The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides

Vader, Willemijn; Kooy, Yvonne; Veelen, Peter A. van; Ru, Arnoud de; Harris, Diana; Benckhuijsen, Willemien E.; Peña, Salvador; Mearin, Luisa; Drijfhout, Jan W.; Koning, Frits

doi:10.1053/gast.2002.33606

Cited by 384 publications

(324 citation statements)

References 20 publications

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“…In children with celiac disease, however, we were often not able to find responses to these immunodominant peptides. Instead, we observed a diverse response to several other gluten sequences, some of which are not found in adults (24). To explain this apparent discrepancy, we have hypothesized that a T cell response to gluten can be initiated against a relatively large number of peptides and that when the response evolves it focuses on the most immunodominant sequences (24).…”

Section: Discussionmentioning

confidence: 88%

Large-Scale Characterization of Natural Ligands Explains the Unique Gluten-Binding Properties of HLA-DQ2

Stepniak

Wiesner

et al. 2008

The Journal of Immunology

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Celiac disease is an enteropathy caused by intolerance to dietary gluten. The disorder is strongly associated with DQA1*0501/DQB1*0201 (HLA-DQ2) as ∼95% of celiac patients express this molecule. HLA-DQ2 has unique Ag-binding properties that allow it to present a diverse set of gluten peptides to gluten-reactive CD4+ T cells so instigating an inflammatory reaction. Previous work has indicated that the presence of negatively charged amino acids within gluten peptides is required for specific binding. This, however, only partly explains the scale of the interaction. We have now characterized 432 natural ligands of HLA-DQ2 representing length variants of 155 distinct sequences. The sequences were aligned and the binding cores were inferred. Analysis of the amino acid distribution of these cores demonstrated that negatively charged residues in HLA-DQ2-bound peptides are favored at virtually all positions. This contrasts with a more restricted presence of such amino acids in T cell epitopes from gluten. Yet, HLA-DQ2 was also found to display a strong preference for proline at several anchor and nonanchor positions that largely match the position of proline in gluten T cell epitopes. Consequently, the bias for proline at p6 and p8 facilitates the enzymatic conversion of glutamine into glutamic acid in gluten peptides at p4 and p6, two important anchor sites. These observations provide new insights in the unique ability of HLA-DQ2 to bind a large repertoire of glutamine- and proline-rich gluten peptides. This knowledge may be an important asset in the development of future treatment strategies.

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Section: Discussionmentioning

confidence: 88%

Large-Scale Characterization of Natural Ligands Explains the Unique Gluten-Binding Properties of HLA-DQ2

Stepniak

Wiesner

et al. 2008

The Journal of Immunology

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“…Finally, and perhaps most importantly, among HLA mediated diseases, Celiac Sprue is unique in that an environmental trigger (dietary gluten) has been identified and extensively dissected at an immunological level (4,5). In turn, these studies have led to the identification of proteolytically resistant gluten peptides that are generated by physiological processes and are efficiently presented to disease associated T cells in a DQ2 restricted fashion (12)(13)(14)(15). Thus, if these naturally occurring T cell stimulatory agents can be transformed into inhibitors of DQ2 mediated antigen presentation, they can be considered as appropriate medicinal leads for Celiac Sprue.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HLA-DQ2-Mediated Antigen Presentation by Analogues of a High Affinity 33-Residue Peptide from α2-Gliadin

