title: The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2.
abstract: Genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocytosis (HLH). Reduced lymphocyte cytotoxicity has been demonstrated in Hermansky-Pudlak syndrome type 2 (HPS2), but only a single patient was reported who developed HLH. Because that patient also carried a potentially contributing heterozygous RAB27A mutation, the risk for HLH in HPS2 remains unclear. We analyzed susceptibility to HLH in the pearl mouse model of HPS2. After infection with lymphocytic choriomeningitis virus, pearl mice developed all key features of HLH, linked to impaired virus control caused by a moderate defect in CTL cytotoxicity in vivo. However, in contrast to perforin-deficient mice, the disease was transient, and all mice fully recovered and controlled the infection. An additional heterozygous Rab27a mutation did not aggravate the cytotoxicity defect or disease parameters. In the largest survey of 22 HPS2 patients covering 234 patient years, we identified only 1 additional patient with HLH and 2 with incomplete transient HLH-like episodes, although cytotoxicity or degranulation was impaired in all 16 patients tested. HPS2 confers a risk for HLH that is lower than in Griscelli or Chediak-Higashi syndrome, probably because of a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.
authors: Centre of Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Breisacher Strasse 117, Freiburg, Germany.
authors: Birthe
authors: B
authors: Jessen
authors: Sebastian F N
authors: SF
authors: Bode
authors: Sandra
authors: S
authors: Ammann
authors: Subarna
authors: S
authors: Chakravorty
authors: Graham
authors: G
authors: Davies
authors: Jana
authors: J
authors: Diestelhorst
authors: Melissa
authors: M
authors: Frei-Jones
authors: William A
authors: WA
authors: Gahl
authors: Bernadette R
authors: BR
authors: Gochuico
authors: Matthias
authors: M
authors: Griese
authors: Gillian
authors: G
authors: Griffiths
authors: Gritta
authors: G
authors: Janka
authors: Christoph
authors: C
authors: Klein
authors: Tamara
authors: T
authors: Kögl
authors: Karin
authors: K
authors: Kurnik
authors: Kai
authors: K
authors: Lehmberg
authors: Andrea
authors: A
authors: Maul-Pavicic
authors: Andrew D
authors: AD
authors: Mumford
authors: David
authors: D
authors: Pace
authors: Nima
authors: N
authors: Parvaneh
authors: Nima
authors: N
authors: Rezaei
authors: Geneviève
authors: G
authors: de Saint Basile
authors: Annette
authors: A
authors: Schmitt-Graeff
authors: Klaus
authors: K
authors: Schwarz
authors: Gulsun T
authors: GT
authors: Karasu
authors: Barbara
authors: B
authors: Zieger
authors: Udo
authors: U
authors: Zur Stadt
authors: Peter
authors: P
authors: Aichele
authors: Stephan
authors: S
authors: Ehl
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D033966:Adaptor Protein Complex beta Subunits / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D022861:Hermanski-Pudlak Syndrome / Q000150:complications / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D012307:Risk Factors; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult; D020691:rab GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000075745:rab27 GTP-Binding Proteins
chemical_list: D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; C418506:Ap3b1 protein, mouse; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins
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