Advertisement

Journal of Clinical Immunology

, Volume 30, Issue 2, pp 314–320 | Cite as

Chronic Inflammatory Bowel Disease as Key Manifestation of Atypical ARTEMIS Deficiency

  • Jan Rohr
  • Ulrich Pannicke
  • Michaela Döring
  • Annette Schmitt-Graeff
  • Elisabeth Wiech
  • Andreas Busch
  • Carsten Speckmann
  • Ingo Müller
  • Peter Lang
  • Rupert Handgretinger
  • Paul Fisch
  • Klaus Schwarz
  • Stephan EhlEmail author
Article

Abstract

Introduction

We describe a girl presenting at age 6 years with a history of chronic ulcerating intestinal inflammation since 9 months of age. She exhibited a severe, steroid-dependent clinical course of intestinal inflammation over several years in the absence of serious infections.

Results and Discussion

Immunodeficiency was first considered at 6 years of age due to chronic lymphopenia. Immunophenotyping revealed low B and T cell counts with few naïve T cells, a skewed TCR repertoire, and TCR γ/δ T cell predominance, suggesting a defect of lymphocyte development. Genetic and functional analyses identified a hypomorphic mutation in the DCLRE1C (ARTEMIS) gene compromising V(D)J recombination efficiency, but allowing residual T and B cell development. Hematopoetic stem cell transplantation reconstituted the lymphocyte compartment and cured the inflammatory bowel disease.

Conclusion

This report illustrates that a genetic disorder of lymphocyte development can present with chronic inflammatory bowel disease as the dominant phenotype in the absence of severe infection susceptibility.

Keywords

Inflammatory bowel disease lymphopenia primary immunodeficiency Artemis 

Abbreviations

EDA-ID

anhidrotic ectodermal dysplasia with immunodeficiency

HSCT

hematopoietic stem cell transplantation

IBD

inflammatory bowel disease

IPEX

immunodysregulation, polyendocrinopathy, enteropathy, X-linked

TCR

T cell receptor

WAS

Wiskott-Aldrich syndrome

Notes

Acknowledgements

This work was supported by the Bundesministerium für Bildung und Forschung (BMBF 01 EO 0803). We acknowledge the excellent technical assistance of S. Braun, I. Janz, and E. M. Rump.

Conflicts of Interest

No conflicts of interest exist for any author.

References

  1. 1.
    Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schäffer AA, Noyan F, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361:2033–45.Google Scholar
  2. 2.
    Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.CrossRefPubMedGoogle Scholar
  3. 3.
    Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol. 1993;5:1461–71.CrossRefPubMedGoogle Scholar
  4. 4.
    Powrie F, Correa-Oliveira R, Mauze S, Coffman RL. Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J Exp Med. 1994;179:589–600.CrossRefPubMedGoogle Scholar
  5. 5.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992;359:693–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–74.CrossRefPubMedGoogle Scholar
  7. 7.
    Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27:20–1.CrossRefPubMedGoogle Scholar
  8. 8.
    Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007;120:744–50. quiz 751-2.CrossRefPubMedGoogle Scholar
  9. 9.
    Mombaerts P, Mizoguchi E, Grusby MJ, Glimcher LH, Bhan AK, Tonegawa S. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell. 1993;75:274–82.CrossRefPubMedGoogle Scholar
  10. 10.
    Enders A, Fisch P, Schwarz K, Duffner U, Pannicke U, Nikolopoulos E, et al. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J Immunol. 2006;176:5060–8.PubMedGoogle Scholar
  11. 11.
    Pannicke U, Ma Y, Hopfner KP, Niewolik D, Lieber MR, Schwarz K. Functional and biochemical dissection of the structure-specific nuclease ARTEMIS. EMBO J. 2004;23:1987–97.CrossRefPubMedGoogle Scholar
  12. 12.
    Moshous D, Pannetier C, Chasseval Rd R, Deist Fl F, Cavazzana-Calvo M, Romana S, et al. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J Clin Invest. 2003;111:381–7.PubMedGoogle Scholar
  13. 13.
    de Villartay JP, Lim A, Al-Mousa H, Dupont S, Déchanet-Merville J, Coumau-Gatbois E, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest. 2005;115:3291–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Ehl S, Schwarz K, Enders A, Duffner U, Pannicke U, Kühr J, et al. A variant of SCID with specific immune responses and predominance of gamma delta T cells. J Clin Invest. 2005;115:3140–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Buck D, et al. Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. Eur J Immunol. 2006;36(1):224–35.CrossRefPubMedGoogle Scholar
  16. 16.
    Kumaki S, et al. Identification of anti-herpes simplex virus antibody-producing B cells in a patient with an atypical RAG1 immunodeficiency. Blood. 2001;98(5):1464–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Pasic S, et al. Recombinase-activating gene 1 immunodeficiency: different immunological phenotypes in three siblings. Acta Paediatr. 2009;98(6):1062–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Karaca NE, et al. Diverse phenotypic and genotypic presentation of RAG1 mutations in two cases with SCID. Clin Exp Med. 2009;9:339–42.Google Scholar
  19. 19.
    Ege M, Ma Y, Manfras B, Kalwak K, Lu H, Lieber MR, et al. Omenn syndrome due to ARTEMIS mutations. Blood. 2005;105:4179–86.CrossRefPubMedGoogle Scholar
  20. 20.
    Peake J, Waugh A, Le Deist F, Priestley A, Rieux-Laucat F, Foray N, et al. Combined immunodeficiency associated with increased apoptosis of lymphocytes and radiosensitivity fibroblasts. Cancer Res. 1999;59:3454–60.PubMedGoogle Scholar
  21. 21.
    Villa A, Marrella V, Rucci F, Notarangelo LD. Genetically determined lymphopenia and autoimmune manifestations. Curr Opin Immunol. 2008;20:318–24.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jan Rohr
    • 1
  • Ulrich Pannicke
    • 2
  • Michaela Döring
    • 3
  • Annette Schmitt-Graeff
    • 4
  • Elisabeth Wiech
    • 4
  • Andreas Busch
    • 5
  • Carsten Speckmann
    • 1
  • Ingo Müller
    • 3
  • Peter Lang
    • 3
  • Rupert Handgretinger
    • 3
  • Paul Fisch
    • 4
  • Klaus Schwarz
    • 2
    • 6
    • 7
  • Stephan Ehl
    • 7
    Email author
  1. 1.Centre of Pediatrics and Adolescent MedicineUniversity Medical CenterFreiburgGermany
  2. 2.Institute for Transfusion MedicineUniversity of UlmUlmGermany
  3. 3.Department of General Pediatrics, Hematology and OncologyUniversity Children’s HospitalTübingenGermany
  4. 4.Institute of PathologyUniversity Medical CenterFreiburgGermany
  5. 5.Division of Pediatric GastroenterologyUniversity Children’s HospitalTübingenGermany
  6. 6.Institute for Clinical Transfusion Medicine and Immunogenetics UlmGerman Red Cross Blood ServiceUlmGermany
  7. 7.Centre of Chronic ImmunodeficiencyUniversity Medical CenterFreiburgGermany

Personalised recommendations