Hereditäre Immundefizienzen und hämatologische Neoplasien

  • Alfons Meindl
Part of the Molekulare Medizin book series (MOLMED)


Zu primären Immundefizienzen (ID) kommt es, wenn eine oder mehrere Komponenten des Immunsystems defekt sind. In den hoch industrialisierten Ländern sind die meisten ID erblich bedingt. Patienten oder Patientinnen mit einer erblichen ID fallen klinisch durch rezidivierende Infekte im Kindesalter auf. Während rezidivierende Infektionen durch pyogene Bakterien auf einen Defekt der Antikörper-, der Komplement- oder der Phagozytenfunktion hinweisen, werden virale Infektionen hauptsächlich durch die Dysregulation T-Zell-vemittelter Immunantworten verursacht.


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  1. Aldrich MB, Blackburn MR, Kellems RE (2000) The importance of adenosine deaminase for lymphocyte development and function. Biochem Biophys Res Comm 272:311–315PubMedGoogle Scholar
  2. Amiet A (1963) Aldrich Syndrom: Beobachtung zweier Fälle. Ann Paediatr 201:315–335PubMedGoogle Scholar
  3. Andrade MA, Bork P (1995) HEAT repeats in the Huntington’s disease protein. Nat Genet 11:115–116PubMedGoogle Scholar
  4. Apasov SG, Blackburn MR, Kellems RE, Smith PT, Sitkvsky MV (2001) Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest 108:131–141PubMedGoogle Scholar
  5. Argyle JC, Kjeldsberg CR, Marty J, Shigeoka AO, Hill HR (1982) T-Cell lymphoma and the Chediak-Higashi syndrome. Blood 60:672–676PubMedGoogle Scholar
  6. Arpaia E, Shahar M, Dadi H, Cohen A, Roifman CM (1994) Defective T-cell receptor signalling and CD8+ thymic selection in humans lacking zap-70 kinase. Cell 76:947–958PubMedGoogle Scholar
  7. Arredondo-Vega FX, Santisteban I, Daniels S, Toutain S, Hershfield MS (1998) Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am J Hum Genet 63:1049–1059PubMedGoogle Scholar
  8. Aust MR, Andrews LG, Barrett MJ, Norby-Slycord CJ, Markert ML (1992) Molecular analysis of mutations in a patient with purine nucleoside Phosphorylase deficiency. Am J Hum Genet 51:763–772PubMedGoogle Scholar
  9. Baba Y, Nonoyama S, Matsushita M et al. (1999) Involvement of Wiskott-Aldrich syndrome protein in in B-cell cytoplasmic tyrosine kinase pathway. Blood 93:2003–2012PubMedGoogle Scholar
  10. Bennett CL, Christie J, Ramsdell F et al. (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–22PubMedGoogle Scholar
  11. Bianchi A, Mariani S, Beggiato E et al. (1997) Distribution of T-cell signalling molecules in human myeloma. Br J Hematol 97:815–820Google Scholar
  12. Brandau O, Schuster V, Weiss M et al. (1999) Epstein-Barr virus negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease. Hum Mol Genet 8:2407–2413PubMedGoogle Scholar
  13. Brown MP, Topham DJ, Sangster MY et al. (1998) Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice. Nat Med 4:1253–1260PubMedGoogle Scholar
  14. Buckley RH (2000) Primary immunodeficiency diseases due to defects in lymphocytes. N Engl J Med 343:1313–1324PubMedGoogle Scholar
  15. Candotti F, Villa A, Notarangelo LD (1999) Severe combined immunodeficiency due to defects of JAK3 tyrosine kinase. In: Ochs HD, Smith CIE, Puck JM (eds) Primary immunodeficiency diseases Oxford University Press, New York, pp 111–120Google Scholar
  16. Chan AC, Desai DM, Weiss A (1994) The role of protein tyrosine kinases and protein tyrosine phosphatases in T-cell antigen receptor signal transduction. Ann Rev Immunol 12:555–592Google Scholar
  17. Clodi K, Wimmer D, Li Y et al. (2000) Expression of TRAIL receptors and sensitivity to TRAIL-induced apoptosis in primary B-cell acute lymphoblastic leukemia cells. Br J Haematol 111:580–586PubMedGoogle Scholar
