specificity, and positive predictive values of IgA antibodies to guinea pig tissue transglutaminase (ELISA), endomysium, and reticulin (immunofluorescence), and gliadin (ELISA), and IgG antibodies to gliadin and tissue transglutaminase. METHODS: Sera from 27 newly diagnosed patients with coeliac disease, 65 biopsied gastrointestinal disease controls, and 50 consecutive blood donors were tested. All cases were adults. RESULTS: IgA anti-tissue transglutaminase showed a sensitivity of 85% (23/27 coeliac disease cases seropositive), specificity 97% (2/65 controls and one blood donor showing low titre positivity), and a positive predictive value of 92%. High titre anti-tissue transglutaminase was only seen in coeliac disease. Disease controls with mucosal damage unrelated to gluten enteropathy were IgA anti-tissue transglutaminase negative. Sensitivity, specificity, and positive predictive values for IgA anti-endomysial antibody (monkey oesophagus) were 100%, 100%, and 100%, respectively, and for IgA anti-gliadin, 93%, 95%, and 89%, respectively. CONCLUSIONS: Tissue transglutaminase is a major autoantigen in coeliac disease. IgA (but not IgG) anti-tissue transglutaminase, especially when in high titre, is closely associated with coeliac disease, but low titres may not be disease specific. In this small pilot study, the established IgA anti-endomysial assay was the superior test.

Anti-gliadin antibodies and small intestinal mucosal damage in dermatitis herpetiformis

Sera from forty‐six patients with dermatitis herpetiformis (DH) were examined for anti‐gliadin antibodies (AGA) by the enzyme linked immunosorbent assay (ELISA) test and by a simple new immunofluorescent (IF) test. AGA were present in fifteen out of thirty‐two patients taking a normal diet, but in none of the fourteen taking a gluten‐free diet (GFD). The presence of circulating AGA was related to the severity of the enteropathy. AGA were present in all ten patients with a flat mucosa and in four of six with a convoluted mucosa, but in only one out of thirty patients with normal morphology of the small intestine. However, in those patients taking a normal diet and with a normal morphology of the intestine there was evidence of gluten sensitivity compared to those taking a GFD, as the intraepithelial lymphocyte count (IELC) was significantly raised in the peri‐nuclear and supra‐nuclear positions. The study shows that the presence of AGA in the serum is a good indication of the degree of gluten sensitivity as expressed by severe mucosal damage in patients with DH.

Is immunoglobulin A anti-tissue transglutaminase antibody a reliable serological marker of coeliac disease?

Background Anti-tissue transglutaminase (tTG) antibody is being used increasingly as a diagnostic tool in the serological investigation of coeliac disease. However, positive predictive values of immunoglobulin A (IgA) anti-tTG for coeliac disease in prospective studies have been disappointing and false-positive results are reported. Objective To assess the clinical utility of cascade testing for anti-tTG and anti-endomysium antibody (AEA). Patients Two unselected retrospective cohorts from routine diagnostic investigation for possible gluten sensitive enteropathy: group 1 comprised 57 cases seropositive for anti-tTG and group 2 comprised 52 cases seronegative for anti-tTG. In both groups, all cases had also undergone small-intestinal biopsy. Methods Patients were assessed for the presence of IgA anti-tTG by enzyme-linked immunosorbent assay and for IgA AEA by immunofluorescence. Results The positive predictive value of IgA anti-tTG for biopsy-confirmed coeliac disease was 54%. The positive predictive value of dual positivity for anti-tTG and AEA was 97%. The negative predictive value of IgA anti-tTG was 100%. Conclusions The data presented here support the use of IgA anti-tTG as an initial screen for coeliac disease. Coeliac disease is unlikely when IgA anti-tTG is absent. However, many false-positive results are seen, and clinical utility and diagnostic efficiency are improved markedly if positive results are confirmed with the more accurate, but labour-intensive, AEA assay.

