Genetic disorders of lymphocyte cytotoxicity predispose 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. Since 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. Following LCMV infection, 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 so far 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. We conclude that HPS2 confers a risk for HLH, which is lower than in Griscelli or Chediak-Higashi syndrome, probably due to a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.
[Show abstract][Hide abstract] ABSTRACT: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease of hyperinflammation resulting from immune dysregulation due to inherited defects in the cytolytic machinery of natural killer and T cells. In humans, mutations in seven genes encoding proteins involved in cytolytic effector functions have so far been identified that predispose to HLH. However, although most affected patients develop HLH eventually, disease onset and severity are highly variable. Due to the genetic heterogeneity and variable time and nature of disease triggers, the immunological basis of these variations in HLH progression is incompletely understood. Several murine models of primary HLH have been established allowing to study HLH pathogenesis under more defined conditions. Here we directly compare the clinical HLH phenotype in six HLH-prone mouse strains with defects in the granule-dependent cytotoxic pathway. A severity gradient of HLH manifestations could be identified that is defined by the genetically determined residual lytic activity of cytotoxic T lymphocytes (CTL) and their ability to control lymphocytic choriomeningitis virus, which was used as a trigger for disease induction. Importantly, analysis of cohorts of HLH patients with severe bi-allelic mutations in the corresponding genes yielded a similar severity gradient in human HLH as reflected by the age at disease onset. Our findings define HLH as a threshold disease determined by subtle differences in the residual lytic activity of CTL.
Frontiers in Immunology 12/2013; 4:448. DOI:10.3389/fimmu.2013.00448
[Show abstract][Hide abstract] ABSTRACT: Humans and mice with impaired perforin-dependent cytotoxic function may develop excessive T cell activation and the fatal disorder, hemophagocytic lymphohistiocytosis (HLH), after infection. Though cytotoxic lymphocytes can kill antigen presenting cells, the physiologic mechanism of perforin-mediated immune regulation has never been demonstrated in a disease-relevant context. We utilized a murine model of HLH to examine how perforin controls immune activation and have defined a feedback loop which is critical for immune homeostasis. This endogenous feedback loop involves perforin-dependent elimination of rare, antigen-presenting dendritic cells (DC's) by CD8+ T cells, and has a dominant influence on the magnitude of T cell activation after viral infection. Antigen presentation by a minor fraction of DC's persisted in T cell or perforin deficient animals and continued to drive T cell activation well beyond initial priming in the latter animals. Depletion of DC's or transfer of perforin sufficient T cells dampened endogenous DC antigen presentation and T cell activation, demonstrating a reciprocal relationship between perforin in CD8+ T cells and DC function. Thus, selective cytotoxic 'pruning' of DC populations by CD8+ T cells limits T cell activation and protects against the development of HLH and potentially other immunopathologic conditions.
[Show abstract][Hide abstract] ABSTRACT: Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, maintains lifelong subclinical persistent infections in humans. In the circulation, EBV primarily infects the B cells, and protective immunity is mediated by EBV-specific cytotoxic T cells (CTLs) and natural killer (NK) cells. However, EBV has been linked to several devastating diseases, such as haemophagocytic lymphohistiocytosis (HLH) and lymphoproliferative diseases in the immunocompromised host. Some types of primary immunodeficiencies (PIDs) are characterized by the development of EBV-associated complications as their predominant clinical feature. The study of such genetic diseases presents an ideal opportunity for a better understanding of the biology of the immune responses against EBV. Here, we summarize the range of PIDs that are predisposed to EBV-associated haematological diseases, describing their clinical picture and pathogenetic mechanisms.
British Journal of Haematology 06/2013; 162(5). DOI:10.1111/bjh.12422 · 4.71 Impact Factor
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