Contemporary diagnostic methods for hemophagocytic lymphohistiocytic disorders

Journal of Immunological Methods

Volumn 364, Issue 1-2, 2011, Pages 1-13

  Johnson, Theodore S ^a   Villanueva, Joyce ^b   Filipovich, Alexandra H ^b   Marsh, Rebecca A ^b   Bleesing, Jack J ^b  

^a MEDICAL COLLEGE OF GEORGIA   (United States)

^b UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

Author keywords

Hemophagocytic lymphohistiocytosis; Hemophagocytosis; Histiocytosis; HLH; Macrophage; T cell

Indexed keywords

CD163 ANTIGEN; CHROMIUM 51; GRANZYME B; LYSOSOME ASSOCIATED MEMBRANE PROTEIN 1; MUNC18 PROTEIN; PERFORIN; SIGNALING LYMPHOCYTE ACTIVATION MOLECULE ASSOCIATED PROTEIN; SOLUBLE INTERLEUKIN 2 RECEPTOR; X LINKED INHIBITOR OF APOPTOSIS;

CELL FUNCTION; CELL SURFACE; CYTOLYSIS; CYTOTOXICITY; DEGRANULATION; DIAGNOSTIC PROCEDURE; DISEASE COURSE; DISEASE PREDISPOSITION; EFFECTOR CELL; FLOW CYTOMETRY; GENETIC SCREENING; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; HUMAN; LYMPHOCYTE; LYMPHOCYTE SUBPOPULATION; MACROPHAGE ACTIVATION; MUTATIONAL ANALYSIS; NATURAL KILLER CELL; PRIORITY JOURNAL; PROGNOSIS; PROTEIN DEGRADATION; PROTEIN EXPRESSION; REVIEW; T LYMPHOCYTE ACTIVATION;

AUTOIMMUNE DISEASES; AUTOIMMUNITY; CYTOKINES; GENETIC PREDISPOSITION TO DISEASE; HUMANS; INFECTION; LYMPHOHISTIOCYTOSIS, HEMOPHAGOCYTIC; NEOPLASMS; PATHOLOGY, MOLECULAR; POLYMORPHISM, GENETIC; T-LYMPHOCYTES, CYTOTOXIC;

EID: 78650811211     PISSN: 00221759     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jim.2010.11.006     Document Type: Review

References (82)

