Coeliac Disease: Is there light at the end of the tunnel? Frits - - PowerPoint PPT Presentation

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Coeliac Disease: Is there light at the end of the tunnel? Frits - - PowerPoint PPT Presentation

Nov 07, 2022 210 likes •545 views

Coeliac Disease: Is there light at the end of the tunnel? Frits Koning LUMC, Leiden, The Netherlands Celiac Disease Consortium HLA-DQ2/8 gluten peptides CD4 + T cell tissue damage Over The Counter commercial enzyme preparations Are these

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Coeliac Disease: Is there light at the end of the tunnel?

Frits Koning LUMC, Leiden, The Netherlands Celiac Disease Consortium

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HLA-DQ2/8 gluten peptides CD4+ T cell tissue damage

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Over The Counter commercial enzyme preparations

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Are these products patients should be using?

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Degradation of Gluten peptides (Mass Spectrometry) control Gluten Guard Gluten Ease Gluten Defence Gluten Digest Gluten Freeze AN-PEP Toxic Non toxic

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Better buy something useful!

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  • Protease: cuts proteins
  • Cuts after proline
  • Food grade
  • Extremely stable
  • pH optimum between 4 and 5
  • resistant to low pH in stomach and pepsin

Prolyl endoprotease from Aspergillus niger (AN-PEP)

Stepniak et al., Am J Physiol Gastrointest Liver Physiol. 2006 Oct;291(4): G621-9

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Artificial Gastrointestinal tract

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Artificial Gastrointestinal tract

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Degradation of gluten in fast food menu

  • AN-PEP

+ AN-PEP Glia-α20

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Effect of:

  • Increasing amounts of AN-PEP
  • pH4
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Seconds

Extremely fast degradation at pH4

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Degradation of gluten in fast food menu

  • AN-PEP

+ AN-PEP Glia-α20

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Positive effect of carbonated drink

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Negative effect of milk Competition

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Safeguard to inadvertent gluten exposure Enzymes are useful to enhance gluten degradation

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HLA-DQ2/8 gluten peptides CD4+ T cell tissue damage

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Figure 3-3 You can make an awful lot of different T cell receptors

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10e15 cells = 1000 kilogram Potential number of TCRs estimated to be between 10e15 and 10e18

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The Chance That Two Randomly Selected T cells Express an IDENTICAL T Cell Receptor = 0

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“Identical” T cells in patients

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The Chance That Two Randomly Selected T cells Express an IDENTICAL T Cell Receptor = 0

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What does this mean?? Selection for high affinity T cells

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Immunity 2012 Structure of complex between T cell receptor and HLA-DQ8-gliadin

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TCR-DQ8-gliadin interface

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The same is true for HLA-DQ2: 95% of patients

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Conclusions

Biased TCR repertoire Structurally conserved INTIMATELY ASSOCIATED WITH DISEASE Emergence of such T cells may be required for disease development Diagnostics/prognostics?? Therapy?? Eliminate T cells with biased TCR??

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Acknowledgements

  • Jeroen van Bergen
  • Yvonne Kooy
  • Veronica Monserrat
  • Allan Thompson
  • Luisa Mearin
  • Chris Mulder
  • Vincent van Unen
  • Luppo Edens
  • Maaike Bruins
  • Chantal Christis
  • Hugh Reid
  • Bob Anderson
  • Jan Petersen
  • Jamie Rossjohn