Monatsschrift Kinderheilkunde

, 157:853

Angeborene Defekte der T- und B-Lymphozyten

Leitthema
  • 141 Downloads

Zusammenfassung

Im Gegensatz zu früheren klinischen Klassifikationen lassen sich angeborene T- und B-Zell-Defekte inzwischen zu einem sehr hohen Prozentsatz auf definierte Genmutationen zurückführen. Dieser Beitrag gibt einen Überblick über die derzeit bekannten Gendefekte und skizziert, welche Konsequenzen die Genveränderungen für die Physiologie der Lymphozytenentwicklung und die Funktionen der T- und B-Zellen haben. Darüber hinaus gewinnt die Kenntnis der genetischen Grundlagen dieser Erkrankungen in zunehmendem Maße therapeutische Bedeutung.

Schlüsselwörter

T-Zell-Defekt B-Zell-Defekt SCID Stammzelltransplantation Immunglobuline 

Congenital T and B lymphocyte deficiencies

Abstract

In contrast to previous clinical classifications a high percentage of primary T and B cell immunodeficiencies are defined by specific gene defects. This report provides an overview over the presently known genetic defects and outlines the consequences of the genetic changes for the physiology of lymphocyte development and for the function of T and B cells. In addition knowledge about the genetic basis of these diseases gains increasing impact on therapeutic decisions.

