Epitopes recognised by tissue transglutaminase antibodies in coeliac disease

Nakachi, Koh; Powell, Michael J.; Swift, G. L.; Amoroso, Marie-Andrée; Ananieva-Jordanova, Rossitza; Arnold, Clare; Sanders, Jane; Furmaniak, Jadwiga; Smith, Bernard Rees

doi:10.1016/j.jaut.2003.09.002

Cited by 22 publications

(12 citation statements)

References 57 publications

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“…1), and antibody recognition was also influenced by the loss of domain IV (aa 585-687) but not at all by the absence of domain III (aa 472-584). These results suggested, in accordance with previous data (16)(17)(18), that parts of celiac epitopes are found both on the N-terminal and C-terminal domains. Importantly, patient antibodies, however, did not bind to the mutant containing only domains I-III-IV but not domain II, so in the absence of the anchor points on the core domain the other celiac epitope parts were not capable to form a functional binding site.…”

Section: Resultssupporting

confidence: 92%

“…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). We applied a special precaution to avoid the disruption of hydrogen bonds or the distorsion of the conformation, and the folded structure of our key mutants were confirmed by CD spectra.…”

Section: Discussionmentioning

confidence: 99%

“…When TG2 is functioning as a Ca 2þ -dependent transglutaminase, C-terminal beta-barrels are displaced by 120 Å and the structure becomes open and extended (2) (PDB ID code 2Q3Z), at least transiently. In earlier studies celiac anti-TG2 antibodies bound to multiple (often complementary) fragments of human TG2 (16)(17)(18), but to none of linear TG2 peptides expressed in phage display (19). In another study, mutagenesis of the normally buried catalytic triad decreased antibody binding (20).…”

mentioning

confidence: 98%

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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: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

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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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“…It was shown that mutagenesis of flexible residues resulted in increased enzymatic activity of microbial transglutaminase [46]. Binding of coeliac antibodies also may interfere with the regulatory function of the C-terminal part where important target epitopes were located [35,36,47]. Autoantibody binding may facilitate proper folding of TG2 and assist to refold enzyme molecules which became less active by various reasons, including normal decay.…”

Section: Discussionmentioning

confidence: 99%

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

Király¹,

Vecsei²,

Deményi³

et al. 2006

Journal of Autoimmunity

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“…In fact, TG2 displays a significant capacity to undergo conformational changes shifting from a more compact protein to a more linear and accessible status, thus affecting the ability of T cells to recognize specific epitopes on its surface. Currently, we do not know whether autoreactive T cells recognize epitopes that are also antibody targets (36). Anti-TG2 autoantibodies, however, do not allow the distinction between active and potential CD since they are present in both, implying that TG2-specific B cell autoimmunity is not predictive of active disease onset.…”

Section: Discussionmentioning

confidence: 99%

Isolation and Characterization of Circulating Tissue Transglutaminase-Specific T Cells in Coeliac Disease

Ciccocioppo

Finamore

Mengheri

et al. 2010

Int J Immunopathol Pharmacol

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Tissue transglutaminase (TG2) was identified as the humoral autoantigen in coeliac disease, but whether it can also serve as T cell autoantigen is still unknown. We aimed, therefore, to firstly explore the presence of TG2-specific T cells in peripheral blood of ten adult patients (four active, i.e. carrying both serological and histological features of the disease; four treated, i.e. with proven mucosal recovery and disappearance of specific antibodies after an adequate period of gluten free diet; and two potential coeliacs, i.e. carrying the serological stigmata of the disease, but not the intestinal lesions), and four healthy controls (two carrying the HLA-DQ2 haplotype of susceptibility to the disease), and secondly to carry out a detailed in vitro characterization of the isolated antigen-specific T cells. T cell lines were first established by means of weekly stimulation with human recombinant TG2 followed by generation of T cell clones through distribution of T cells on plates at one cell/well limiting dilution and further rounds of stimulation. Antigen specificity and HLA-DQ2 restriction were both assessed by evaluating the proliferative response to TG2 in the absence and presence of human sera blocking HLA-DQ2 molecules, after exclusion of impurities in the antigen preparation. Immune phenotyping of T cell clones was performed by flow cytometry, and the expression of IL-1â, IL-4, IL-6, IL-10, IL-12, TGF-beta, IFN-gamma and TNF-alpha was determined by ELISA assay on the supernatants of these clones. A total of 91 T cell clones were isolated from the three HLA-DQ2-positive, active patients, but none from the other patients and controls. The immune phenotyping showed that the majority of them (85.7 percent) were CD3/CD4+ and only a small percentage (14.3 percent) were CD3/CD8+, all carried the TCR alphabeta, and had a memory phenotype. The cytokine profile showed high levels of IFN-gamma and IL-6 that, together with the absence of IL-4, placed these T cell clones in the T helper type 1-like category. Further in vitro analysis was carried out on 32/91 CD4+ clones and showed a specific and dose-dependent proliferative response towards TG2 and an HLA-DQ2 restriction. Finally, when incubating duodenal mucosal specimens of treated patients with the supernatant of TG2-specific T cell clones, characteristic disease lesions were found, indicating a role for TG2-specific cellular immune response in the pathogenesis of coeliac disease.

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Epitopes recognised by tissue transglutaminase antibodies in coeliac disease

Cited by 22 publications

References 57 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

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

Isolation and Characterization of Circulating Tissue Transglutaminase-Specific T Cells in Coeliac Disease

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