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.
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.
Literatur
Aiuti A, Cattaneo F, Galimberti S et al (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360:447–458
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 361:553–560
Cavazzana-Calvo M, Fischer A (2007) Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest 117:1456–1465
Conley ME, Dobbs AK, Farmer DM S et al (2009) Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol 27:199–227
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 179:2055–2059
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 264:1596–1599
Feske S (2007) Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7:690–702
Fischer A, de Saint Basile G, Le Deist F (2005) CD3 deficiencies. Curr Opin Allergy Clin Immunol 5:491–495
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 120:776–794
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 203:110–126
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 118:3132–3142
Hirschhorn R (2003) In vivo reversion to normal of inherited mutations in humans. J Med Genet 40:721–728
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 169–196
Honig M, Schwarz K (2006) Omenn syndrome: a lack of tolerance on the background of deficient lymphocyte development and maturation. Curr Opin Rheumatol 18:383–388
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 6:343–345
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 41:106–111
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 18:125–133
Notarangelo LD, Mella P, Jones A et al (2001) Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum Mutat 18:255–263
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 41:101–105
Peron S, Metin A, Gardes P et al (2008) Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med 205:2465–2472
Picard C, McCarl CA, Papolos A et al (2009) STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med 360:1971–1980
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 2:1099–1104
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 354:1913–1921
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 38:620–622
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 113:1967–1976
Salzer U, Chapel HM, Webster AD et al (2005) Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 37:820–828
Sawada A, Takihara Y, Kim JY et al (2003) A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest 112:1707–1713
Schwarz K, Gauss GH, Ludwig L et al (1996) RAG mutations in human B cell-negative SCID. Science 274:97–99
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 27:640–646
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 104:7193–7198
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 9:1307–1315
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 182:5515–5527
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 354:1901–1912
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 107:3045–3052
Interessenkonflikt
Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.
Author information
Authors and Affiliations
Corresponding author
Additional information
___ ___
M. Hönig und J. Thiel: Koerstautorenschaft
K.W. und K.S. unterstützt durch: BMBF grant CCI-01E O0803
Rights and permissions
About this article
Cite this article
Hönig, M., Thiel, J., Warnatz, K. et al. Angeborene Defekte der T- und B-Lymphozyten. Monatsschr Kinderheilkd 157, 853–860 (2009). https://doi.org/10.1007/s00112-009-1985-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00112-009-1985-y