Coeliac autoantibodies can enhance transamidating and inhibit GTPase activity of tissue transglutaminase: Dependence on reaction environment and enzyme fitness

Király, Róbert; Vecsei, Zsófia; Deményi, Tamás; Korponay-Szabó, Ilma Rita; Fesus, L.

doi:10.1016/j.jaut.2006.03.002

Cited by 39 publications

(29 citation statements)

References 52 publications

(55 reference statements)

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“…The competition between different ScFv-groups or natural IgA and IgG patient antibodies recognizing Arg19 differently and effective displacement of diverse patient antibodies by mAb 885 targeting only Glu153 demonstrates that Glu153, Arg19 and Met659 constitute one composite epitope when the protein is in the closed conformation. Binding of celiac antibodies to a surface area close to the interface of adjacent domains may be the structural basis for certain conformation stabilizing effect responsible for the earlier observed gain in catalytic activity in the presence of celiac antibodies (8,25). The variable involvement of N-terminal and Cterminal domains explains why earlier studies typically found a sufficient binding if either the N-terminal or C-terminal TG2 parts were missing, but not if both were missing or if the core domain had been disrupted (16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

“…S4B). IgA and IgG antibodies differently recognizing R19S were purified from sera of celiac patients (25), and these competed as well with each other but not with nonceliac human IgG (Fig. S4C).…”

Section: Antibodies Of Different Celiac Patients Recognize Parts Of Tmentioning

confidence: 99%

“…To establish the relative importance of Arg19 and Met659 in celiac antibody binding, we studied fibronectin-bound TG2 (25) as a model of accessibility of TG2 epitopes in the extracellular matrix where antibodies primarily encounter the autoantigen in patients. Under these conditions, the mutations of Arg19 and Glu153 had similar effects as seen above (Fig.…”

Section: -D)mentioning

confidence: 99%

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A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects

Simon-Vecsei

Király

Bagossi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The multifunctional, protein cross-linking transglutaminase 2 (TG2) is the main autoantigen in celiac disease, an autoimmune disorder with defined etiology. Glutamine-rich gliadin peptides from ingested cereals, after their deamidation by TG2, induce T-lymphocyte activation accompanied by autoantibody production against TG2 in 1-2% of the population. The pathogenic role and exact binding properties of these antibodies to TG2 are still unclear. Here we show that antibodies from different celiac patients target the same conformational TG2 epitope formed by spatially close amino acids of adjacent domains. Glu153 and 154 on the first alpha-helix of the core domain and Arg19 on first alpha-helix of the N-terminal domain determine the celiac epitope that is accessible both in the closed and open conformation of TG2 and dependent on the relative position of these helices. Met659 on the C-terminal domain also can cooperate in antibody binding. This composite epitope is diseasespecific, recognized by antibodies derived from celiac tissues and associated with biological effects when passively transferred from celiac mothers into their newborns. These findings suggest that celiac antibodies are produced in a surface-specific way for which certain homology of the central glutamic acid residues of the TG2 epitope with deamidated gliadin peptides could be a structural basis. Monoclonal mouse antibodies with partially overlapping epitope specificity released celiac antibodies from patient tissues and antagonized their harmful effects in cell culture experiments. Such antibodies or similar specific competitors will be useful in further functional studies and in exploring whether interference with celiac antibody actions leads to therapeutic benefits.conformational epitope | endomysial antibodies | immunotherapy

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Section: Discussionmentioning

confidence: 99%

Section: Antibodies Of Different Celiac Patients Recognize Parts Of Tmentioning

confidence: 99%

Section: -D)mentioning

confidence: 99%

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A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects

Simon-Vecsei

Király

Bagossi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Tissue transglutaminase transamidation assays were performed using fibronectin bound tTG as described earlier by Király et al 42 with minor modifications. Briefly, universal binding 96-well microtiter plate (Thermo Fisher Scientific Oy, Vantaa, Finland) wells were coated with 100 ml human fibronectin (Sigma-Aldrich) at a concentration of 5 mg/ml in carbonate/bicarbonate buffer (pH 9.6) overnight at 4 uC.…”