  18. Coffey AJ, Brooksbank RA, Brandau O et al. (1998) Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 20:129–135PubMedGoogle Scholar
  19. Cunningham-Rundles C, Siegal FP, Cunnigham-Rundles S, Lieberman P (1987) Incidence of cancer in 98 patients with common varied immunodeficiency. J Clin Immunol 7:294–299PubMedGoogle Scholar
  20. Derry JMJ, Ochs HD, Francke U (1994) Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 78:635–644PubMedGoogle Scholar
  21. De Saint-Basile G, Fischer A (2001) The role of cytotoxicity in lymphocyte homeostasis. Curr Opin Immunol 13:549–554PubMedGoogle Scholar
  22. Dillo D, Brown M, Roskrow M et al. (1997) CD40 ligand induces an antileukemia response in vivo. Blood 90:1927–1933Google Scholar
  23. Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB (1996) Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med 336:1457–148Google Scholar
  24. Eck SC, Turka LA (1999) Generation of protective immunity against an immunogenic carcinoma requires CD40/CD40L and B7/CD28 interactions but not CD4(+) T cells. Cancer Immunol Immunother 48:336–341PubMedGoogle Scholar
  25. Eischen CM, Williams BL, Zhang W et al. (1997) ZAP-70 tyrosine kinase is required for the up-regulation of Fas ligand in activation-induced T cell apoptosis. J Immunol 159:1135–1139PubMedGoogle Scholar
  26. Fargnoli MC, Edelson RL, Berger CL et al. (1997) Diminished TCR signaling in cutaneous T cell lymphoma is associated with decreased activities of Zap70, Syk and membrane-associated Csk. Leukemia 11:1338–1346PubMedGoogle Scholar
  27. Filipovich AH, Shapiro RS, Robinson L, Mertens A, Frizzera G (1990) Lymphoproliferative disorders associated with immunodeficiency. In: Magrath IT (ed) The Non-Hodgkin’s lymphomas. Edward Arnold, London, pp 135–154Google Scholar
  28. Fischer A, Hacein-Bey S, Le Deist F et al. (2000) Gene therapy of severe combined immunodeficiencies. Immunol Rev 178:13–20PubMedGoogle Scholar
  29. Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ (1972) Adenosine deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 2:1067–1069PubMedGoogle Scholar
  30. Grierson H, Purtiilo DT (1987) Epstein-Barr virus infections in males with the X-linked lymphoproliferative syndrome. Ann Intern Med 106:538–545PubMedGoogle Scholar
  31. Guinamard R, Aspenström P, Fougereau M, Chavrier P, Guillemot JC (1998) Tyrosine phosphorylation of the Wiskott-Aldrich syndrome protein by Lyn and Btk is regulated by CDC42. FEBS Lett 434:431–436PubMedGoogle Scholar
  32. Hansson H, Mattsson PT, Allard P et al. (1998) Solution structure of the SH3 domain from Bruton’s tyrosine kinase. Biochemistry 37:2912–2924PubMedGoogle Scholar
  33. Harrington DS, Weisenburger DD, Purtilo DT (1987) Malignant lymphoma in the X-linked lymphoproliferative syndrome. Cancer 59:1419–1429PubMedGoogle Scholar
  34. Hatada MH, Lu X, Laird ER et al. (1995) Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor. Nature 377:32–38PubMedGoogle Scholar
  35. Hershfield MS, Kerdich NM, Ownby DR, Buckley R (1979) In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2′-desoxyadenosine in adenosine deaminase-deficient patients. J Clin Invest 63:807–811PubMedGoogle Scholar
  36. Holinski-Feder E, Weiss M, Brandau O et al. (1998) Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics 101:276–284PubMedGoogle Scholar
  37. Ichihara Y, Hirai M, Kurosawa Y (1992) Sequence and chromosome assignment to 11p13-p12 of human RAG genes. Immunol Lett 33:277–284PubMedGoogle Scholar
  38. Ishii E, Yoshida N, Kimura N et al. (1999) Clonal dissemination of T-lymphocytes in seid mice from familial hemophagocytic lymphohistiocytosis. Med Pediatr Oncol 32:201–208PubMedGoogle Scholar
