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

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 products patients should be using?

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

Better buy something useful!

Prolyl endoprotease from Aspergillus niger (AN-PEP)  Protease: cuts proteins  Cuts after proline  Food grade  Extremely stable  pH optimum between 4 and 5  resistant to low pH in stomach and pepsin Stepniak et al ., Am J Physiol Gastrointest Liver Physiol. 2006 Oct;291(4): G621-9

Artificial Gastrointestinal tract

Artificial Gastrointestinal tract

Degradation of gluten in fast food menu Glia- α 20 - AN-PEP + AN-PEP

Effect of: - Increasing amounts of AN-PEP - pH4

Extremely fast degradation at pH4 Seconds

Degradation of gluten in fast food menu Glia- α 20 - AN-PEP + AN-PEP

Positive effect of carbonated drink

Negative effect of milk Competition

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

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

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

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

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

“Identical” T cells in patients

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

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

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

TCR-DQ8-gliadin interface

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

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??

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