Skip to main content
SpringerLink
Log in

Pathophysiologie der Zöliakie

Pathophysiology of celiac disease

  • Schwerpunkt: Zöliakie und Darmlymphome
  • Published:
Der Gastroenterologe Aims and scope

Zusammenfassung

Die Zöliakie wurde bereits von Martin Kagnoff zutreffend als immunogenetische Modellerkrankung beschrieben, da Gluten bezüglich der zöliakieverursachenden Immunreaktion quasi wie ein Schalter funktioniert: Durch Hinzunahme bzw. Elimination von Gluten aus der täglichen Kost lässt sich die Erkrankung „ein-“ und „ausschalten“. Erfreulicherweise wurde diese Situation von einer großen Zahl wissenschaftlicher Arbeitsgruppen in den letzten Jahrzehnten genutzt, sodass aus der Aufklärung komplexer immunologischer Zusammenhänge vielversprechende neue Therapiestrategien erwachsen sind, die sich z. T. bereits in verschiedenen Phasen der klinischen Erprobung befinden.

Abstract

Celiac disease is an immunogenetic disorder that is initiated by the ingestion of glutens, which are proteins that occur in wheat, barley and rye. The celiac immune reaction includes the presentation of deamidated gliadin peptide sequences to T cells. Recently, B cell function within this process was shown to extend beyond production of antitransglutaminase and antideamidated gliadin IgA antibodies. Moreover, gliadin peptide sequences also activate the nonadaptive arm of the immune system. This article summarizes recent research on the immunopathology of celiac disease and deduces future treatment concepts from these new pathophysiological insights.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2

Literatur

  1. Felber J, Aust D, Baas S et al (2014) Ergebnisse einer S2k-Konsensuskonferenz der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselerkrankungen (DGVS) gemeinsam mit der Deutschen Zöliakie-Gesellschaft (DZG e. V.) zur Zöliakie, Weizenallergie und Weizensensitivitä. Z Gastroenterol 52:711–743

    Article  CAS  PubMed  Google Scholar 

  2. Ludvigsson JF, Leffler DA, Bai JC et al (2013) The Oslo definitions for coeliac disease and related terms. Gut 62:43–52

    Article  PubMed Central  PubMed  Google Scholar 

  3. Arentz-Hansen H, McAdam SN, Molberg O et al (2002) Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues. Gastroenterology 123:803–809

    Article  PubMed  Google Scholar 

  4. Molberg O, McAdam S, Lundin KE et al (2001) T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur J Immunol 31:1317–1323

    Article  CAS  PubMed  Google Scholar 

  5. Shan L, Molberg O, Parrot I et al (2002) Structural basis for gluten intolerance in celiac sprue. Science 297:2275–2279

    Article  CAS  PubMed  Google Scholar 

  6. Vader W, Kooy Y, Van Veelen P et al (2002) The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology 122:1729–1737

    Article  CAS  PubMed  Google Scholar 

  7. Schumann M, Kamel S, Jöhrens K, Daum S (2014) Zöliakie – Eine Übersicht zur Leitlinie der DGVS. Gastroenterol Up2date 10(04):235–245

    Article  Google Scholar 

  8. Matysiak-Budnik T, Moura IC, Arcos-Fajardo M et al (2008) Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med 205:143–154

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Schumann M, Richter JF, Wedell I et al (2008) Mechanisms of epithelial translocation of the {alpha}2-gliadin-33mer in celiac sprue. Gut 57(6):747–754

    Article  CAS  PubMed  Google Scholar 

  10. du Pre MF, Sollid LM (2015) T-cell and B-cell immunity in celiac disease. Best Pract Res Clin Gastroenterol 29:413–423

    Article  CAS  PubMed  Google Scholar 

  11. Daum S, Bauer U, Foss HD et al (1999) Increased expression of mRNA for matrix metalloproteinases-1 and -3 and tissue inhibitor of metalloproteinases-1 in intestinal biopsy specimens from patients with coeliac disease. Gut 44:17–25

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Bodd M, Raki M, Tollefsen S et al (2010) HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol 3:594–601

