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Angeborene Störungen der Immunregulation

Congenital disorders of immune regulation

  • Leitthema
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Zusammenfassung

In der Gruppe von angeborenen Störungen der Immunregulation werden verschiedenartige Erkrankungen zusammengefasst, die alle im klinischen Bild vorrangig durch Autoimmunerkrankungen an verschiedenen Organen und/oder eine Lymphoproliferation auffallen. Bei der Erforschung dieser Erkrankungen wird deutlich, dass sehr unterschiedliche Pathomechanismen zur Immundysregulation bzw. Autoimmunität führen können: So führen eine defekte Apoptose der Lymphozyten bei ALPS und eine gestörte Zytotoxizität der NK-Zellen und zytotoxischen T-Zellen bei HLH-Syndromen zu einer Lymphoproliferation, Hepatosplenomegalie und zu Zytopenien. Daneben zeigen Störungen in der Toleranzentwicklung des Immunsystems Autoimmunerkrankungen mit v. a. autoimmunen Endokrinopathien. Der Defekt der zentralen Toleranzentwicklung im Thymus beim APECED-Syndrom führt neben diesen multiplen Endokrinopathien zu einer chronischen mukokutanen Candidiasis, während sich der Defekt in der peripheren Toleranzentwicklung beim IPEX-Syndrom zusätzlich durch eine schwere, chronisch-entzündliche Darmerkrankung mit früher Manifestation zeigt. Die Entdeckung der ursächlichen Gene dieser Erkrankungen und die Studien an entsprechenden Mausmodellen leisten einen wichtigen Beitrag, um die komplexen Mechanismen zur Entstehung der Immundysregulation zu verstehen und möglicherweise neue Therapiestrategien für die Patienten zu entwickeln.

Abstract

The term diseases of immune dysregulation is an umbrella term for various diseases which stand out due to autoimmunity and/or lymphoproliferation of secondary lymphoid organs. The investigation of these diseases linked to single-gene defects provides an insight into different pathomechanisms of immune dysregulation or rather autoimmune phenomena. A defect of lymphocyte apoptosis in ALPS syndromes and an impairment of cellular cytotoxicity in hemophagocytic lymphohistiocytosis syndromes lead to lymphoproliferation, hepatosplenomegaly and autoimmune cytopenia. In addition a dysfunction in the development of immune tolerance causes autoimmune disease often with the involvement of endocrine organs. The APECED syndrome is caused by a disruption of central tolerance and shows in addition to autoimmune polyendocrinopathy a chronic mucocutaneous candidiasis. The defect in the development of peripheral tolerance in IPEX syndrome leads to a severe enteropathy in early childhood. The discovery of the responsible gene defects of these diseases and studies using the corresponding mouse models make an important contribution to the understanding of immune dysregulation and can possibly help in the development of new therapeutic strategies for these patients.

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Literatur

  1. Arneson LN, Brickshawana A, Segovis CM et al (2007) Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity. J Immunol 179:3397–3401

    CAS  PubMed  Google Scholar 

  2. Magerus-Chatinet A, Stolzenberg MC, Loffredo MS et al (2009) FAS-L, IL-10 and double-negative CD4–CD8–TCR alpha/beta+ T cells are reliable markers of ALPS associated with FAS loss of function. Blood 113(13):3027–3030

    Article  CAS  PubMed  Google Scholar 

  3. Bacchetta R, Passerini L, Gambineri E et al (2006) Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest 116:1713–1722

    Article  CAS  PubMed  Google Scholar 

  4. Betts MR, Brenchley JM, Price DA et al (2003) Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 281:65–78

    Article  CAS  PubMed  Google Scholar 

  5. Bindl L, Torgerson T, Perroni L et al (2005) Successful use of the new immune-suppressor sirolimus in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). J Pediatr 147:256–259

    Article  PubMed  Google Scholar 

  6. Bryceson YT, Rudd E, Zheng C et al (2007) Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis (FHL4) patients. Blood 110:1906–1915

    Article  CAS  PubMed  Google Scholar 

  7. Chun HJ, Zheng L, Ahmad M et al (2002) Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419:395–399

    Article  CAS  PubMed  Google Scholar 

  8. Del Rey M, Ruiz-Contreras J, Bosque A et al (2006) A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome. Blood 108:1306–1312

    Article  Google Scholar 

  9. Feldmann J, Callebaut I, Raposo G et al (2003) Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115:461–473

    Article  CAS  PubMed  Google Scholar 

  10. Fisher GH, Rosenberg FJ, Straus SE et al (1995) Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81:935–946

    Article  CAS  PubMed  Google Scholar 

  11. Geha RS, Notarangelo LD, Casanova J-L 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

    Article  PubMed  Google Scholar 

  12. Holzelova E, Vonarbourg C, Stolzenberg MC et al (2004) Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med 351:1409–1418