  39. Itoh N, Yonehara S, Ishii A et al. (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233–243PubMedGoogle Scholar
  40. Jackson CE, Puck JM (1999) Autoimmune lymphoproliferative syndrome, a disorder of apoptosis. Curr Opin Pediatr 11:521–527PubMedGoogle Scholar
  41. Janeway CA, Travers P, Walport M, Shlomchick M (2001) Immunobiology, Garland Publishing, NY, USAGoogle Scholar
  42. Karim MA, Nagle DL, Kandil HH, Bürger J, Moore KJ, Spritz KA (1997) Mutations in the Chediak-Higashi syndrome gene (CHS1) indicate requirement for the complete 3801 amino acid CHS protein. Hum Mol Genet 6:1087–1089PubMedGoogle Scholar
  43. Karpusas M, Hsu YM, Wang JH et al. (1995) 2A crystal structure of an extracellular fragment of human CD40 ligand. Structure 3:1031–1039PubMedGoogle Scholar
  44. Kinlen LJ, Webster ADB, Bird AG et al. (1985) Prospective study of cancer in patients with hypogammaglobulinemia. Lancet 1:263–266PubMedGoogle Scholar
  45. Kitada S, Zapata JM, Andreeff M, Reed JC (1999) Bryostatin and CD40 ligand enhance apoptosis resistance and induce expression of survival genes in B-cell chronic lymphocytic leukemia. Br J Haematol 106:995–1004PubMedGoogle Scholar
  46. Knecht H, Berger C, Rothenberger S, Odermatt BF, Brousset P (2001) The role of Epstein-Barr virus in neoplastic transformation. Oncology 60:289–302PubMedGoogle Scholar
  47. Lavilla P, Gil A, Rodriguez MCG, Dupla ML, Pintado V, Fontan G (1993) X-linked agammaglobulinemia and gastric adenocarcinoma. Cancer 72:1528–1531PubMedGoogle Scholar
  48. Lederman HM, Winkelstein JA (1985) X-linked agammaglobulinemia: an analysis of 96 patients. Medicine (Baltimore) 64:145–156Google Scholar
  49. Li T, Tsukada S, Satterthwaite A et al. (1995) Activation of Bruton’s tyrosine kinase (Btk) by a point mutation in its pleckstrin homology (PH) domain. Immunity 2:451–460PubMedGoogle Scholar
  50. Löffler G (2003) Biochemie und Pathobiochemie. Springer, Heidelberg Berlin, p 642Google Scholar
  51. Macchi P, Villa A, Giliani S et al. (1995) Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377:65–68PubMedGoogle Scholar
  52. Mache CJ, Slave I, Schmid C et al. (1994) Familial hemophagocytic lymphohistiocytosis associated with disseminated T-cell lymphoma: a report of two siblings. Ann Hematol 69:85–91PubMedGoogle Scholar
  53. Markert ML (1991) Purine nucleoside Phosphorylase deficiency. Immunodef Rev 3:45–81PubMedGoogle Scholar
  54. Martin DA, Zheng L, Siegel RM et al. (1999) Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type la. Proc Natl Acad Sci USA 96:4552–4557PubMedGoogle Scholar
  55. Mayer L, Kwan SP, Thompson C et al. (1986) Evidence for a defect in „switch“T cells in patients with immunodeficiency and hypergammaglobulinemia. N Engl J Med 314:409–413PubMedGoogle Scholar
  56. Menasche G, Pastural E, Feldman J et al. (2000) Mutations in RAB27A cause Griscelli syndrome associated with hemosphagocytic syndrome. Nat Genet 25:173–176PubMedGoogle Scholar
  57. Meydan N, Grunberger T, Dadi H et al. (1996) Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379:645–648PubMedGoogle Scholar
  58. Mikhalap SV, Shlapatska LM, Berdova AG, Law CL, Clark EA, Sidorenko SP (1999) Cdw150 associates with src-homology 2-containing inositol phosphatase and modulates CD95-mediated apoptosis. J Immunol 162:5719–5727PubMedGoogle Scholar
  59. Morra M, Howie D, Grande MS et al. (2001) X-linked lymphoproliferative disease: a progressive immunodeficiency. Ann Rev Immunol 19:657–682Google Scholar
  60. Mroczek E, Weisenburger DD, Grierson HL, Markin R, Purtilo DT (1987) Fatal infectious mononucleosis and virusassociated hemophagocytic syndrome. Arch Pathol Lab Med 111:530PubMedGoogle Scholar