1. Aktas E., Kucuksezer U.C., Bilgic S., Erten G., Deniz G. Relationship between CD107a expression and cytotoxic activity. Cell. Immunol. 2009, 254:149.
2. Allen C.E., Yu X., Kozinetz C.A., McClain K.L. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 2008, 50:1227.
3. Alter G., Malenfant J.M., Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J. Immunol. Methods 2004, 294:15.
4. Arico M., Bettinelli A., Maccario R., Clementi R., Bossi G., Danesino C. Hemophagocytic lymphohistiocytosis in a patient with deletion of 22q11.2. Am. J. Med. Genet. 1999, 87:329.
5. Arico M., Imashuku S., Clementi R., Hibi S., Teramura T., Danesino C., Haber D.A., Nichols K.E. Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood 2001, 97:1131.
6. Arneson L.N., Brickshawana A., Segovis C.M., Schoon R.A., Dick C.J., Leibson P.J. Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity. J. Immunol. 2007, 179:3397.
7. Betts M.R., Brenchley J.M., Price D.A., De Rosa S.C., Douek D.C., Roederer M., Koup R.A. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J. Immunol. Methods 2003, 281:65.
8. Bleesing J., Prada A., Siegel D.M., Villanueva J., Olson J., Ilowite N.T., Brunner H.I., Griffin T., Graham T.B., Sherry D.D., Passo M.H., Ramanan A.V., Filipovich A., Grom A.A. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum. 2007, 56:965.
9. Breda L., Nozzi M., De Sanctis S., Chiarelli F. Laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update. Semin. Arthritis Rheum. 2010, 40:53.
10. Bryceson Y.T., Rudd E., Zheng C., Edner J., Ma D., Wood S.M., Bechensteen A.G., Boelens J.J., Celkan T., Farah R.A., Hultenby K., Winiarski J., Roche P.A., Nordenskjold M., Henter J.I., Long E.O., Ljunggren H.G. Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood 2007, 110:1906.
11. Burkett M.W., Shafer-Weaver K.A., Strobl S., Baseler M., Malyguine A. A novel flow cytometric assay for evaluating cell-mediated cytotoxicity. J. Immunother. 2005, 28:396.
12. Cetica V., Pende D., Griffiths G.M., Arico M. Molecular basis of familial hemophagocytic lymphohistiocytosis. Haematologica 2010, 95:538.
13. Cetica V., Santoro A., Gilmour K.C., Sieni E., Beutel K., Pende D., Marcenaro S., Koch F., Grieve S., Wheeler R., Zhao F., zur Stadt U., Griffiths G.M., Arico M. STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5. J. Med. Genet. 2010, 47:595.
14. Cooper N., Rao K., Gilmour K., Hadad L., Adams S., Cale C., Davies G., Webb D., Veys P., Amrolia P. Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood 2006, 107:1233.
15. Cooper N., Rao K., Goulden N., Webb D., Amrolia P., Veys P. The use of reduced-intensity stem cell transplantation in haemophagocytic lymphohistiocytosis and Langerhans cell histiocytosis. Bone Marrow Transplant. 2008, 42(Suppl 2):S47.
16. Cote M., Menager M.M., Burgess A., Mahlaoui N., Picard C., Schaffner C., Al-Manjomi F., Al-Harbi M., Alangari A., Le Deist F., Gennery A.R., Prince N., Cariou A., Nitschke P., Blank U., El-Ghazali G., Menasche G., Latour S., Fischer A., de Saint Basile G. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J. Clin. Invest. 2009, 119:3765.
17. Dufourcq-Lagelouse R., Jabado N., Le Deist F., Stephan J.L., Souillet G., Bruin M., Vilmer E., Schneider M., Janka G., Fischer A., de Saint Basile G. Linkage of familial hemophagocytic lymphohistiocytosis to 10q21-22 and evidence for heterogeneity. Am. J. Hum. Genet. 1999, 64:172.
18. Dupre L., Andolfi G., Tangye S.G., Clementi R., Locatelli F., Arico M., Aiuti A., Roncarolo M.G. SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood 2005, 105:4383.
19. Dvorak C.C., Sandford A., Fong A., Cowan M.J., George T.I., Lewis D.B. Maternal T-cell engraftment associated with severe hemophagocytosis of the bone marrow in untreated X-linked severe combined immunodeficiency. J. Pediatr. Hematol. Oncol. 2008, 30:396.
20. Egeler R.M., Shapiro R., Loechelt B., Filipovich A. Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis. J. Pediatr. Hematol. Oncol. 1996, 18:340.
21. Enders A., Zieger B., Schwarz K., Yoshimi A., Speckmann C., Knoepfle E.M., Kontny U., Muller C., Nurden A., Rohr J., Henschen M., Pannicke U., Niemeyer C., Nurden P., Ehl S. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II. Blood 2006, 108:81.
