Inherited Hemophagocytic Lymphohistiocytosis (HLH)

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal immune disorder characterized by uncontrolled lymphocyte- and macrophage-activation. The resulting hypercytokinemia and cell infiltration of organs lead to the clinical and laboratory features of HLH. Viral infections and other triggers can induce both, inherited and acquired forms of HLH. Disease-causing mutations in the genes encoding perforin (PRF1, FHL2), munc13-4 (UNC13D, FHL3), syntaxin 11 (STX11, FHL4), and munc18-2 (UNC18-2/STXBP2, FHL5) have been previously identified in Familial Hemophagocyic Lymphohistiocytosis (FHL), whereas mutation in RAB27A and LYST account for Griscelli syndome type 2 and Chediak-Higashi syndrome, respectively. These genes all encode proteins which are involved in the cytotoxic activity of lymphocytes. The inability of activated cytotoxic cells to clear antigen-presenting targets results in sustained immune stimulation, likely accounting for the unremitting polyclonal CD8 T-cell activation and hyperimmune reaction which characterizes FHL. Treatment of HLH consists of elimination of the trigger and immunosuppressive treatment in order to induce remission from the uncontrolled inflammation. Allogeneic hematopoietic stem cell transplantation can be indicated in the inherited forms of HLH.

Zusammenfassung

Die hämophagozytische Lymphohistiozytose (HLH) ist eine potenziell fatale Entzündungsreaktion, die durch eine übermäßige Aktivierung und Vermehrung von Lymphozyten und Makrophagen charakterisiert ist. Virale Infekte und andere Trigger vermögen sowohl angeborene als auch erworbene Formen der HLH auszulösen. Mutationen in den Genen, welche für Perforin (PRF1, FHL2), Munc13-4 (UNC13D, FHL3), Syntaxin 11 (STX11, FHL4) und Munc18-2 (UNC18-2/STXBP2, FHL5) kodieren, werden für die familiäre hämophagozytische Lymphohistiozytose (FHL) verantwortlich gemacht, Mutationen in RAB27A für das Griscelli-Syndrom und Mutationen in LYST für das Chediak-Higashi-Syndrom. Alle diese Gene kodieren für Proteine, welche für die Zytotoxizität von Lymphozyten wichtig sind. Die Unfähigkeit der zytotoxischen Lymphozyten, antigenpräsentierende Zellen zu eliminieren, führt wahrscheinlich dazu, dass die Zytokinausschüttung länger und intensiver unterhalten wird. Die Behandlung der HLH besteht einerseits in der Beseitigung des Auslösers, anderseits in der Eindämmung der überschießenden Immunreaktion mittels immunsuppressiver Medikamente. Bei angeborenen Formen der HLH kann eine Knochenmarktransplantation indiziert sein.

hemophagocytic lymphohistiozytosis HLH - macrophage activation - immunodeficiency - hemophagocytosis - fever - genetic diseases

hämophagozytische Lymphohistiozytose HLH - Makrophagenaktivierung - Immundefekt - Hämophagozytose - Fieber - genetische Krankheit

