Presence of anti-‘tissue’ transglutaminase antibodies in inflammatory intestinal diseases: an apoptosis-associated event?

Farrace, Maria Grazia; Picarelli, Antonio; Tola, Marco Di; Sabbatella, L.; Marchione, Orazio Paolo; Ippolito, Giuseppe; Piacentini, Mauro

doi:10.1038/sj.cdd.4400880

Cited by 40 publications

(31 citation statements)

References 19 publications

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“…Biagi et al (23) have suggested that enterocytes might have a role in the induction of the immune response in CD, acting as antigenpresenting cells. Recently, an accumulation of active tTG as well as the presence of Gln-donor and Lys-donor tTG substrates have been demonstrated in the enterocytes of celiac patients compared with controls (24,34). The identification of the potentially dangerous substrates of tTG in intestinal mucosa may therefore offer an understanding of the role of the enzyme in CD.…”

Section: Discussionmentioning

confidence: 99%

Proteomics Identification of Acyl-acceptor and Acyl-donor Substrates for Transglutaminase in a Human Intestinal Epithelial Cell Line

Orrú

Caputo

D’Amato

et al. 2003

Journal of Biological Chemistry

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Transglutaminase (TG)-catalyzed cross-linking of both intracellular and extracellular proteins is an important biochemical event. However, increased concentrations of cross-linked proteins have been observed in many disorders. Moreover, TG-catalyzed modification of proteins might generate new self-antigens responsible for the autoimmune response, as in celiac disease. The identification of available substrates may offer an understanding of how the TG-catalyzed post-translational modification has an impact on physiology and disease. We used a proteomic approach to identify TG-modified protein targets in human intestinal epithelial cells to determine the extent to which transglutaminase specifically contributes to celiac disease. Two probes were used for endogenous TG activity: 5-(biotinamido)pentylamine, which represents the acyl-acceptor, and a biotinylated glutamine-containing peptide, which represents the acyl-donor. This approach identified >25 proteins, which range from 30,000 to 300,000 Daltons and can serve as acyl-acceptor and/or acyl-donor for transglutaminase. Some of them were known transglutaminase substrates, whereas others had not been previously identified. These targets include proteins involved in cytoskeletal network organization, folding of proteins, transport processes, and miscellaneous metabolic functions.

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Section: Discussionmentioning

confidence: 99%

Proteomics Identification of Acyl-acceptor and Acyl-donor Substrates for Transglutaminase in a Human Intestinal Epithelial Cell Line

Orrú

Caputo

D’Amato

et al. 2003

Journal of Biological Chemistry

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“…The high apoptotic rate observed in cirrhosis is associated with tTG overexpression by hepatocytes and with an abnormal release of the enzyme into the extracellular matrix, where it mediates polymerization of extracellular proteins (34). Hence, it has been hypothesized that the tTG-mediated polymerization of extracellular matrix proteins may generate new self antigens contributing to the elicitation of autoimmune responses (14,34). On the other hand, a distinguishing feature of cirrhosis is portal hypertension, which is known to induce histological changes in the intestinal mucosa and increased intestinal permeability (1,44).…”

Section: Discussionmentioning

confidence: 99%

“…Another reason underlying the discordant data may be related to the emergence of anti-tTG antibodies in some patients with chronic liver diseases, independently of the presence of CD. Farrace et al (14) have reported data suggesting that the presence of anti-tTG antibodies is not a specific event characterizing CD but a general phenomenon related to mucosal lesions rather than to the autoimmune nature of the disease. In this context, damage and increased permeability of the intestinal mucosa, possibly able to induce the production of anti-tTG antibodies, have been observed in patients with portal hypertension and liver cirrhosis (1,44).…”

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confidence: 99%

Prevalence and Clinical Significance of Immunoglobulin A Antibodies against Tissue Transglutaminase in Patients with Diverse Chronic Liver Diseases