22. Farquhar J.W., Claireaux A.E. Familial haemophagocytic reticulosis. Arch. Dis. Child. 1952, 27:519.
23. Feldmann J., Callebaut I., Raposo G., Certain S., Bacq D., Dumont C., Lambert N., Ouachee-Chardin M., Chedeville G., Tamary H., Minard-Colin V., Vilmer E., Blanche S., Le Deist F., Fischer A., de Saint Basile G. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003, 115:461.
24. Filipovich A.H. Hemophagocytic lymphohistiocytosis and related disorders. Curr. Opin. Allergy Clin. Immunol. 2006, 6:410.
25. Filipovich A.H. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol. Allergy Clin. North Am. 2008, 28:293. viii.
26. Filipovich A.H. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am. Soc. Hematol. Educ. Program 2009, 127.
27. Filipovich A.H., Zhang K., Snow A.L., Marsh R.A. X-linked lymphoproliferative syndromes: brothers or distant cousins?. Blood 2010, 116:3398.
28. Garcia-Astudillo L.A., Fontalba A., Mazorra F., Marin M.J., Castellanos A., Fernandez S., Tejido R., Lopez-Hoyos M. Severe course of community-acquired pneumonia in an adult patient who is heterozygous for Q481P in the perforin gene: are carriers of the mutation free of risk?. J. Investig. Allergol. Clin. Immunol. 2009, 19:311.
29. Geisberg M., Trapani J.A., Dupont B. Monoclonal antibodies detecting discrete epitopes of human perforin. Tissue Antigens 1990, 35:229.
30. Grom A.A., Villanueva J., Lee S., Goldmuntz E.A., Passo M.H., Filipovich A. Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. J. Pediatr. 2003, 142:292.
31. Han H.J., Lim G.Y., Yeo D.M., Chung N.G. Kikuchi's disease in children: clinical manifestations and imaging features. J. Korean Med. Sci. 2009, 24:1105.
32. Henter J.I., Elinder G., Soder O., Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr. Scand. 1991, 80:428.
33. Henter J.I., Samuelsson-Horne A., Arico M., Egeler R.M., Elinder G., Filipovich A.H., Gadner H., Imashuku S., Komp D., Ladisch S., Webb D., Janka G. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002, 100:2367.
34. Henter J.I., Horne A., Arico M., Egeler R.M., Filipovich A.H., Imashuku S., Ladisch S., McClain K., Webb D., Winiarski J., Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 2007, 48:124.
35. Horne A., Zheng C., Lorenz I., Lofstedt M., Montgomery S.M., Janka G., Henter J.I., Marion Schneider E. Subtyping of natural killer cell cytotoxicity deficiencies in haemophagocytic lymphohistocytosis provides therapeutic guidance. Br. J. Haematol. 2005, 129:658.
36. Imashuku S., Hibi S., Sako M., Ishida Y., Mugishima H., Chen J., Tsunematsu Y. Soluble interleukin-2 receptor: a useful prognostic factor for patients with hemophagocytic lymphohistiocytosis. Blood 1995, 86:4706.
37. Janka G.E. Familial and acquired hemophagocytic lymphohistiocytosis. Eur. J. Pediatr. 2007, 166:95.
38. Katano H., Cohen J.I. Perforin and lymphohistiocytic proliferative disorders. Br. J. Haematol. 2005, 128:739.
39. Kogawa K., Lee S.M., Villanueva J., Marmer D., Sumegi J., Filipovich A.H. Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members. Blood 2002, 99:61.
40. Komp D.M., McNamara J., Buckley P. Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes. Blood 1989, 73:2128.
41. Lee J.S., Kang J.H., Lee G.K., Park H.J. Successful treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with HLH-94 protocol. J. Korean Med. Sci. 2005, 20:209.
42. Lin T.F., Ferlic-Stark L.L., Allen C.E., Kozinetz C.A., McClain K.L. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr. Blood Cancer 2010, 56:154.
43. Mahajan S.D., Aalinkeel R., Schwartz S.A., Chawda R.P., Nair M.P. Effector cell mediated cytotoxicity measured by intracellular Granzyme B release in HIV infected subjects. Biol. Proced. Online 2003, 5:182.
44. Marcenaro S., Gallo F., Martini S., Santoro A., Griffiths G.M., Arico M., Moretta L., Pende D. 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 2006, 108:2316.
45. Marsh R.A., Villanueva J., Zhang K., Snow A.L., Su H.C., Madden L., Mody R., Kitchen B., Marmer D., Jordan M.B., Risma K.A., Filipovich A.H., Bleesing J.J. A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency. Cytometry B Clin. Cytom. 2009, 76:334.
