Prolyl Endopeptidase-Mediated Destruction of T Cell Epitopes in Whole Gluten: Chemical and Immunological Characterization

Marti, Thomas; Molberg, Øyvind; Li, Qing; Gray, Gary M.; Khosla, Chaitan; Sollid, Ludvig M.

doi:10.1124/jpet.104.073312

Cited by 119 publications

(91 citation statements)

References 22 publications

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“…POP activity has been shown to negatively affect the generation of a subset of CD4 + T cell epitopes derived from gluten (42). Our data obtained from pp65 [490][491][492][493][494][495][496][497][498][499][500][501][502][503] in vitro digestion experiments with rPOP show a dominant cleavage after P498 within the epitope.…”

Section: Discussionmentioning

confidence: 97%

The Efficiency of Human Cytomegalovirus pp65495–503 CD8+ T Cell Epitope Generation Is Determined by the Balanced Activities of Cytosolic and Endoplasmic Reticulum-Resident Peptidases

Urban

Textoris-Taube

Reimann

et al. 2012

The Journal of Immunology

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Control of human CMV (HCMV) infection depends on the cytotoxic activity of CD8+ CTLs. The HCMV phosphoprotein (pp)65 is a major CTL target Ag and pp65495–503 is an immunodominant CTL epitope in infected HLA-A*0201 individuals. As immunodominance is strongly determined by the surface abundance of the specific epitope, we asked for the components of the cellular Ag processing machinery determining the efficacy of pp65495–503 generation, in particular, for the proteasome, cytosolic peptidases, and endoplasmic reticulum (ER)-resident peptidases. In vitro Ag processing experiments revealed that standard proteasomes and immunoproteasomes generate the minimal 9-mer peptide epitope as well as N-terminal elongated epitope precursors of different lengths. These peptides are largely degraded by the cytosolic peptidases leucine aminopeptidase and tripeptidyl peptidase II, as evidenced by increased pp65495–503 epitope presentation after leucine aminopeptidase and tripeptidyl peptidase II knockdown. Additionally, with prolyl oligopeptidase and aminopeptidase B we identified two new Ag processing machinery components, which by destroying the pp65495–503 epitope limit the availability of the specific peptide pool. In contrast to cytosolic peptidases, silencing of ER aminopeptidases 1 and 2 strongly impaired pp65495–503-specific T cell activation, indicating the importance of ER aminopeptidases in pp65495–503 generation. Thus, cytosolic peptidases primarily interfere with the generation of the pp65495–503 epitope, whereas ER-resident aminopeptidases enhance such generation. As a consequence, our experiments reveal that the combination of cytosolic and ER-resident peptidase activities strongly shape the pool of specific antigenic peptides and thus modulate MHC class I epitope presentation efficiency.

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Section: Discussionmentioning

confidence: 97%

The Efficiency of Human Cytomegalovirus pp65495–503 CD8+ T Cell Epitope Generation Is Determined by the Balanced Activities of Cytosolic and Endoplasmic Reticulum-Resident Peptidases

Urban

Textoris-Taube

Reimann

et al. 2012

The Journal of Immunology

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“…1 Celiac disease is characterized by villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia. 2 New advances in serologic and endoscopic modalities have markedly facilitated the diagnosis of CD. The gluten-free diet is the standard treatment for patients with CD and necessitates avoidance of wheat, rye, and barley.…”

Section: Introductionmentioning

confidence: 99%

Unintentional Weight Loss in a Renal Transplant Recipient: Do Not Overlook Coeliac Disease

Solak

Gaipov²,

Bıyık

et al. 2013

Exp Clin Transplant

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Unintentional weight loss in a renal transplant recipient is an important condition, requiring diagnostic search within the framework of malignancy and opportunistic infections. To the best of our knowledge, there are no data in the literature reporting underlying coeliac disease as the cause of significant weight loss after renal transplant. We report a 32-year-old woman, who complained of significant weight loss during the 3.5 years posttransplant. Diagnostic work-up revealed coeliac disease, and a gluten-free diet stabilized her weight loss. Considering the high frequency of coeliac disease, this should be kept in the differential diagnosis of renal transplant recipients presented with weight loss and other suggestive features.

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“…pH-dependent activity profiles of FM and MX PEPs were determined at 50 mU∕mL in HCl/KCl solution USP (pH 1.2), acetate buffer USP (pH 4.5), phosphate buffer (100 mM, pH 7.0), and trometamol/ sodium chloride buffer (50∕100 mM, pH 9). Activity was assessed by measuring the cleavage of Z-Gly-Pro-pNA using an Infinite M200 microplate reader (Tecan Ltd.) (20).…”

Section: Methodsmentioning

confidence: 99%

“…Among these, oral administration of prolyl endopeptidases (PEPs) is one of the most studied approaches (18). Unlike human GI enzymes, PEPs can efficiently hydrolyze proline-rich gluten peptides (9) and they have been shown to alleviate gluten immunotoxicity under simulated intestinal conditions (19,20). Earlier studies conducted with PEPs from Flavobacterium meningosepticum (FM) and Myxococcus xanthus (MX) revealed moderate enzyme stability in vitro under artificial GI conditions (21).…”

mentioning

confidence: 99%

In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract

Fuhrmann

Leroux

2011

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

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Exogenous enzymes are administered orally to treat several diseases, such as pancreatic insufficiency and lactose intolerance. Due to the proteinaceous nature of enzymes, they are subject to inactivation and/or digestion in the gastrointestinal (GI) tract. Here we describe a convenient fluorescence-based assay to monitor the activity of therapeutic enzymes in real time in vivo in the GI tract. To establish the proof of principle, the assay was applied to proline-specific endopeptidases (PEPs), a group of enzymes recently proposed as adjuvant therapy for celiac disease (a highly prevalent immunogenetic enteropathy). A short PEP-specific peptide sequence which is part of larger immunotoxic sequences of gluten was labeled with a fluorescent dye and a corresponding quencher. Upon enzymatic cleavage, the fluorescence emission was dequenched and detected with an in vivo imaging system. PEPs originating from Flavobacterium meningosepticum (FM) and Myxococcus xanthus (MX) were evaluated after oral administration in rats. While MX PEP could not cleave the peptide in the stomach, FM PEP showed significant gastric activity reaching 40–60% of the maximal in vivo signal intensity. However, both enzymes produced comparable fluorescence signals in the small intestine. Coadministration of an antacid drug significantly enhanced MX PEP’s gastric activity due to increased pH and/or inhibition of stomach proteases. With this simple procedure, differences in the in vivo performance of PEPs, which could not be identified under in vitro conditions, were detected. This imaging assay could be used to study other oral enzymes in vivo and therefore be instrumental in improving their therapeutic efficiency.

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Prolyl Endopeptidase-Mediated Destruction of T Cell Epitopes in Whole Gluten: Chemical and Immunological Characterization

Cited by 119 publications

References 22 publications

The Efficiency of Human Cytomegalovirus pp65495–503 CD8+ T Cell Epitope Generation Is Determined by the Balanced Activities of Cytosolic and Endoplasmic Reticulum-Resident Peptidases

The Efficiency of Human Cytomegalovirus pp65495–503 CD8+ T Cell Epitope Generation Is Determined by the Balanced Activities of Cytosolic and Endoplasmic Reticulum-Resident Peptidases

Unintentional Weight Loss in a Renal Transplant Recipient: Do Not Overlook Coeliac Disease

In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract

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