Germenis

Yiannaki

Zachou

et al. 2005

Clin Vaccine Immunol

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The prevalence of celiac disease (CD) and the prevalence and clinical significance of anti-tissue transglutaminase (tTG) antibodies (tTGAbs) in a large series of patients with chronic liver diseases were assessed. We studied 738 patients (462 with chronic viral hepatitis, 117 with autoimmune liver diseases, 113 with alcoholic or nonalcoholic fatty liver disease, and 46 with other liver disorders) and 1,350 healthy controls (HC). Immunoglobulin A (IgA) tTGAbs were measured by enzyme-linked immunosorbent assay and a microspherebased flow cytometric assay. Positive sera were investigated for IgA antiendomysial antibodies (EmA). IgA tTGAb-positive subjects were invited to undergo a small-intestinal biopsy and HLA-DQ allele typing. Four of 1,350 HC (0.3%) tested tTGAb ؉ EmA ؉ and underwent a biopsy (CD confirmation in all). Four of 738 liver disease patients tested tTGAbs ؉ EmA ؉ (0.54%; not statistically significant). Two were HCV infected (1.24%; not statistically significant), and two had transaminasemia of unknown origin. Forty-three patients tested tTGAbs ؉ EmA ؊ (5.8%; P < 0.001 compared to HC). Inhibition experiments verified the existence of specific IgA anti-tTG reactivity. Twenty-six of 43 patients underwent a biopsy (all negative for CD). Binary logistic regression analysis revealed age (P ‫؍‬ 0.008), cirrhosis (P ‫؍‬ 0.004), alkaline phosphatase (P ‫؍‬ 0.026), and antinuclear antibodies (P ‫؍‬ 0.012) as independent risk factors for tTGAb reactivity among the patients. It was concluded that CD prevalence is the same in HC and patients with chronic liver diseases. The prevalence of tTGAbs is higher in hepatic patients compared to HC, but their specificity for CD diagnosis in this group of patients is low. tTGAbs in patients appear to be associated with the presence of autoimmunity, cirrhosis, and cholestasis, irrespective of the origin of the liver disease.Over the past few years, the identification of tissue transglutaminase (tTG) as the main, if not the sole, autoantigen recognized by antiendomysial antibodies (EmA) in celiac disease (CD) patients (12) allowed an increased number of asymptomatic and oligosymptomatic patients to be diagnosed and numerous associations of the disease with a range of conditions to be unveiled (15). Despite, however, the fact that the association between CD and various hepatic diseases has been extensively investigated (8, 9, 11, 16-19, 23, 26, 40, 41, 43, 45, 47, 48), a definite correlation between these pathological conditions has not been unequivocally established.Conflicting results have been reported that, at least in part, can be attributed to differences in the performance of serological tests used by different investigators for initial screening for CD. Patients with chronic liver diseases frequently have immunological and other disturbances, like hypergammaglobulinemia, that might interfere with the detection of serological markers for CD. Another reason underlying the discordant data may be related to the emergence of anti-tTG antibodies in some patients with chronic...

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“…For example, IgG-TTG in absence of IgA-TTG has been described in patients with DMT1 [30]. Positive IgA-TTG and negative IgA-EMA were reported in patients with Crohn's disease [31], with unclear results on the presence of IgG-TTG [32]. There are reports in rheumatoid arthritis describing patients positive for IgA-TTG and negative for IgA-EMA [33] or IgG-TTG [34].…”

Section: Autoimmunitymentioning

confidence: 99%

IgA and IgG Antitransglutaminase 2 Antibodies in the Diagnosis of Celiac Disease

Villanueva¹,

Rojas²,

Araya³

2017

IJCD

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Screening for celiac disease (CD) dramatically improved when techniques able to measure blood autoantibodies against tissue transglutaminase 2 (TTG) were developed. Although typically increased in CD, these antibodies are not pathognomonic since they are also detected in several other autoimmune processes. IgA deficiency among celiac patients is more frequent than in general population (up to 25% vs 1-3%). This led to develop kits able to measure IgG-TTG, which until today represent a helpful diagnostic tool during diagnosis of CD in IgA deficient individuals. Today, commercial kits measuring IgG-TTG (and other) antibodies are widely available, are frequently used and create confusion in diagnosing CD in IgA-sufficient individuals. This is attributed to the fact that sensitivity and specificity of IgG-TTG is lower when applied to IgA-sufficient persons, and also because IgG-TTG is detected in several autoimmune disorders, with variable frequency and isotypes depending on the condition. Evidence analyzed indicate that to date available data: i) is insufficient to understand the difference of classes and subclasses detected in CD and other autoimmune conditions; ii) does not support the use of IgG-TTG for diagnosing CD in IgA-sufficient individuals and therefore iii) IgG should not be used in the routine diagnostic process of CD.

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Presence of anti-‘tissue’ transglutaminase antibodies in inflammatory intestinal diseases: an apoptosis-associated event?

Cited by 40 publications

References 19 publications

Proteomics Identification of Acyl-acceptor and Acyl-donor Substrates for Transglutaminase in a Human Intestinal Epithelial Cell Line

Proteomics Identification of Acyl-acceptor and Acyl-donor Substrates for Transglutaminase in a Human Intestinal Epithelial Cell Line

Prevalence and Clinical Significance of Immunoglobulin A Antibodies against Tissue Transglutaminase in Patients with Diverse Chronic Liver Diseases

IgA and IgG Antitransglutaminase 2 Antibodies in the Diagnosis of Celiac Disease

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