46. Marsh R.A., Madden L., Kitchen B.J., Mody R., McClimon B., Jordan M.B., Bleesing J.J., Zhang K., Filipovich A.H. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood 2010, 116:1079.
47. Marsh R.A., Satake N., Biroschak J., Jacobs T., Johnson J., Jordan M.B., Bleesing J.J., Filipovich A.H., Zhang K. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr. Blood Cancer 2010, 55:134.
48. Marsh R.A., Bleesing J.J., Filipovich A.H. Using flow cytometry to screen patients for X-linked lymphoproliferative disease due to SAP deficiency and XIAP. J. Immunol. Methods 2010, 362:1.
49. McClure P.D., Strachan P., Saunders E.F. Hypofibrinogenemia and thrombocytopenia in familial hemophagocytic reticulosis. J. Pediatr. 1974, 85:67.
50. Meeths M., Bryceson Y.T., Rudd E., Zheng C., Wood S.M., Ramme K., Beutel K., Hasle H., Heilmann C., Hultenby K., Ljunggren H.G., Fadeel B., Nordenskjold M., Henter J.I. Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations. Pediatr. Blood Cancer 2010, 54:563.
51. Meeths M., Entesarian M., Al-Herz W., Chiang S.C., Wood S.M., Al-Ateeqi W., Almazan F., Boelens J.J., Hasle H., Ifversen M., Lund B., van den Berg J.M., Gustafsson B., Hjelmqvist H., Nordenskjold M., Bryceson Y.T., Henter J.I. Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis (FHL) type 5 patients with mutations in STXBP2. Blood 2010, 116:2635.
52. Menasche G., Pastural E., Feldmann J., Certain S., Ersoy F., Dupuis S., Wulffraat N., Bianchi D., Fischer A., Le Deist F., de Saint Basile G. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat. Genet. 2000, 25:173.
53. Menasche G., Feldmann J., Houdusse A., Desaymard C., Fischer A., Goud B., de Saint Basile G. Biochemical and functional characterization of Rab27a mutations occurring in Griscelli syndrome patients. Blood 2003, 101:2736.
54. Migueles S.A., Osborne C.M., Royce C., Compton A.A., Joshi R.P., Weeks K.A., Rood J.E., Berkley A.M., Sacha J.B., Cogliano-Shutta N.A., Lloyd M., Roby G., Kwan R., McLaughlin M., Stallings S., Rehm C., O'Shea M.A., Mican J., Packard B.Z., Komoriya A., Palmer S., Wiegand A.P., Maldarelli F., Coffin J.M., Mellors J.W., Hallahan C.W., Follman D.A., Connors M. Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 2008, 29:1009.
55. Molleran Lee S., Villanueva J., Sumegi J., Zhang K., Kogawa K., Davis J., Filipovich A.H. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J. Med. Genet. 2004, 41:137.
56. Nagle D.L., Karim M.A., Woolf E.A., Holmgren L., Bork P., Misumi D.J., McGrail S.H., Dussault B.J., Perou C.M., Boissy R.E., Duyk G.M., Spritz R.A., Moore K.J. Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat. Genet. 1996, 14:307.
57. Ohadi M., Lalloz M.R., Sham P., Zhao J., Dearlove A.M., Shiach C., Kinsey S., Rhodes M., Layton D.M. Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am. J. Hum. Genet. 1999, 64:165.
58. Okur H., Balta G., Akarsu N., Oner A., Patiroglu T., Bay A., Sayli T., Unal S., Gurgey A. Clinical and molecular aspects of Turkish familial hemophagocytic lymphohistiocytosis patients with perforin mutations. Leuk. Res. 2008, 32:972.
59. Pasic S., Micic D., Kuzmanovic M. Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis in Wiskott-Aldrich syndrome. Acta Paediatr. 2003, 92:859.
60. Rigaud S., Fondaneche M.C., Lambert N., Pasquier B., Mateo V., Soulas P., Galicier L., Le Deist F., Rieux-Laucat F., Revy P., Fischer A., de Saint Basile G., Latour S. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 2006, 444:110.
61. Rininsland F.H., Helms T., Asaad R.J., Boehm B.O., Tary-Lehmann M. Granzyme B ELISPOT assay for ex vivo measurements of T cell immunity. J. Immunol. Methods 2000, 240:143.
62. Risma K.A., Frayer R.W., Filipovich A.H., Sumegi J. Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J. Clin. Invest. 2006, 116:182.
63. Sawhney S., Woo P., Murray K.J. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch. Dis. Child. 2001, 85:421.
64. Schaer D.J., Schaer C.A., Schoedon G., Imhof A., Kurrer M.O. Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsis. Eur. J. Haematol. 2006, 77:432.
