title: Pathophysiology and spectrum of diseases caused by defects in lymphocyte cytotoxicity.
abstract: In experimental settings, lymphocyte cytotoxicity has been recognized as a central mechanism for immune defense against infected and neoplastic cells. More recently, molecular determinants of lymphocyte cytotoxicity have been identified through studies of rare, inherited hyperinflammatory and lymphoproliferative syndromes that include hemophagocytic lymphohistiocytosis (HLH). These studies have unraveled a set of genes pivotal for the biogenesis and directed release of perforin-containing lysosomes that mediate target cell killing, in addition to other pathways including Fas that also contribute to induction of cell death. Furthermore, studies of such human primary immunodeficiencies have highlighted non-redundant roles of perforin for maintenance of immune homeostasis. Besides providing mechanistic insights to lymphocyte cytotoxicity, studies of individuals with rare hyperinflammatory diseases are highlighting the relevance of lymphocyte cytotoxicity to more common human diseases. It is increasingly recognized that mutations abrogating lymphocyte cytotoxicity not only cause HLH, but also are associated with susceptibility to cancer and autoimmune syndromes. In addition, patients may initially be present with neurological symptoms or severe infectious disease masquerading as variable immunodeficiency syndrome. Here, we highlight new knowledge regarding the molecular mechanisms regulating lymphocyte cytotoxicity and review how mutations in genes associated with HLH cause disease. We also discuss the wider implications of impairments in lymphocyte cytotoxicity for human disease predisposition.
authors.affiliation: Childhood Cancer Research Unit, Department of Women׳s and Children׳s Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Meeths
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Samuel C C
authors.initials: SC
authors.lastname: Chiang
authors.affiliation: Childhood Cancer Research Unit, Department of Women׳s and Children׳s Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Löfstedt
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Martha-Lena
authors.initials: ML
authors.lastname: Müller
authors.affiliation: Childhood Cancer Research Unit, Department of Women׳s and Children׳s Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Bianca
authors.initials: B
authors.lastname: Tesi
authors.affiliation: Childhood Cancer Research Unit, Department of Women׳s and Children׳s Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Broegelmann Research Laboratory, Institute of Clinical Sciences, University of Bergen, Bergen, Norway. Electronic address: yenan.bryceson@ki.se.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
mesh_terms: D000818:Animals; D015551:Autoimmunity; D015550:Cell Degranulation; D003602:Cytotoxicity, Immunologic; D020022:Genetic Predisposition to Disease; D019337:Hematologic Neoplasms / Q000235:genetics / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
keywords: Cellular cytotoxicity; Cytotoxic T lymphocytes; Exocytosis; Hemophagocytic lymphohistiocytosis; Natural killer cells; Perforin; Secretory lysosomes