    Article  CAS  PubMed  Google Scholar 

  13. Nilsen EM, Lundin KE, Krajci P et al (1995) Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 37:766–776

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Hue S, Mention JJ, Monteiro RC et al (2004) A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21:367–377

    Article  PubMed  Google Scholar 

  15. Meresse B, Chen Z, Ciszewski C et al (2004) Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21:357–366

    Article  CAS  PubMed  Google Scholar 

  16. Schumann M, Gunzel D, Buergel N et al (2012) Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease. Gut 61:220–228

    Article  CAS  PubMed  Google Scholar 

  17. Di Niro R, Mesin L, Zheng NY et al (2012) High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med 18:441–445

    Article  PubMed Central  PubMed  Google Scholar 

  18. Fleckenstein B, Qiao SW, Larsen MR et al (2004) Molecular characterization of covalent complexes between tissue transglutaminase and gliadin peptides. J Biol Chem 279:17607–17616

    Article  CAS  PubMed  Google Scholar 

  19. Nistico L, Fagnani C, Coto I et al (2006) Concordance, disease progression, and heritability of coeliac disease in Italian twins. Gut 55:803–808

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Vader W, Stepniak D, Kooy Y et al (2003) The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci USA 100:12390–12395

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Kumar V, Wijmenga C, Withoff S (2012) From genome-wide association studies to disease mechanisms: celiac disease as a model for autoimmune diseases. Semin Immunopathol 34:567–580

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Meresse B, Malamut G, Cerf-Bensussan N (2012) Celiac disease: an immunological jigsaw. Immunity 36:907–919

    Article  CAS  PubMed  Google Scholar 

  23. Schumann M, Siegmund B (2015) Gluten-Enteropathie. In: Stange F (Hrsg) Entzündliche Darmerkrankungen. Schattauer, Stuttgart

    Google Scholar 

  24. Lähdeaho M-L, Lindfors K, Airaksinen L, Kaukinen K, Mäki RM (2012) Advances in the development of new treatments for celiac disease. Expert Opin Biol Ther 12(12):1589–1600

    Article  PubMed  Google Scholar 

  25. Lähdeaho M-L, Kaukinen K, Laurila K et al (2014) Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology 146:1649–1658

    Article  PubMed  Google Scholar 

  26. Paterson BM, Lammers KM, Arrieta MC et al (2007) The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther 26:757–766

    Article  CAS  PubMed  Google Scholar 

  27. ClinicalTrials.gov. Identifier: NCT00492960

  28. Sulic AM, Kurppa K, Rauhavirta T et al (2015) Transglutaminase as a therapeutic target for celiac disease. Expert Opin Ther Targets 19:335–348

    Article  CAS  PubMed  Google Scholar 

  29. Xia J, Bergseng E, Fleckenstein B et al (2007) Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease. Bioorg Med Chem 15:6565–6573

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Tye-Din JA, Stewart JA, Dromey JA et al (2010) Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci Transl Med 2:41ra51

    Article  PubMed  Google Scholar 

  31. Brown G (2011) A phase 1 study to determine safety, tolerability and bioactivity of Nexvax in HLADQ2+volunteers with celiac disease following a long term, strict gluten-free diet. Gastroenterology 140:S437–438

    Article  Google Scholar 

  32. Kagnoff MF (2007) Celiac disease: pathogenesis of a model immunogenetic disease. J Clin Invest 117:41–49

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Klinik I m.S. Gastroenterologie, Infektiologie und Rheumatologie, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Deutschland

    M. Schumann, S. Daum & B. Siegmund

Authors
  1. M. Schumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Daum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Siegmund
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Schumann.

Ethics declarations

Interessenkonflikt

M. Schumann, S. Daum und B. Siegmund geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

Additional information

Redaktion

B. Siegmund, Berlin

M. Schumann, Berlin

W. Fischbach, Aschaffenburg

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schumann, M., Daum, S. & Siegmund, B. Pathophysiologie der Zöliakie. Gastroenterologe 10, 464–472 (2015). https://doi.org/10.1007/s11377-015-0014-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11377-015-0014-z

Schlüsselwörter

Keywords

Search

Navigation