    Article  CAS  PubMed  Google Scholar 

  13. Ilmarinen T, Eskelin P, Halonen M et al (2005) Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228 W mutation. Hum Mutat 26(4):322–331

    Article  CAS  PubMed  Google Scholar 

  14. Kekalainen E, Tuovinen H, Joensuu J et al (2007) A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Immunol 178:1208–1215

    PubMed  Google Scholar 

  15. Kuroda N, Mitani T, Takeda N et al (2005) Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J Immunol 174:1862–1870

    CAS  PubMed  Google Scholar 

  16. Mathis D, Benoist C (2009) Aire. Annu Rev Immunol 27:287–312

    Article  CAS  PubMed  Google Scholar 

  17. Marcenaro S, Gallo F, Martini S et al (2006) Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. Blood 108:2316–2323

    Article  CAS  PubMed  Google Scholar 

  18. Marsh RA, Villanueva J, Zhang K et al (2009) A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency. Cytometry B Clin Cytom Mar 13 76B (5):334–344

    Article  CAS  Google Scholar 

  19. Mays LE, Chen YH (2007) Maintaining immunological tolerance with Foxp3. Cell Res 17(11):904–918

    Article  CAS  PubMed  Google Scholar 

  20. Ménasché G, Pastural E, Feldmann J et al (2000) Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 25:173–176

    Article  PubMed  Google Scholar 

  21. Moraes-Vasconcelos D, Costa-Carvalho BT, Torgerson TR, Ochs HD (2008) Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED. J Clin Immunol 28:S11–S19

    Article  CAS  PubMed  Google Scholar 

  22. Oliveira JB, Bidere N, Niemela JE et al (2007) NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci USA 104:8953–8958

    Article  CAS  PubMed  Google Scholar 

  23. Rao A, Kamani N, Filipovich A et al (2007) Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood 109(1):383–385

    Article  CAS  PubMed  Google Scholar 

  24. Rieux-Laucat F, Le Deist F, Hivroz C et al (1995) Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268:1347–1349

    Article  CAS  PubMed  Google Scholar 

  25. Rieux-Laucat F, Fischer A, Deist FL (2003) Cell-death signaling and human disease. Curr Opin Immunol 15:325–331

    Article  CAS  PubMed  Google Scholar 

  26. Rigaud S, Fondanèche MC, Lambert N et al (2006) XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444:110–114

    Article  CAS  PubMed  Google Scholar 

  27. Stepp SE, Dufourcq-Lagelouse R, Le Deist F et al (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286:1957–1959

    Article  CAS  PubMed  Google Scholar 

  28. Toda A, Piccirillo CA (2006) Development and function of naturally occurring CD4+CD25+ regulatory T cells. J Leukoc Biol 80:458–470

    Article  CAS  PubMed  Google Scholar 

  29. Vogel A, Strassburg CP, Obermayer-Straub P et al (2002) The genetic background of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and its autoimmune disease components. J Mol Med 80:201–211

    Article  CAS  PubMed  Google Scholar 

  30. 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 98:47–58

    Article  CAS  PubMed  Google Scholar 

  31. Wu J, Wilson J, He J et al (1996) Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest 98:1107–1113

    Article  CAS  PubMed  Google Scholar 

  32. zur Stadt U, Schmidt S, Kasper B et al (2005) Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 14:827–834

    Article  Google Scholar 

  33. Henter JI, Horne A, Aricó M et al (2007) HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48(2):124–131

    Article  PubMed  Google Scholar 

  34. Mahlaoui N, Ouachée-Chardin M, de Saint Basile G et al (2007) Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics 120(3):e622–e628

    Article  PubMed  Google Scholar 

  35. Speckmann C, Rohr J, Ehl S (2008) Genetic disorders of immunregulation. In: Rezaei N, Aghamohammadi A, Notarangelo LD (eds) Primary immunodeficiency diseases: definition, diagnosis and management, Chapter 5, Springer, Berlin Heidelberg New York Tokyo, pp 167

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  1. Zentrum für Chronische Immundefizienz (CCI), Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Freiburg, Mathildenstr. 1, 79106, Freiburg, Deutschland

    I. Schulze, J. Rohr & C. Speckmann

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  1. I. Schulze
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  2. J. Rohr
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Schulze, I., Rohr, J. & Speckmann, C. Angeborene Störungen der Immunregulation. Monatsschr Kinderheilkd 157, 878–885 (2009). https://doi.org/10.1007/s00112-009-1988-8

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