  61. Nagle DL, Karim MA, Woolf EA et al. (1996) Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet 14:307–311PubMedGoogle Scholar
  62. Nakanishi M, Kikuta H, Tomizawa K et al. (1993) Distinct clonotypic Epstein-Barr virus-induced fatal lymphoproliferative disorder in a patient with Wiskott-Aldrich syndrome. Cancer 72:1376–1381PubMedGoogle Scholar
  63. Okano M, Gross TG (2000) A review of Epstein-Barr virus infection in patients with immunodeficiency disorders. Am J Med Sci 319:392–396PubMedGoogle Scholar
  64. Parolini S, Bottino C, Falco M et al. (2000) X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function killer cells to kill Epstein-Barr virus infected cells. J Exp Med 192:337–346PubMedGoogle Scholar
  65. Peifer M, Berg S, Reynolds AB (1994) A repeating amino acid motif shared by proteins with diverse cellular roles. Cell 76:789–791PubMedGoogle Scholar
  66. Puck JM (1999) X-linked severe combined immunodeficiency. In: Ochs HD, Smith CIE, Puck JM (eds) Primary immunodeficiency diseases. Oxford University Press, New York, pp 99–110Google Scholar
  67. 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 2:1099–1104PubMedGoogle Scholar
  68. Puel A, Leonard WJ (2000) Mutations in the gene for the IL-7 receptor result in T-B+NK+ severe combined immunodeficiency disease. Curr Opin Immunol 12:468–473PubMedGoogle Scholar
  69. Puel A, Ziegler SF, Buckley RH, Leonard WJ (1998) Defective ILR7 expression in T-B+NK+ severe combined immunodeficiency. Nat Genet 20:394–397PubMedGoogle Scholar
  70. Ramesh N, Geha RS, Notarangelo LD (1999) CD40-ligand and the Hyper-IgM syndrome. In: Ochs HD, Smith CIE, Puck JM (eds) Primary immunodeficiency diseases. Oxford University Press, New York, pp 233–249Google Scholar
  71. Ratter F, Germer M, Fischbach T et al. (1996) S-Adenosylhomocysteine as a physiological modulator of Apo-1-mediated apoptosis. Int Immunol 8:1139–1147PubMedGoogle Scholar
  72. Remold-O’Donnell E, Cooley J, Shcherbina A et al. (1997) Variable expression of WASP in B cell lines of Wiskott-Aldrich syndrome patients. J Immunol 158:4021–4025PubMedGoogle Scholar
  73. Royer-Pokora B, Kunkel LM, Monaco AP et al. (1986) Cloning the gene for an inherited human disorder — chronic granulomatous disease — on the basis of its chromosomal location. Nature 322:32–38PubMedGoogle Scholar
  74. Rozenfeld-Granot G, Toren A, Amariglio N, Brok-Simoni F, Rechavi G (2001) Mutation analysis of the FAS and TNFR apoptotic cascade genes in hematological malignancies. Exp Hematol 29:228–233PubMedGoogle Scholar
  75. Russell SM, Tayebi N, Nakajima H et al. (1995) Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270:707–800Google Scholar
  76. Salim K, Bottomley MJ, Querfurth E et al. (1996) Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton’s tyro-sine kinase. EMBO J 15:6241–6250PubMedGoogle Scholar
  77. Sayos J, Wu C, Morra M et al. (1998) The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395:462–469PubMedGoogle Scholar
  78. Schindelhauer D, Hellebrand H, Grimm L et al. (1996) Long range map of a 3.5-Mb region in Xp11.23–22 with a sequence ready map from a 1.1 Mb gene-rich interval. Gen Res 6:1056–1069Google Scholar
  79. Schultze JL, Gribben JG, Nadler LM (1998) Tumor-specific adoptive T-cell therapy for CD40+ B-cell malignancies. Curr Opin Oncol 10:542–547PubMedGoogle Scholar
  80. Schwarz K, Hansen-Hagge TE, Knobloch C, Friedrich W, Kleihauer E, Bartram CR (1991) Severe combined immunodefiency (SCID) in man: B-cell negative (B-) SCID patients exhibit an irregular recombination pattern at the JH locus. J Exp Med 174:1039–1048PubMedGoogle Scholar
