Judit Kovács

Transglutaminase 2-/- mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells

Tissue transglutaminase (TGase2) is a protein-crosslinking enzyme known to be associated with the in vivo apoptosis program. Here we report that apoptosis could be induced in TGase2-/- mice; however, the clearance of apoptotic cells was defective during the involution of thymus elicited by dexamethasone, anti-CD3 antibody, or γ-irradiation, and in the liver after induced hyperplasia. The lack of TGase2 prevented the production of active transforming growth factor-β1 in macrophages exposed to apoptotic cells, which is required for the up-regulation of TGase2 in the thymus in vivo, for accelerating deletion of CD4+CD8+ cells and for efficient phagocytosis of apoptotic bodies. The deficiency is associated with the development of splenomegaly, autoantibodies, and immune complex glomerulonephritis in TGase2-/- mice. These findings have broad implications not only for diseases linked to inflammation and autoimmunity but also for understanding the interrelationship between the apoptosis and phagocytosis process.

Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency

Background: IgA serum autoantibodies against tissue transglutaminase (tTG) have an established diagnostic value in coeliac disease, and high efficacy tests are widely available for their detection. However, serological evaluation of IgA deficient subjects is still difficult. Aims: To evaluate the diagnostic potential of IgG class anti-tTG autoantibodies measured quantitatively using an enzyme linked immunosorbent assay (ELISA) compared with immunofluorescent detection of coeliac autoantibodies. Patients: We tested serum samples from 325 IgA deficient subjects, including 78 patients with coeliac disease, 73 disease controls, and 174 blood donors. Methods: IgG antibodies against human recombinant tTG were measured with an ELISA. IgG antiendomysium antibodies (EMA) were assayed by indirect immunofluorescence on human jejunum and appendix sections. Results: The IgG anti-tTG ELISA had a sensitivity of 98.7% and a specificity of 98.6%, and the correlation with IgG EMA titres was high (rs=0.91). One coeliac patient, initially negative in all autoantibody tests, displayed both IgG anti-tTG antibodies and IgG EMA during later gluten exposure. IgG anti-tTG antibodies and EMA titres showed significant decreases (p<0.001) in treated patients. The frequency of IgG anti-tTG autoantibody positivity was 9.8% among IgA deficient blood donors and 11 of the 12 positive subjects with known HLA-DQ haplotypes carried DQ2 or DQ8 alleles. Conclusions: IgG anti-tTG and IgG EMA autoantibody tests are highly efficient in detecting coeliac disease in IgA deficient patients. The high prevalence of coeliac antibodies among symptom free IgA deficient blood donors who also carry coeliac-type HLA-DQ genes indicates that all IgA deficient persons should be evaluated for coeliac disease.

High prevalence of silent celiac disease in preschool children screened with IgA/IgG antiendomysium antibodies

BACKGROUND Because of the different sensitivity and specificity of serologic tests, the search for silent celiac disease is usually performed with the combined or sequential use of several tests. Among these, the IgA-class endomysium antibody test has the highest specificity and positive predictive value, but it may overlook IgA-deficient patients. METHODS To test a new one-step screening approach, serum samples from 427 apparently healthy, 3- to 6-year-old Hungarian children were investigated for IgA-class and IgG-class endomysium antibodies using monkey esophagus and human jejunum as substrates. RESULTS Five new cases with flat mucosa were identified by strong endomysium antibody positivity and subsequent jejunal biopsy, yielding a celiac disease prevalence of 1:85. An additional child may have latent celiac disease (slight histologic changes at present). Two of the screening-detected celiac patients exhibited only IgG-class endomysium antibodies due to associated IgA-deficiency. Despite the young age of the screened population, antigliadin antibodies were positive in only three of the five celiac patients. CONCLUSIONS Prevalence of celiac disease in the study population was much higher than expected on the basis of antigliadin antibody-based studies. The screening system used detected celiac cases in which there was IgA-deficiency and those in which there was not and also those negative for antigliadin antibodies. The findings suggest the importance of the primary testing of autoantibodies in future celiac disease screening policies.

Prediction of clinical and mucosal severity of coeliac disease and dermatitis herpetiformis by quantification of IgA/IgG serum antibodies to tissue transglutaminase.

Objectives: We analysed whether the quantification of autoantibodies against tissue transglutaminase could be used to predict mucosal destruction and disease severity in patients with gluten sensitivity. Patients and Methods: One hundred seventy patients with coeliac disease (CD), comprising 52 children with severe malabsorption (group I), 59 children with mild symptoms (group II), 59 adults (group III), 134 patients with dermatitis herpetiformis (DH), and 131 disease controls, were studied. Serial serum samples of patients in groups I and II on a gluten-free diet were also included. Serum levels of antibodies against recombinant tissue transglutaminase were determined with ELISA using standard curves for quantification of antibodies. Results: Immunoglobulin (Ig)A antibodies against tissue transglutaminase (IgA-TGA) were detected in all of the patients with CD and in 95% of the DH patients. The IgA-TGA and IgG-TGA levels were higher in group I (P < 0.001). The IgG-TGA levels and positivity rate in group I (100%) were higher than in group II (81%), group III (73%), and the DH group (67%). Elevated IgA-TGA and IgG-TGA levels in combination predicted a more severe small intestinal atrophy (P < 0.0001) with a specificity of 99% for Marsh IIIb–IIIc (flat) lesions. The kinetics of the IgA-TGA decrease during diet differed between groups I and II. Conclusions: High levels of IgA-TGA and IgG-TGA antibodies were associated with the grade of mucosal villous atrophy and a more severe clinical presentation. The combined measurement of IgA-TGA and IgG-TGA enables a noninvasive prediction of small intestinal villous atrophy with high accuracy, and may reduce the need for a biopsy in patients with suspected CD.

