Skip to main content
Erschienen in: Monatsschrift Kinderheilkunde 9/2009

01.09.2009 | Leitthema

Angeborene Defekte der T- und B-Lymphozyten

verfasst von: M. Hönig, J. Thiel, K. Warnatz, Dr. K. Schwarz

Erschienen in: Monatsschrift Kinderheilkunde | Ausgabe 9/2009

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat Aiuti A, Cattaneo F, Galimberti S et al (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360:447–458CrossRefPubMed Aiuti A, Cattaneo F, Galimberti S et al (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360:447–458CrossRefPubMed
2.
Zurück zum Zitat 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 361:553–560CrossRefPubMed 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 361:553–560CrossRefPubMed
3.
Zurück zum Zitat Cavazzana-Calvo M, Fischer A (2007) Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest 117:1456–1465CrossRefPubMed Cavazzana-Calvo M, Fischer A (2007) Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest 117:1456–1465CrossRefPubMed
4.
Zurück zum Zitat Conley ME, Dobbs AK, Farmer DM S et al (2009) Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol 27:199–227CrossRefPubMed Conley ME, Dobbs AK, Farmer DM S et al (2009) Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol 27:199–227CrossRefPubMed
5.
Zurück zum Zitat 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 179:2055–2059PubMed 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 179:2055–2059PubMed
6.
Zurück zum Zitat 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 264:1596–1599CrossRefPubMed 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 264:1596–1599CrossRefPubMed
7.
Zurück zum Zitat Feske S (2007) Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7:690–702CrossRefPubMed Feske S (2007) Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7:690–702CrossRefPubMed
8.
Zurück zum Zitat Fischer A, de Saint Basile G, Le Deist F (2005) CD3 deficiencies. Curr Opin Allergy Clin Immunol 5:491–495CrossRefPubMed Fischer A, de Saint Basile G, Le Deist F (2005) CD3 deficiencies. Curr Opin Allergy Clin Immunol 5:491–495CrossRefPubMed
9.
Zurück zum Zitat 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 120:776–794CrossRefPubMed 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 120:776–794CrossRefPubMed
10.
Zurück zum Zitat 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 203:110–126CrossRefPubMed 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 203:110–126CrossRefPubMed
11.
Zurück zum Zitat 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 118:3132–3142CrossRefPubMed 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 118:3132–3142CrossRefPubMed
12.
Zurück zum Zitat Hirschhorn R (2003) In vivo reversion to normal of inherited mutations in humans. J Med Genet 40:721–728CrossRefPubMed Hirschhorn R (2003) In vivo reversion to normal of inherited mutations in humans. J Med Genet 40:721–728CrossRefPubMed
13.
Zurück zum Zitat 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 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
14.
Zurück zum Zitat Honig M, Schwarz K (2006) Omenn syndrome: a lack of tolerance on the background of deficient lymphocyte development and maturation. Curr Opin Rheumatol 18:383–388CrossRefPubMed Honig M, Schwarz K (2006) Omenn syndrome: a lack of tolerance on the background of deficient lymphocyte development and maturation. Curr Opin Rheumatol 18:383–388CrossRefPubMed
15.
Zurück zum Zitat 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 6:343–345CrossRefPubMed 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 6:343–345CrossRefPubMed
16.
Zurück zum Zitat 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 41:106–111CrossRefPubMed 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 41:106–111CrossRefPubMed
17.
Zurück zum Zitat 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 18:125–133CrossRefPubMed 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 18:125–133CrossRefPubMed
18.
Zurück zum Zitat Notarangelo LD, Mella P, Jones A et al (2001) Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum Mutat 18:255–263CrossRefPubMed Notarangelo LD, Mella P, Jones A et al (2001) Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum Mutat 18:255–263CrossRefPubMed
19.
Zurück zum Zitat 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 41:101–105CrossRefPubMed 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 41:101–105CrossRefPubMed
20.
Zurück zum Zitat Peron S, Metin A, Gardes P et al (2008) Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med 205:2465–2472CrossRefPubMed Peron S, Metin A, Gardes P et al (2008) Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med 205:2465–2472CrossRefPubMed
21.
Zurück zum Zitat Picard C, McCarl CA, Papolos A et al (2009) STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med 360:1971–1980CrossRefPubMed Picard C, McCarl CA, Papolos A et al (2009) STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med 360:1971–1980CrossRefPubMed
22.
Zurück zum Zitat 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 2:1099–1104CrossRefPubMed 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 2:1099–1104CrossRefPubMed
23.
Zurück zum Zitat 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 354:1913–1921CrossRefPubMed 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 354:1913–1921CrossRefPubMed
24.
Zurück zum Zitat 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 38:620–622CrossRefPubMed 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 38:620–622CrossRefPubMed
25.
Zurück zum Zitat 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 113:1967–1976CrossRefPubMed 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 113:1967–1976CrossRefPubMed
26.
Zurück zum Zitat Salzer U, Chapel HM, Webster AD et al (2005) Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 37:820–828CrossRefPubMed Salzer U, Chapel HM, Webster AD et al (2005) Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 37:820–828CrossRefPubMed
27.
Zurück zum Zitat Sawada A, Takihara Y, Kim JY et al (2003) A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest 112:1707–1713PubMed Sawada A, Takihara Y, Kim JY et al (2003) A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest 112:1707–1713PubMed
28.
Zurück zum Zitat Schwarz K, Gauss GH, Ludwig L et al (1996) RAG mutations in human B cell-negative SCID. Science 274:97–99CrossRefPubMed Schwarz K, Gauss GH, Ludwig L et al (1996) RAG mutations in human B cell-negative SCID. Science 274:97–99CrossRefPubMed
29.
Zurück zum Zitat 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 27:640–646CrossRefPubMed 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 27:640–646CrossRefPubMed
30.
Zurück zum Zitat 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 104:7193–7198CrossRefPubMed 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 104:7193–7198CrossRefPubMed
31.
Zurück zum Zitat 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 9:1307–1315CrossRefPubMed 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 9:1307–1315CrossRefPubMed
32.
Zurück zum Zitat 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 182:5515–5527CrossRefPubMed 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 182:5515–5527CrossRefPubMed
33.
Zurück zum Zitat 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 354:1901–1912CrossRef 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 354:1901–1912CrossRef
34.
Zurück zum Zitat 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 107:3045–3052CrossRefPubMed 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 107:3045–3052CrossRefPubMed
Metadaten
Titel
Angeborene Defekte der T- und B-Lymphozyten
verfasst von
M. Hönig
J. Thiel
K. Warnatz
Dr. K. Schwarz
Publikationsdatum
01.09.2009
Verlag
Springer-Verlag
Erschienen in
Monatsschrift Kinderheilkunde / Ausgabe 9/2009
Print ISSN: 0026-9298
Elektronische ISSN: 1433-0474
DOI
https://doi.org/10.1007/s00112-009-1985-y

Weitere Artikel der Ausgabe 9/2009

Monatsschrift Kinderheilkunde 9/2009 Zur Ausgabe

Update Pädiatrie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.