  81. Schwarz K, Gauss GH, Ludwig L et al. (1996) RAG mutations in human B cell-negative SCID. Science 274:97–99PubMedGoogle Scholar
  82. Seemayer TA, Gross TG, Egeler RM et al. (1995) X-linked lymphoproliferative disease: twenty-five years after the dicovery. Pediatr Res 38:471–477PubMedGoogle Scholar
  83. Sivori S, Parlini S, Falco M et al. (2000) 2B4 functions as a co-receptor in human NK cell activation. Eur J Immunol 30:787–793PubMedGoogle Scholar
  84. Snapper SB, Rosen FS (1999) The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Ann Rev Immunol 17:905–929Google Scholar
  85. Stepp S, Dufourcq-Lagelouse R, Le Deist F et al. (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286:1957–1959PubMedGoogle Scholar
  86. Strauss SE, Jaffe ES, Puck JM et al. (2001) The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 98:194–200Google Scholar
  87. Su I-J, Wang C-H, Cheng A-L, Chen R-L (1995) Hemophagocytic syndrome in Epstein-Barr virus-associated T-lymphoproliferative disorders. Leuk Lymphoma 19:401–406PubMedGoogle Scholar
  88. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA (1994) A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Paediatr 125:876–885Google Scholar
  89. Takemoto S, Mulloy JC, Cereseto A et al. (1997) Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins. Proc Natl Acad Sci USA 94:13897–13902PubMedGoogle Scholar
  90. Takeshita T, Asao H, Ohtani K et al. (1992) Cloning of the gamma chain of the human IL-2 receptor. Science 257:379–382PubMedGoogle Scholar
  91. Taniguchi T (1995) Cytokine signaling through nonreceptor protein tyrosine kinases. Science 268:251–255PubMedGoogle Scholar
  92. Tsukada S, Saffran DC, Rawlings DJ et al. (1993) Deficient expression of a B cell tyrosine kinase in human X-linked agammaglobulinemia. Cell 72:279–290PubMedGoogle Scholar
  93. Van der Meer JWM, Weening RS, Schellekens PTA, Van Muster IP, Nagengast FM (1993) Colorectal cancer in patients with X-linked agammaglobulinemia. Lancet 341:1439–1440PubMedGoogle Scholar
  94. Vetrie D, Vorechovsky I, Sideras P et al. (1993) The gene involved in agammaglobulinemia is a member of the Src family of protein-tyrosine kinases. Nature 361:226–233PubMedGoogle Scholar
  95. Vorechovsky I, Zetterquist H, Paganelli R et al. (1995) Family and linkage study of selective IgA deficiency and common variable immunodeficiency. Clin Immunol Immunopathol 77:214–218Google Scholar
  96. Wang J, Zheng L, Lobito A et al. (1999) Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98:47–58PubMedGoogle Scholar
  97. Wiginton DA, Kaplan DJ, States JC et al. (1986) Complete sequence and structure of the gene for human adenosine desaminase. Biochemistry 25:3211–3217Google Scholar
  98. Wildin RS, Ramsdell F, Peake J et al. (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27:18–20PubMedGoogle Scholar
  99. Williams SR, Gekeler V, Mclvor RS, Martin DW (1987) A human nucleoside Phosphorylase deficiency caused by a single base change. J Biol Chem 262:2332–2338PubMedGoogle Scholar
  100. Xagoraris I, Paterakis G, Zolota B, Zikos P, Maniatis A, Mouzaki A (2001) Expression of granzyme B and perforin in multiple myeloma. Acta Haematol 105:125–129PubMedGoogle Scholar
  101. Younes A, Carbone A (1999) CD30/CD30 ligand and CD40/CD40 ligand in malignant lymphoid disorders. Intern J Biol Markers 14:135–143Google Scholar
  102. Zhu Q, Watanabe C, Liu T et al. (1997) Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP mutations, protein expression, and phenotype. Blood 90:2680–2689PubMedGoogle Scholar

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  • Alfons Meindl

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