References

• 1 Badovinac VP, Hamilton SE, Harty JT. Viral infection results in massive CD8+ T-cell expansion and mortality in vaccinated perforin-deficient mice.  Immunity. 2003;  18 463-474
• 2 Barbosa MD, Nguyen QA, Tchernev VT. et al . Identification of the homologous beige and Chediak-Higashi syndrome genes.  Nature. 1996;  382 262-265
• 3 Behrens EM, Beukelman T, Paessler M. et al . Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis.  J Rheumatol. 2007;  34 1133-1138
• 4 Binder D, van den Broek MF, Kagi D. et al . Aplastic anemia rescued by exhaustion of cytokine-secreting CD8+ T-cells in persistent infection with lymphocytic choriomeningitis virus.  J Exp Med. 1998;  187 1903-1920
• 5 Bolitho P, Street SE, Westwood JA. et al . Perforin-mediated suppression of B-cell lymphoma.  Proc Natl Acad Sci USA. 2009;  106 2723-2728
• 6 Bryceson YT, Rudd E, Zheng C. et al . Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients.  Blood. 2007;  110 1906-1915
• 7 Cannella S, Santoro A, Bruno G. et al . Germline mutations of the perforin gene are a frequent occurrence in childhood anaplastic large cell lymphoma.  Cancer. 2007;  109 2566-2571
• 8 Chia J, Yeo KP, Whisstock JC. et al . Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer.  Proc Natl Acad Sci USA. 2009;  106 9809-9814
• 9 Clementi R, Locatelli F, Dupre L. et al . A proportion of patients with lymphoma may harbor mutations of the perforin gene.  Blood. 2005;  105 4424-4428
• 10 Coffey AJ, Brooksbank RA, Brandau O. et al . Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.  Nat Genet. 1998;  20 129-135
• 11 Côte M, Ménager MM, Burgess A. et al . Munc18-2/STXBP2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 (FHL5) and impairs cytotoxic granule exocytosis in patient NK cells.  J Clin Invest. 2009;  119 in press.
• 12 de Saint Basile G, Fischer A. The role of cytotoxicity in lymphocyte homeostasis.  Curr Opin Immunol. 2001;  13 549-554
• 13 Enders A, Zieger B, Schwarz K. et al . Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II.  Blood. 2006;  108 81-87
• 14 Feldmann J, Callebaut I, Raposo G. et al . Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3).  Cell. 2003;  115 461-473
• 15 Feldmann J, Le Deist F, Ouachee-Chardin M. et al . Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis.  Br J Haematol. 2002;  117 965-972
• 16 Haddad E, Sulis ML, Jabado N. et al . Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis.  Blood. 1997;  89 794-800
• 17 Henter JI, Arico M, Egeler RM. et al . HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society.  Med Pediatr Oncol. 1997;  28 342-347
• 18 Henter JI, Elinder G, Soder O. et al . Hypercytokinemia in familial hemophagocytic lymphohistiocytosis.  Blood. 1991;  78 2918-2922
• 19 Henter JI, Elinder G, Soder O. et al . Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis.  Acta Paediatr Scand. 1991;  80 428-435
• 20 Henter JI, Horne A, Arico M. et al . HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.  Pediatr Blood Cancer. 2007;  48 124-131
• 21 Henter JI, Samuelsson-Horne A, Arico M. et al . Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation.  Blood. 2002;  100 2367-2373
• 22 Horne A, Janka G, Maarten Egeler R. et al . Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis.  Br J Haematol. 2005;  129 622-630
• 23 Horne A, Trottestam H, Arico M. et al . Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis.  Br J Haematol. 2008;  140 327-335
• 24 Jabado N, de Graeff-Meeder ER, Cavazzana-Calvo M. et al . Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors.  Blood. 1997;  90 4743-4748
• 25 Janka G. Hemophagocytic lymphohistiocytosis: when the immune system runs amok.  Klin Padiatr. 2009;  221 278-285
• 26 Jordan MB, Hildeman D, Kappler J. et al . An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T-cells and interferon gamma are essential for the disorder.  Blood. 2004;  104 735-743
• 27 Lipton JM, Westra S, Haverty CE. et al . Case records of the Massachusetts General Hospital, Weekly clinicopathological exercises. Case, 28-2004, Newborn, twins, with thrombocytopenia, coagulation defects, and hepatosplenomegaly.  N Engl J Med. 2004;  351 1120-1130
• 28 Mahlaoui N, Ouachee-Chardin M, de Saint Basile G. et al . Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients.  Pediatrics. 2007;  120 e622-e628
• 29 Malloy CA, Polinski C, Alkan S. et al . Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis.  J Perinatol. 2004;  24 458-460
• 30 Mamishi S, Modarressi MH, Pourakbari B. et al . Analysis of RAB27A gene in griscelli syndrome type 2: novel mutations including a deletion hotspot.  J Clin Immunol. 2008;  28 384-389
• 31 Mazodier K, Marin V, Novick D. et al . Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome.  Blood. 2005;  106 3483-3489
• 32 Mehta PA, Davies SM, Kumar A. et al . Perforin polymorphism A91 V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group.  Leukemia. 2006;  20 1539-1541
• 33 Menager MM, Menasche G, Romao M. et al . Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4.  Nat Immunol. 2007;  8 257-267
• 34 Menasche G, Fischer A, de Saint Basile G. Griscelli syndrome types 1 and 2.  Am J Hum Genet. 2002;  71 1237-1238 author reply 1238.
• 35 Menasche G, Ho CH, Sanal O. et al . Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1).  J Clin Invest. 2003;  112 450-456
• 36 Menasche G, Pastural E, Feldmann J. et al . Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome.  Nat Genet. 2000;  25 173-176
• 37 Milone MC, Tsai DE, Hodinka RL. et al . Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy.  Blood. 2005;  105 994-996
• 38 Nagasawa M, Yi Z, Imashuku S. et al . Soluble TWEAK is markedly elevated in hemophagocytic lymphohistiocytosis.  Am J Hematol. 2008;  83 222-225
• 39 Nagle DL, Karim MA, Woolf EA. et al . Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome.  Nat Genet. 1996;  14 307-311
• 40 Osugi Y, Hara J, Tagawa S. et al . Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis.  Blood. 1997;  89 4100-4103
• 41 Pachlopnik Schmid J, Ho CH, Chretien F. et al . Neutralization of IFNγ defeats hemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice.  EMBO Mol Med. in press 2009a; 
• 42 Pachlopnik Schmid J, Moshous D, Boddaert N. et al . Hematopoietic stem cell transplantation in Griscelli syndrome type 2: a single-center report on 10 patients.  Blood. 2009b;  114 211-218
• 43 Parolini S, Bottino C, Falco M. et al . X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.  J Exp Med. 2000;  192 337-346
• 44 Rigaud S, Fondaneche MC, Lambert N. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.  Nature. 2006;  444 110-114
• 45 Santoro A, Cannella S, Trizzino A. et al . A single amino acid change A91V in perforin: a novel, frequent predisposing factor to childhood acute lymphoblastic leukemia?.  Haematologica. 2005;  90 697-698
• 46 Smyth MJ, Thia KY, Street SE. et al . Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.  J Exp Med. 2000;  192 755-760
• 47 Stepp SE, Dufourcq-Lagelouse R, Le Deist F. et al . Perforin gene defects in familial hemophagocytic lymphohistiocytosis.  Science. 1999;  286 1957-1959
• 48 Suzuki N, Morimoto A, Ohga S. et al . Characteristics of hemophagocytic lymphohistiocytosis in neonates: a nationwide survey in Japan.  2009;  155 235.e1-238.e1
• 49 Torrents D, Mykkanen J, Pineda M. et al . Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.  Nat Genet. 1999;  21 293-296
• 50 Ueda I, Ishii E, Morimoto A. et al . Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL).  Pediatr Blood Cancer. 2006;  46 482-488
• 51 Voskoboinik I, Sutton VR, Ciccone A. et al . Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function.  Blood. 2007;  110 1184-1190
• 52 zur Stadt U, Rohr J, Seifert W. et al . Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.  Am J Hum Genet. 2009;  85 482-492
• 53 zur Stadt U, Schmidt S, Kasper B. et al . Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11.  Hum Mol Genet. 2005;  14 827-834

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