Identifying immunoglobulin : A deficient children and adults does not necessarily help the serologic diagnosis of coeliac disease

BACKGROUND Immunoglobulin A deficiency is more common in patients with coeliac disease and also in patients with other gastrointestinal diseases than in normal people. There is a concern, therefore, that routine serum immunoglobulin (Ig) A testing of all cases of suspected coeliac disease may lead to unnecessary biopsy. METHODS Four hundred eighty-two routine consecutive samples from cases of suspected coeliac disease or malabsorption (109 children) were tested for IgA anti-endomysium and total IgA. Four hundred twenty-four sera samples also had IgG antigliadin checked for high-titre antibody. Archived adult sera from 31 patients with coeliac disease and 52 disease control subjects were included in the study. RESULTS Seven routine cases with serum IgA less than 15% of the mean normal for age and four cases with undetectable IgA were identified. Four patients, including three of four with clear deficiency, underwent small bowel biopsy, and all four had normal histologic findings and normal intraepithelial lymphocyte counts. Only one of the seven had high-titre IgG antigliadin antibody but that patient had normal histologic findings. One (3%) of 31 adults with established coeliac disease and 1 (2%) of 52 control subjects were IgA deficient. CONCLUSIONS Of patients with IgA deficiency, only those with both IgA deficiency and high-titre IgG antigliadin antibody should be routinely considered for biopsy.

Tissue transglutaminase antibodies in dermatitis herpetiformis

details. Of note, a recent announcement from British Biotech indicates that their PAF-receptor antagonist Lexipafant was not effective against pancreatitis in a large multicenter clinical trial. In the opossum duct ligation model, we routinely observe morphological acinar cell injury/necrosis that is significantly more extensive than the 11% reported by Gukovskaya et al.7 We do not know the reason for these differences, but they are certainly not due to our inability to detect apoptosis in this model because neither we8 nor Gukovskaya et al.7 have found evidence of significant apoptosis after 7 days of duct ligation in opossums. Dr. Blackstone is correct in pointing out that PAF might regulate ICAM-1 expression and, as a result, the neutrophil sequestration in the pancreas that is observed during pancreatitis. We are in the process of studying such interactions. However, we do not believe that PAF and ICAM-1 are the only players in this game. Sandoval et al.,6 in the article referred to by Dr. Blackstone, state that ‘‘. . . [we] hypothesize that an initial pancreatic injury causes expression of PAF that mediates activation and infiltration of neutrophils in the tissues [during pancreatitis].’’ We basically agree with this hypothesis but would argue that the initial pancreatic injury referred to by Sandoval et al. is the result of premature activation of digestive enzyme zymogens within pancreatic acinar cells.

Wiskott-Aldrich syndrome: acute retinal necrosis as a further late complication.

Wiskott–Aldrich syndrome (WAS) is a rare X-linked disorder characterised by eczema, thrombocytopenia, autoimmunity and immunodeficiency. Median survival in 1980 ranged from 5 to 7 years. Improved survival (related to better medical and surgical care) has identified further complications, including vasculitis.1 2 The treatment of choice is HLA identical bone marrow transplantation, ideally below the age of 10. In the absence of a suitable donor, prophylactic antibiotics, intravenous immunoglobulin and splenectomy provide a significant survival advantage.3 Acute retinal necrosis (ARN) is a necrotising retinopathy mainly caused by varicella-zoster virus (VZV; …

Pitfalls in the performance and interpretation of clinical immunology tests

A broad overview, with examples, of the potential pitfalls encountered in the clinical immunology laboratory is presented. Illustrative examples and case scenarios are provided from autoimmunity, immunochemistry and cellular immunology, looking at both technical and interpretative pitfalls.

Anti-tissue transglutaminase antibodies in coeliac disease are not a response to gut damage alone.

Background Anti-tissue transglutaminase (tTG) antibody is being used increasingly as a diagnostic tool in the serological investigation of coeliac disease. However, positive predictive values of immunoglobulin A anti-tTG for coeliac disease in prospective studies have been disappointing. Objective To determine whether anti-tTG can arise as a non-specific consequence of abnormal gut permeability. Patients A cohort from routine investigation for possible gluten-sensitive enteropathy, with 44 cases selected based on whether permeability studies had been performed. Methods The cohort was assessed for anti-tTG by enzyme-linked immunosorbent assay, small-bowel biopsy and 14C-mannitol absorbency. Results Eighteen of the 44 patients had biopsy-proven coeliac disease and 23 showed abnormal permeability. There was poor correlation between the level of anti-tTG and gut permeability. Conclusions These data confirm an association between anti-tTG and coeliac disease but no clear relationship with other forms of increased gut permeability.