et al. 2006

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Human leukocyte antigen DQ2 is a class II major histocompatibility complex protein that plays a critical role in the pathogenesis of Celiac Sprue by binding to epitopes derived from dietary gluten and triggering the inflammatory response of disease-specific T cells. Inhibition of DQ2 mediated antigen presentation in the small intestinal mucosa of Celiac Sprue patients therefore represents a potentially attractive mode of therapy for this widespread but unmet medical need. Starting from a pro-inflammatory, proteolytically resistant, 33-residue peptide, LQLQPFPQPELPYPQPELPYPQPELPYPQPQPF, we embarked upon a systematic effort to dissect the relationships between peptide structure and DQ2 affinity, and to translate these insights into prototypical DQ2 blocking agents. Three structural determinants within the first 20 residues of this 33-mer peptide, including a PQPELPYPQ epitope, its N-terminal flanking sequence and a downstream Glu residue, were found to be important for DQ2 binding. Guided by the X-ray crystal structure of DQ2, the L11 and L18 residues in the truncated 20-mer analogue were replaced with sterically bulky groups so as to retain high DQ2 affinity but abrogate T cell recognition. A dimeric ligand, synthesized by regiospecific coupling of the 20-mer peptide with a bifunctional linker, was identified as an especially potent DQ2 binding agent. Two such ligands were able to attenuate the proliferation of disease-specific T cell lines in response to gluten antigens, and therefore represent prototypical examples of pharmacologically suitable DQ2 blocking agents for the potential treatment of Celiac Sprue.

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“…Celiac disease (CD) is an autoimmune enteropathy characterized by villous atrophy, crypt hyperplasia and heavy inflammatory infiltrate of both epithelium and lamina propria, caused by a T-cell response to an array of epitopes of dietary gliadin 1,2 in genetically susceptible individuals 3 carrying the HLA-DQ2 or -DQ8 phenotype. It is supposed that tissue transglutaminase, the CD autoantigen, 4 increasingly released as a consequence of increasing tissue injury, 5 catalyses gliadin deamidation and focuses T-cell response towards immunodominant gliadin fragments.…”

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confidence: 99%

Matrix metalloproteinase pattern in celiac duodenal mucosa

Ciccocioppo

Sabatino

Bauer

et al. 2005

Laboratory Investigation

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Matrix metalloproteinases (MMPs) are a family of endopeptidases playing a key role in tissue remodelling in both physiological and pathological conditions. Since little information is available about their role in celiac disease (CD), our aims were to quantify their expression/activity and to investigate their relation to proinflammatory cytokines in this condition. Duodenal biopsies from untreated, treated celiac patients and controls were used to quantify the expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, MMP-14, their inhibitor TIMP-1, IFN-c and TNF-a by using real-time reverse transcription-polymerase chain reaction and the gelatin/casein/elastin activities by gel zymography, and to isolate lamina propria mononuclear cells (LPMCs). These cells and myofibroblasts isolated from jejunal specimens were incubated in the absence or presence of IFN-c and TNF-a. MMP-1 and MMP-12 mRNA levels were significantly increased in active CD compared to treated (Po0.01 and Po0.0005, respectively) and normal mucosa (Po0.01 and Po0.0005, respectively), and this was paralleled by an upregulation of caseinolytic and elastolytic activities. Furthermore, MMP-12 levels significantly (Po0.05) correlated with those of IFN-c and the degree of villous flattening. MMP-2 turned out to be significantly (Po0.05) reduced in untreated and treated celiacs compared to controls. In active CD, transcripts of TIMP-1 were higher than in treated and controls (Po0.005 and Po0.05, respectively), such as those of IFN-c (Po0.05), whereas TNF-a levels were suppressed (P ¼ 0.0001). In physiological condition, myofibroblasts represent the main source of MMP-2, whereas LPMCs produce almost all MMPs only after cytokine stimulation. Conversely, cells isolated from active patients constitutively express MMPs without any increase after cytokine stimulation, while those from treated patients are in a resting condition. In conclusion, our results show the presence of a peculiar MMP pattern in active CD strongly dominated by MMP-12, correlating either with IFN-c or the degree of mucosal damage.

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The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides

Cited by 384 publications

References 20 publications

Large-Scale Characterization of Natural Ligands Explains the Unique Gluten-Binding Properties of HLA-DQ2

Large-Scale Characterization of Natural Ligands Explains the Unique Gluten-Binding Properties of HLA-DQ2

Inhibition of HLA-DQ2-Mediated Antigen Presentation by Analogues of a High Affinity 33-Residue Peptide from α2-Gliadin

Matrix metalloproteinase pattern in celiac duodenal mucosa

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