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Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis
  1. S Molleran Lee1,
  2. J Villanueva1,
  3. J Sumegi1,
  4. K Zhang2,
  5. K Kogawa3,
  6. J Davis4,
  7. A H Filipovich1
  1. 1Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
  2. 2Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
  3. 3Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan
  4. 4Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NB, USA
  1. Correspondence to:
 Ms S M Lee
 Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, CHRF 1301, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA;

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Haemophagocytic lymphohistiocytosis (HLH, OMIM #267700, #603553) is a rare, lethal, cellular immunological disorder that draws attention to critical, genetically determined checkpoints in the regulatory pathways that normally maintain homeostasis within the immune system and ensure the natural termination of effector immune responses. HLH encompasses several entities, including the primary or familial form and the secondary forms associated with infections or malignancies.1,2 In all forms, HLH is believed to be a reactive process resulting from hyperactivation, proliferation, and migration of macrophages and type 1 T cells.3 Cytotoxic chemotherapy and/or immune suppressive therapy are usually effective in achieving symptomatic remission of HLH.4,5 The proven curative potential of haematopoietic stem cell transplantation underscores the premise that all forms of HLH result from genetic defects intrinsic to the immune system.5–7 Abnormalities in the function (but rarely the quantity) of cytotoxic immune cells, principally natural killer (NK) cells, but also cytotoxic T cells, have been observed in patients with HLH for nearly 20 years.8–11 Several genetic changes are thought to contribute to the development of HLH. Linkage analysis identified two loci at 10q21 and 9q21;12,13 additional studies provided evidence for the presence of at least one more locus.14 In 1999, the first molecular aetiology of HLH was described. Deficiency of perforin, a key lytic molecule of cytotoxic cells, was identified in a proportion of patients with HLH.15 Mutations of the coding sequence of PRF1 have since been reported in approximately 20–30% of primary HLH cases.16,17 Most of the families involved in previous studies came from southern Europe, North Africa, Turkey, and Japan.16–20 Only four cases from North America have previously been published.21

In the present study, we investigated the immunophenotypes of HLH in relation to the presence …

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