Journal of Clinical Immunology

, Volume 16, Issue 3, pp 151–158

Abnormalin vitro thymocyte differentiation in a patient with severe combined immunodeficiency-Nezelof's syndrome

  • Alan P. Knutsen
  • Donna Wall
  • Kathleen R. Mueller
  • John D. Bouhasin
Original Articles


Anin vitro coculture model system of CD34+ stem cells and allogenic cultured thymic epithelia fragments was used to evaluate thymocyte differentiation in a 9-month-old child of Amish descent with Nezelof syndrome. Though the patient's stem cells differentiate to acquire normal expression of CD2 and CD7, later steps of maturation were abnormal. There was detectable but reduced expression of CD3 and CD4 phenotypes. CD44+ expression, however, was markedly reduced. CD44 is an adhesion molecule, interacting with the matrix ligands hyaluronan and fibronectin, and is expressed early in thymocyte differentiation and subsequently in mature T cells. It is hypothesized that abnormal expression of CD44 in a variant of severe combined immunodeficiency, Nezelof's syndrome, interferes with normal thymocyte and thymic epithelial interaction, which leads to abnormal thymocyte differentiation.

Key words

Severe combined immunodeficiency (SCID) CD34+ stem cells cultured thymic epithelia thymocyte differentiation 


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  1. 1.
    WHO: Primary immunodeficiency diseases—Report of a WHO sponsored meeting. Immunodefic Rev 1:173–205, 1989Google Scholar
  2. 2.
    Fischer A: Severe combined immunodeficiencies. Immunodefic Rev 3:83–100, 1992PubMedGoogle Scholar
  3. 3.
    Puck JM: Molecular and genetic basis of X-linked immunodeficiency disorders. J Clin Immunol 14:81–89, 1994PubMedGoogle Scholar
  4. 4.
    Markert ML: Molecular basis of adenosine deaminase deficiency. Immunodeficiency 5:141–157, 1994PubMedGoogle Scholar
  5. 5.
    Markert ML: Purine nucleoside phosphorylase deficiency. Immunodefic Rev 3:45–81, 1991PubMedGoogle Scholar
  6. 6.
    Noguchi M, Huafang Y, Rosenblatt HM, Filipovitch AH, Adelstein S, Modi WS, McBride OW, Leonard WJ: Interleukin-2 receptorγ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:147–157, 1993PubMedGoogle Scholar
  7. 7.
    Schwarz K, Hansen-Hagge TE, Bartram CR; Recombinase deficiency in mouse and man. Immunodeficiency 4:249–252, 1993PubMedGoogle Scholar
  8. 8.
    Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG: Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264:1596–1599, 1994PubMedGoogle Scholar
  9. 9.
    Chan AC, Kadlecek TA, Elder ME, Filipovitch AH, Kuo WL, Iwashima M, Parslow TG, Weiss A: ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264:1599–1601, 1994PubMedGoogle Scholar
  10. 10.
    Griscelli C, Lisowska-Grospierre B, Mach B: Combined immunodeficiency with defective expression in MHC class II genes. Immunodefic Rev 1:135–153, 1989PubMedGoogle Scholar
  11. 11.
    Klein C, Lisowska-Grospierre B, LeDeist F, Fischer A, Griscelli C: Major histocompatibility complex II deficiency: Clinical manifestations, immunologic features, and outcome. J Pediatr 123:921–928, 1993PubMedGoogle Scholar
  12. 12.
    Haynes BF, Warren RW, Buckley RH, McClure JE, Goldstein AL, Henderson FW, Hensley LL, Eisenbarth GS: Demonstration of abnormalities in expression of thymic epithelial surface antigens in severe cellular immunodeficiency diseases. J Immunol 130:1182–1188, 1983PubMedGoogle Scholar
  13. 13.
    Adkins B, Mueller C, Okada CY, Reichert RA, Weissman IL, Spangrude GJ: Early events in T-cell maturation. Annu Rev Immunol 5:325–365, 1987PubMedGoogle Scholar
  14. 14.
    Haynes BF, Denning SM, Le PT, Singer KH: Human intrathymic T cell differentiation. Semin Immunol 2:66–77, 1990Google Scholar
  15. 15.
    Haynes BF, Heinly CS: Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment. J Exp Med 181:1445–1458, 1995PubMedGoogle Scholar
  16. 16.
    Godfrey DI, Zlotnik: Controls points in early T-cell development. Immunol Today 14:547–553, 1993PubMedGoogle Scholar
  17. 17.
    Barcena A, Muench MO, Galy AHM, Cupp J, Roncarolo MG, Phillips JH, Spits H: Phenotypic and functional analysis of T-cell precursors in the human fetal liver and thymus: CD7 expression in the early stages of T-cell and myeloid-cell development. Blood 82:3401–3414, 1993PubMedGoogle Scholar