Intrinsic motivation and extrinsic incentives in a repeated game with incomplete contracts

Abstract Important features of labor relations are that contracts are incomplete, that workers and firms very often interact repeatedly and that there are opportunities for social exchange. To assess the relative importance of these features, we experimentally examine behavior in a game with incomplete contracts. Our main results are that mere repeated interaction with the same player increased effort levels as compared to one-shot interactions. Social approval incentives were not very important in our experiments. Reciprocal behavior clearly was the dominant pattern. Most of it was intrinsic reciprocity, i.e., neither repeated play nor approval incentives influenced the extent of reciprocity very much. We also show that there exist treatment-dependent equity considerations. PsycINFO classification: 3020; 2360; 3660

Missing endomysial and reticulin binding of coeliac antibodies in transglutaminase 2 knockout tissues

Background: Autoantibodies against transglutaminase 2 (TG2) are thought to be responsible for the endomysial (EMA), reticulin (ARA), and jejunal antibody (JEA) tissue binding of serum samples from coeliac patients but the exclusive role of TG2 in these staining patterns has not yet been established. Aims: To evaluate whether antigens other than TG2 contribute to EMA/ARA/JEA reactions. Patients: Serum samples from 61 EMA/ARA/JEA positive untreated patients with coeliac disease, 40 dermatitis herpetiformis patients, and 34 EMA/ARA/JEA negative non-coeliac controls were tested. Methods: TG2 knockout (TG2−/−) and wild-type mouse oesophagus, jejunum, liver, and kidney sections, and TG2−/− sections coated with human recombinant TG2 were used as substrates in single and double immunofluorescent studies for patient IgA binding and tissue localisation of TG2, fibronectin, actin, and calreticulin. Results: None of the patient serum samples elicited EMA, ARA, or JEA binding in TG2−/− morphologically normal tissues. In contrast, 96 of 101 gluten sensitive patient samples (95%) reacted with wild-type mouse tissues and all 101 reacted in EMA/ARA/JEA patterns with TG2−/− mouse tissues coated with human TG2. Serum IgA binding to TG2−/− smooth muscle cells was observed in low titres in 31.1%, 27.5%, and 20.5%, and to TG2−/− epithelium in 26.3%, 5.0%, and 8.8% of coeliac, dermatitis herpetiformis, and control samples, respectively. These positivities partly colocalised with actin and calreticulin but not with TG2 or fibronectin. Conclusions: EMA/ARA/JEA antibody binding patterns are exclusively TG2 dependent both in coeliac and dermatitis herpetiformis patients. Actin antibodies are responsible for some positivities which are not part of the EMA/ARA/JEA reactions.

Fairness Within Firms: The Case of One Principal and Multiple Agents

Many experimental studies report evidence of fairness in bargaining games. More recently fairness and its consequences for productive efficiency have been explored in principal-agent games, in which a single principal meets a single agent. However, in most organizations, there are usually many agents in one layer of a firm’s hierarchy. Consequently, fairness considerations may be based on a comparison between layers (vertical fairness) as well as within a layer (horizontal fairness). In this paper we report an experiment in which a principal faces two agents with deterministic but unequal productivity. The experimental treatment variable is the information that one agent has about the other agent’s contract offer. When work contracts are observable, the principal offers less asymmetric contracts (pay compression) than when contracts are not observable, i.e., horizontal fairness matters.

Self transglutaminase-based rapid coeliac disease antibody detection by a lateral flow method

The conventional coeliac disease antibody tests require patients sera, and are laborious and time‐consuming.

Analysis of the oral manifestations of systemic sclerosis

The oral signs and symptoms in 32 patients with systemic sclerosis were evaluated. Oral mucosal telangiectasia was present in 18 cases (56.3%) and was not restricted to the limited form of systemic sclerosis. The interincisal distance was significantly decreased in the patients with systemic sclerosis compared with the 17 controls (p < 0.001). The distance between the vermillion borders was also significantly decreased when the 14 patients with salivary hypofunction were compared with the 18 cases without decreased salivary secretion (p < 0.05). Twenty-two (69%) of the patients exhibited keratoconjunctivitis sicca, salivary hypofunction, or both. Lip biopsy was performed in 16 cases. Two cases with inflammatory signs characteristic of Sjögrens syndrome were found, and six patients showed the histologic signs of labial gland fibrosis. Five of these cases belonged to the group of limited cutaneous systemic sclerosis that indicates the generalized nature of the fibrotic processes even in systemic sclerosis with less extensive skin involvement. Of the 10 cases investigated by electron microscopy, all but one showed a thickening of the capillary basal lamina, lamellar arrangement within the basement membrane, or capillary endothelial vacuolization. Three of these cases belonged to the patients with disease onset within 2 years, showing that capillary vascular lesion is present in the early cases and that vascular injury affects even those tissues that do not seem to be evidently involved by clinical examination.

Coeliac disease case finding and diet monitoring by point-of-care testing

Background : Immunoglobulin A class transglutaminase autoantibodies are highly predictive markers of active coeliac disease, a disorder difficult to recognize solely on clinical grounds.