Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza

被引:121
作者
Schulert, Grant S. [1 ]
Zhang, Mingce [3 ]
Fall, Ndate [1 ]
Husami, Ammar [2 ]
Kissell, Diane
Hanosh, Andrew [4 ]
Zhang, Kejian [2 ]
Davis, Kristina [4 ]
Jentzen, Jeffrey M. [4 ]
Napolitano, Lena [5 ]
Siddiqui, Javed [4 ]
Smith, Lauren B. [4 ]
Harms, Paul W. [4 ,6 ,7 ]
Grom, Alexei A. [1 ]
Cron, Randy Q. [3 ]
机构
[1] Cincinnati Childrens Hosp Med Ctr, Div Pediat Rheumatol, Cincinnati, OH 45229 USA
[2] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA
[3] Univ Alabama Birmingham, Childrens Hosp Alabama, Div Pediat Rheumatol, Childrens Pk Pl,Ste 210,1601 4th Ave S, Birmingham, AL 35233 USA
[4] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA
[5] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI USA
[6] Univ Michigan, Sch Med, Dept Dermatol, Ann Arbor, MI USA
[7] Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Ann Arbor, MI USA
基金
美国国家卫生研究院;
关键词
hemophagocytosis; macrophage activation syndrome; H1N1; influenza; perforin; cytolytic pathway; LYST; JUVENILE IDIOPATHIC ARTHRITIS; VIRUS; DIAGNOSIS; CYTOTOXICITY; GUIDELINES; DEFECTS; CELLS; PATHOGENESIS; INHIBITION; INFECTION;
D O I
10.1093/infdis/jiv550
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza. Methods. Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells. Results. Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS. Conclusions. This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection.
引用
收藏
页码:1180 / 1188
页数:9
相关论文
共 51 条
  • [1] Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients
    An, Omer
    Gursoy, Attila
    Gurgey, Aytemiz
    Keskin, Ozlem
    [J]. PROTEIN SCIENCE, 2013, 22 (06) : 823 - 839
  • [2] [Anonymous], TURK J PEDIAT
  • [3] Mutations of familial hemophagocytic lymphohistiocytosis (FHL) related genes and abnormalities of cytotoxicity function tests in patients with macrophage activation syndrome (MAS) occurring in systemic juvenile idiopathic arthritis (sJIA)
    Claudia Bracaglia
    Elena Sieni
    Martina Da Ros
    Carmela De Fusco
    Concetta Micalizzi
    Valentina Cetica
    Benedetta Ciambotti
    Maria Luisa Coniglio
    Antonella Insalaco
    Fabrizio De Benedetti
    Maurizio Aricò
    [J]. Pediatric Rheumatology, 12 (Suppl 1)
  • [4] Identification of the homologous beige and Chediak-Higashi syndrome genes
    Barbosa, MDFS
    Nguyen, QA
    Tchernev, VT
    Ashley, JA
    Detter, JC
    Blaydes, SM
    Brandt, SJ
    Chotai, D
    Hodgman, C
    Solari, RCE
    Lovett, M
    Kingsmore, SF
    [J]. NATURE, 1996, 382 (6588) : 262 - 265
  • [5] Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection
    Beutel, Gernot
    Wiesner, Olaf
    Eder, Matthias
    Hafer, Carsten
    Schneider, Andrea S.
    Kielstein, Jan T.
    Kuehn, Christian
    Heim, Albert
    Ganzenmueller, Tina
    Kreipe, Hans-Heinrich
    Haverich, Axel
    Tecklenburg, Andreas
    Ganser, Arnold
    Welte, Tobias
    Hoeper, Marius M.
    [J]. CRITICAL CARE, 2011, 15 (02)
  • [6] Recent advances in the diagnosis and treatment of hemophagocytic lymphohistiocytosis
    Bode, Sebastian F. N.
    Lehmberg, Kai
    Maul-Pavicic, Andrea
    Vraetz, Thomas
    Janka, Gritta
    zur Stadt, Udo
    Ehl, Stephan
    [J]. ARTHRITIS RESEARCH & THERAPY, 2012, 14 (03)
  • [7] Macrophage Activation Syndrome Induced by A/H1N1 Influenza in Cystic Fibrosis
    Casciaro, Rosaria
    Cresta, Federico
    Favilli, Federica
    Naselli, Aldo
    De Alessandri, Alessandra
    Minicucci, Laura
    [J]. PEDIATRIC PULMONOLOGY, 2014, 49 (02) : E10 - E12
  • [8] Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry
    Cetica, Valentina
    Sieni, Elena
    Pende, Daniela
    Danesino, Cesare
    De Fusco, Carmen
    Locatelli, Franco
    Micalizzi, Concetta
    Putti, Maria Caterina
    Biondi, Andrea
    Fagioli, Franca
    Moretta, Lorenzo
    Griffiths, Gillian M.
    Luzzatto, Lucio
    Arico, Maurizio
    [J]. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2016, 137 (01) : 188 - +
  • [9] Inhibition of Natural Killer Cell Cytotoxicity by Interleukin-6: Implications for the Pathogenesis of Macrophage Activation Syndrome
    Cifaldi, Loredana
    Prencipe, Giusi
    Caiello, Ivan
    Bracaglia, Claudia
    Locatelli, Franco
    De Benedetti, Fabrizio
    Strippoli, Raffaele
    [J]. ARTHRITIS & RHEUMATOLOGY, 2015, 67 (11) : 3037 - 3046
  • [10] Performance of Current Guidelines for Diagnosis of Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis
    Davi, Sergio
    Minoia, Francesca
    Pistorio, Angela
    Horne, AnnaCarin
    Consolaro, Alessandro
    Rosina, Silvia
    Bovis, Francesca
    Cimaz, Rolando
    Gamir, Maria Luz
    Ilowite, Norman T.
    Kone-Paut, Isabelle
    Feitosa de Oliveira, Sheila Knupp
    McCurdy, Deborah
    Silva, Clovis Artur
    Sztajnbok, Flavio
    Tsitsami, Elena
    Unsal, Erbil
    Weiss, Jennifer E.
    Wulffraat, Nico
    Abinun, Mario
    Aggarwal, Amita
    Apaz, Maria Teresa
    Astigarraga, Itziar
    Corona, Fabrizia
    Cuttica, Ruben
    D'Angelo, Gianfranco
    Eisenstein, Eli M.
    Hashad, Soad
    Lepore, Loredana
    Mulaosmanovic, Velma
    Nielsen, Susan
    Prahalad, Sampath
    Rigante, Donato
    Stanevicha, Valda
    Sterba, Gary
    Susic, Gordana
    Takei, Syuji
    Trauzeddel, Ralf
    Zletni, Mabruka
    Ruperto, Nicolino
    Martini, Alberto
    Cron, Randy Q.
    Ravelli, Angelo
    [J]. ARTHRITIS & RHEUMATOLOGY, 2014, 66 (10) : 2871 - 2880