Keywords

T cell deficiency B cell deficiency SCID HSC Transplantation Immunoglobulins 

Literatur

  1. 1.
    Aiuti A, Cattaneo F, Galimberti S et al (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360:447–458CrossRefPubMedGoogle Scholar
  2. 2.
    Antoine C, Muller S, Cant A et al (2003) Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99. Lancet 361:553–560CrossRefPubMedGoogle Scholar
  3. 3.
    Cavazzana-Calvo M, Fischer A (2007) Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest 117:1456–1465CrossRefPubMedGoogle Scholar
  4. 4.
    Conley ME, Dobbs AK, Farmer DM S et al (2009) Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol 27:199–227CrossRefPubMedGoogle Scholar
  5. 5.
    Dobbs AK, Yang T, Farmer D et al (2007) Cutting edge: a hypomorphic mutation in Igbeta (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development. J Immunol 179:2055–2059PubMedGoogle Scholar
  6. 6.
    Elder ME, Lin D, Clever J et al (1994) Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264:1596–1599CrossRefPubMedGoogle Scholar
  7. 7.
    Feske S (2007) Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7:690–702CrossRefPubMedGoogle Scholar
  8. 8.
    Fischer A, de Saint Basile G, Le Deist F (2005) CD3 deficiencies. Curr Opin Allergy Clin Immunol 5:491–495CrossRefPubMedGoogle Scholar
  9. 9.
    Geha RS, Notarangelo LD, Casanova JL et al (2007) Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 120:776–794CrossRefPubMedGoogle Scholar
  10. 10.
    Giliani S, Mori L, de Saint Basile G et al (2005) Interleukin-7 receptor alpha (IL-7Ralpha) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients. Immunol Rev 203:110–126CrossRefPubMedGoogle Scholar
  11. 11.
    Hacein-Bey-Abina S, Garrigue A, Wang GP et al (2008) Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 118:3132–3142CrossRefPubMedGoogle Scholar
  12. 12.
    Hirschhorn R (2003) In vivo reversion to normal of inherited mutations in humans. J Med Genet 40:721–728CrossRefPubMedGoogle Scholar
  13. 13.
    Hirschhorn R, Candotti F (2007) Immunodeficiency due to defects of purine metabolism. In: Ochs HD, Smith CI, Puck JM (eds) Primary Immunodeficiency Diseases Oxford University Press, New York, pp 169–196Google Scholar
  14. 14.
    Honig M, Schwarz K (2006) Omenn syndrome: a lack of tolerance on the background of deficient lymphocyte development and maturation. Curr Opin Rheumatol 18:383–388CrossRefPubMedGoogle Scholar
  15. 15.
    Kung C, Pingel JT, Heikinheimo M et al (2000) Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat Med 6:343–345CrossRefPubMedGoogle Scholar
  16. 16.
    Lagresle-Peyrou C, Six EM, Picard C et al (2009) Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nat Genet 41:106–111CrossRefPubMedGoogle Scholar
  17. 17.
    Lieber MR, Lu H, Gu J, Schwarz K (2008) Flexibility in the order of action and in the enzymology of the nuclease, polymerases, and ligase of vertebrate non-homologous DNA end joining: relevance to cancer, aging, and the immune system. Cell Res 18:125–133CrossRefPubMedGoogle Scholar
  18. 18.
    Notarangelo LD, Mella P, Jones A et al (2001) Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum Mutat 18:255–263CrossRefPubMedGoogle Scholar
  19. 19.
    Pannicke U, Honig M, Hess I et al (2009) Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat Genet 41:101–105CrossRefPubMedGoogle Scholar
  20. 20.
    Peron S, Metin A, Gardes P et al (2008) Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med 205:2465–2472CrossRefPubMedGoogle Scholar
  21. 21.
    Picard C, McCarl CA, Papolos A et al (2009) STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med 360:1971–1980CrossRefPubMedGoogle Scholar
  22. 22.
    Puck JM, Deschenes SM, Porter JC et al (1993) The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet 2:1099–1104CrossRefPubMedGoogle Scholar
  23. 23.
    Rieux-Laucat F, Hivroz C, Lim A et al (2006) Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency. N Engl J Med 354:1913–1921CrossRefPubMedGoogle Scholar
  24. 24.
    Roscioli T, Cliffe ST, Bloch DB et al (2006) Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease. Nat Genet 38:620–622CrossRefPubMedGoogle Scholar
  25. 25.
    Salzer U, Bacchelli C, Buckridge S et al (2009) Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113:1967–1976CrossRefPubMedGoogle Scholar
  26. 26.
    Salzer U, Chapel HM, Webster AD et al (2005) Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 37:820–828CrossRefPubMedGoogle Scholar
  27. 27.
    Sawada A, Takihara Y, Kim JY et al (2003) A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest 112:1707–1713PubMedGoogle Scholar
  28. 28.
    Schwarz K, Gauss GH, Ludwig L et al (1996) RAG mutations in human B cell-negative SCID. Science 274:97–99CrossRefPubMedGoogle Scholar
  29. 29.
    Sediva A, Smith CI, Asplund AC et al (2007) Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. J Clin Immunol 27:640–646CrossRefPubMedGoogle Scholar
  30. 30.
    Sekine H, Ferreira RC, Pan-Hammarstrom Q et al (2007) Role for Msh5 in the regulation of Ig class switch recombination. Proc Natl Acad Sci USA 104:7193–7198CrossRefPubMedGoogle Scholar
  31. 31.
    Shiow LR, Roadcap DW, Paris K et al (2008) The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nat Immunol 9:1307–1315CrossRefPubMedGoogle Scholar
  32. 32.
    Takahashi N, Matsumoto K, Saito H et al (2009) Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients. J Immunol 182:5515–5527CrossRefPubMedGoogle Scholar
  33. 33.
    van Zelm MC, Reisli I, van der Burg M et al (2006) An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 354:1901–1912CrossRefGoogle Scholar
  34. 34.
    Warnatz K, Bossaller L, Salzer U et al (2006) Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107:3045–3052CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag 2009

Authors and Affiliations

  • M. Hönig
    • 1
  • J. Thiel
    • 2
    • 4
  • K. Warnatz
    • 2
    • 4
  • K. Schwarz
    • 3
    • 4
  1. 1.Klinik für Kinder- und JugendmedizinUniversitätsklinikum UlmUlmDeutschland
  2. 2.Abtlg. Rheumatologie und Klin. ImmunologieMed. Universitätsklinik FreiburgFreiburgDeutschland
  3. 3.Institut für Transfusionsmedizin, Universität UlmInstitut für Klinische Transfusionsmedizin und Immungenetik UlmUlmDeutschland
  4. 4.Centrum für Chronische ImmundefizienzUniversitätsklinikum FreiburgFreiburgDeutschland

Personalised recommendations