65. Schmid I., Reiter K., Schuster F., Wintergerst U., Meilbeck R., Nicolai T., Behloradsky B.H., Stachel D.K. Allogeneic bone marrow transplantation for active Epstein-Barr virus-related lymphoproliferative disease and hemophagocytic lymphohistiocytosis in an infant with severe combined immunodeficiency syndrome. Bone Marrow Transplant. 2002, 29:519.
66. Schneider E.M., Lorenz I., Muller-Rosenberger M., Steinbach G., Kron M., Janka-Schaub G.E. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis. Blood 2002, 100:2891.
67. Shafer-Weaver K.A., Sayers T., Kuhns D.B., Strobl S.L., Burkett M.W., Baseler M., Malyguine A. Evaluating the cytotoxicity of innate immune effector cells using the GrB ELISPOT assay. J. Transl. Med. 2004, 2:31.
68. Shinozaki K., Kanegane H., Matsukura H., Sumazaki R., Tsuchida M., Makita M., Kimoto Y., Kanai R., Tsumura K., Kondoh T., Moriuchi H., Miyawaki T. Activation-dependent T cell expression of the X-linked lymphoproliferative disease gene product SLAM-associated protein and its assessment for patient detection. Int. Immunol. 2002, 14:1215.
69. Snow A.L., Marsh R.A., Krummey S.M., Roehrs P., Young L.R., Zhang K., van Hoff J., Dhar D., Nichols K.E., Filipovich A.H., Su H.C., Bleesing J.J., Lenardo M.J. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. J. Clin. Invest. 2009, 119:2976.
70. Stephan J.L., Kone-Paut I., Galambrun C., Mouy R., Bader-Meunier B., Prieur A.M. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford) 2001, 40:1285.
71. Stepp S.E., Dufourcq-Lagelouse R., Le Deist F., Bhawan S., Certain S., Mathew P.A., Henter J.I., Bennett M., Fischer A., de Saint Basile G., Kumar V. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999, 286:1957.
72. Tabata Y., Villanueva J., Lee S.M., Zhang K., Kanegane H., Miyawaki T., Sumegi J., Filipovich A.H. Rapid detection of intracellular SH2D1A protein in cytotoxic lymphocytes from patients with X-linked lymphoproliferative disease and their family members. Blood 2005, 105:3066.
73. Timmermann M., Buck F., Sorg C., Hogger P. Interaction of soluble CD163 with activated T lymphocytes involves its association with non-muscle myosin heavy chain type A. Immunol. Cell Biol. 2004, 82:479.
74. van Montfrans J.M., Rudd E., van de Corput L., Henter J.I., Nikkels P., Wulffraat N., Boelens J.J. Fatal hemophagocytic lymphohistiocytosis in X-linked chronic granulomatous disease associated with a perforin gene variant. Pediatr. Blood Cancer 2009, 52:527.
75. Villanueva J., Lee S., Giannini E.H., Graham T.B., Passo M.H., Filipovich A., Grom A.A. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res. Ther. 2005, 7:R30.
76. Weren A., Bonnekoh B., Schraven B., Gollnick H., Ambach A. A novel flow cytometric assay focusing on perforin release mechanisms of cytotoxic T lymphocytes. J. Immunol. Methods 2004, 289:17.
77. Wheeler R.D., Cale C.M., Cetica V., Arico M., Gilmour K.C. A novel assay for investigation of suspected familial haemophagocytic lymphohistiocytosis. Br. J. Haematol. 2010.
78. Zamai L., Ahmad M., Bennett I.M., Azzoni L., Alnemri E.S., Perussia B. Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. J. Exp. Med. 1998, 188:2375.
79. Zhang K., Johnson J.A., Biroschak J., Villanueva J., Lee S.M., Bleesing J.J., Risma K.A., Wenstrup R.J., Filipovich A.H. Familial haemophagocytic lymphohistiocytosis in patients who are heterozygous for the A91V perforin variation is often associated with other genetic defects. Int. J. Immunogenet. 2007, 34:231.
80. Zhang K., Biroschak J., Glass D.N., Thompson S.D., Finkel T., Passo M.H., Binstadt B.A., Filipovich A., Grom A.A. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheum. 2008, 58:2892.
81. zur Stadt U., Schmidt S., Kasper B., Beutel K., Diler A.S., Henter J.I., Kabisch H., Schneppenheim R., Nurnberg P., Janka G., Hennies H.C. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum. Mol. Genet. 2005, 14:827.
82. zur Stadt U., Rohr J., Seifert W., Koch F., Grieve S., Pagel J., Strauss J., Kasper B., Nurnberg G., Becker C., Maul-Pavicic A., Beutel K., Janka G., Griffiths G., Ehl S., Hennies H.C. 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.