Section: Detection Of Serum Antibodiesmentioning

confidence: 99%

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

et al. 2011

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Two common chronic childhood diseases-celiac disease (CD) and type 1 diabetes (T1D)-result from complex pathological mechanisms where genetic susceptibility, environmental exposure, alterations in intestinal permeability and immune responses play central roles. In this study, we investigated whether these characteristics were universal for CD independently of T1D association. For this purpose, we studied 36 children with normal small-bowel mucosa and 26 children with active CD, including 12 patients with T1D. In samples from the small-bowel mucosa, we detected the lowest expression of tight junction protein 1 (TJP1) mRNA in CD patients with T1D, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker for regulatory T cells, as compared with other patient groups. At the same time, serum levels of IgA antibodies specific for the CD-related antigens deamidated gliadin and tissue transglutaminase (tTG) were the highest in CD patients with T1D. In contrast, no significant differences were found in IgA or IgG antibodies specific for bovine beta-lactoglobulin or Bifidobacterium adolescentis DSM 20083-derived proteins. There were also no differences in the transamidating activity of serum autoantibodies between patients and control individuals. Our results show that patients with T1D and newly detected CD exhibit severely altered intestinal permeability, strong local immune activation and increased immunoregulatory mechanisms in the small bowel. Further study is required to determine whether these extreme changes in this CD subgroup are due to some specific environmental factors (virus infections), unknown genetic effects or autoimmune reactions to antigenic targets in intracellular tight junctions. INTRODUCTIONWith an approximate prevalence of 1.0% in Western countries, celiac disease (CD) is one of the most common lifelong chronic disorders. 1 CD and type 1 diabetes (T1D) form a significant sector of childhood diseases with high rate of co-occurrence. 2 Both diseases are autoimmune in origin and develop as a result of complex pathological mechanisms, involving several common genetic, environmental and immunological factors. Among these, the common susceptibility loci of HLA and other immune system-related genes, 3 permeability changes in the small-bowel mucosa, 4 and association with wheat consumption 4,5 are prominent. Both diseases are increasing in most regions of the world, 6,7 as are several other autoimmune diseases, but the actual cause of the disease remains unknown. However, several recent studies have highlighted the role of environmental and social changes that have taken place over the last several decades. 8,9 The central event in the pathogenesis of CD is damage to the small intestinal mucosa that occurs after ingestion of gluten or related prolamins in genetically susceptible individuals. During this process, several morphological and immunological alterations have been demonstrated in the small-bowel mucos...

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“…They were shown to enhance transamidation, modulate vascular permeability and ameliorate antiangiogenesis, [36,[38][39][40]. Despite the physiological TG2 importance in cell biology and survival, its gain of functions induced by its specific autoantibody results in pathological processes enhancing CD intestinal damage.…”

Section: Are Anti Tg2 Autoantibodies Bystander Protective or Pathogementioning

confidence: 99%

Transglutaminase 2 and Anti Transglutaminase 2 Autoantibodies in Celiac Disease and Beyond: Anti- Transglutaminase 2 Autoantibodies: Friends or Enemies

Lerner¹,

Neidhöfer²,

Tenbusch³

2015

Immunome Res

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Tissue transglutaminase is a multifunctional enzyme, exerting intra and extracellular, enzymatic and nonenzymatic, Ca 2+ dependent and independent functions. Its specific autoantibody, the anti transglutaminase2 autoantibody is multifunctional, affecting many of the enzyme activities. Most of them are due to loss of function, the minority being gain of function of the enzyme. No beneficial protective effects, but only pathogenic ones, were assigned to those celiac disease associated anti TG2 autoantibodies. Taken together, celiac antibodies could collectively promote small bowel intestinal or extraintestinal damage. Yet, most of the transglutaminase2 autoantibody activities where explored in vitro and ex-vivo, very few in animal model but none in vivo, in human. The celiac disease serum contains numerous antibodies, IgA-transglutaminase2 is only one of them and up till now, its differential role in celiac disease induction and maintenance is far from being unraveled. Unraveling them might open some new therapeutic strategies for celiac disease.

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Coeliac autoantibodies can enhance transamidating and inhibit GTPase activity of tissue transglutaminase: Dependence on reaction environment and enzyme fitness

Cited by 39 publications

References 52 publications

A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects

A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

Transglutaminase 2 and Anti Transglutaminase 2 Autoantibodies in Celiac Disease and Beyond: Anti- Transglutaminase 2 Autoantibodies: Friends or Enemies

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