  18. 18.
    Denning SM, Dustin ML, Springer TA, Singer KH, Haynes BF: Purified lymphocyte function-associated antigen-3 (LFA-3) activates human thymocytes via the CD2 pathway. J Immunol 141: 2980–2985, 1988PubMedGoogle Scholar
  19. 19.
    Hollander GA, Wang B, Nichogiannopoulou A, Platenburg PP, van Ewijk W, Burakoff SJ, Gutierrez-Ramos J-C, Terhorst: Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373:350–356, 1995PubMedGoogle Scholar
  20. 20.
    Patel DD, Hale LP, Whichard LP, Radcliff G, MacKay CR, Haynes BF: Expression of CD44 molecules and CD44 ligands during human fetal development: Expression of CD44 isoforms is developmentally regulated. Inter Immunol 7:277–286, 1995Google Scholar
  21. 21.
    Nossal GJV: Negative selection of lymphocytes. Cell 76:229–239, 1994PubMedGoogle Scholar
  22. 22.
    von Boehmer H: Positive selection of lymphocytes. Cell 76:219–228, 1994PubMedGoogle Scholar
  23. 23.
    Janeway CA Jr: Thymic selection: Two pathways to life and two to death. Immunity 1:3–6, 1994PubMedGoogle Scholar
  24. 24.
    Buckley RH, Schiff SE, Sampson HA, Schiff RI, Markert ML, Knutsen AP, Lawton AF, Hershfield MS, Huang AT, Mickey GH, Ward FE: Development of immunity in human severe primary T cell deficiency following haploidentical bone marrow stem cell transplantation. J Immunol 136:2398–2407, 1986PubMedGoogle Scholar
  25. 25.
    Lebkowski JS, Schain LR, Okrongly D, Levinsky R, Harvey MJ, Okarma TB: Rapid isolation of human CD34 hematopoietic stem cells—purging of human tumor cells. Transplantation 53:1011–1019, 1992PubMedGoogle Scholar
  26. 26.
    Knutsen AP, Slavin RG: In vitro T-cell responses in patients with cystic fibrosis and allergic bronchopulmonary aspergillosis. J Lab Clin Med 113:428–435, 1989PubMedGoogle Scholar
  27. 27.
    Collins NH, Lebkowski J, O'Reilly RJ, Okarma T: T-cell depletion of SBA-cells by adherence in the AIS collector—T cell.In E Areman, HJ Deeg, RA Sacher (eds), Bone Marrow and Stem Cell Processing: A Manual of Current Techniques. Philadelphia, F. A. Davis, 1992, pp 205–207Google Scholar
  28. 28.
    Funderud S, Nustad K, Lea T, Vanrtal F, Guadomcak G, Stansted P, Ugelstad J: Fractionation of lymphocytes by immunomagnetic beads.In Lymphocytes: A Practical Approach, GGB Klaus (ed). New York, Oxford University Press, 1987, pp 55–61Google Scholar
  29. 29.
    Ruiz ME, Roodman ST, Bouhasin JD, Knutsen AP: T cell differentiation/maturation of CD34+ stem cells from HIV+ hemophiliacs in cultured thymic epithelial fragments. Stem Cells 14:132–145, 1996PubMedGoogle Scholar
  30. 30.
    Barcena A, Galy AHM, Punnonen J, Muench MO, Schols D, Roncarolo MG, de Vries JE, Phillips JH, Spits H: Lymphoid and myeloid differentiation of fetal CD34+ lineage-cells in human thymic organ culture. J Exp Med 180:123–132, 1994PubMedGoogle Scholar
  31. 31.
    Knutsen AP, Slavin RG: In vitro T-cell responses in patients with cystic fibrosis and allergic bronchopulmonary aspergillosis. J Lab Clin Med 113:428–435, 1989PubMedGoogle Scholar
  32. 32.
    Knutsen AP, Mueller KR, Hutcheson PS, Slavin RG: T- and B-cell dysregulation of IgE synthesis in cystic fibrosis patients with allergic bronchopulmonary aspergillosis. Clin Immunol Immunopathol 55:129–138, 1990PubMedGoogle Scholar
  33. 33.
    Kraft DL, Weissman IL, Waller EK: Differentiation of CD3-4-8-human fetal thymocytes in vivo: characterization of a CD3-4+8−intermediate. J Exp Med 178:265–277, 1993PubMedGoogle Scholar
  34. 34.
    Ochs HD, Davis SD, Mickelson E, Lerner KG, Wedgwood RJ: Combined immunodeficiency and reticuloendotheliosis with eosinophilia. J Pediatr 85:463–465, 1974PubMedGoogle Scholar
  35. 35.
    Blaese RM, Culver KW: Gene therapy for primary immunodeficiency disease. Immunodefic Rev 3:329–349, 1992PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Alan P. Knutsen
    • 1
  • Donna Wall
    • 1
  • Kathleen R. Mueller
    • 1
  • John D. Bouhasin
    • 1
  1. 1.Department of Pediatrics, Pediatric Research InstituteSt. Louis University Health Sciences CenterSt. Louis

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