The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2.
ABSTRACT 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.
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ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) covers a wide array of related life-threatening conditions featuring ineffective immunity characterized by an uncontrolled hyperinflammatory response. HLH is often triggered by infection. Familial forms result from genetic defects in natural killer cells and cytotoxic T-cells, typically affecting perforin and intracellular vesicles. HLH is likely under-recognized, which contributes to its high morbidity and mortality. Early recognition is crucial for any reasonable attempt at curative therapy to be made. Current treatment regimens include immunosuppression, immune modulation, chemotherapy, and biological response modification, followed by hematopoietic stem-cell transplant (bone marrow transplant). A number of recent studies have contributed to the understanding of HLH pathophysiology, leading to alternate treatment options; however, much work remains to raise awareness and improve the high morbidity and mortality of these complex conditions.Hematology Research and Reviews 01/2014; 5:69-86. DOI:10.2147/JBM.S46255
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ABSTRACT: Macrophage activation syndrome is the rheumatic disease-associated member of a group of hyperinflammatory syndromes characterized by uncontrolled cytokine storm. In this review, we highlight recent publications related to the pathoetiology of hyperinflammatory syndromes with an emphasis on how this new knowledge will guide our diagnosis, treatment, and future research efforts to better understand these deadly conditions.Current Opinion in Rheumatology 07/2014; DOI:10.1097/BOR.0000000000000093 · 5.07 Impact Factor
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ABSTRACT: Adaptor protein-3 (AP-3) is a heterotetrameric complex, which regulates vesicular trafficking. Mutations of the b3A subunit cause the Hermansky–Pudlak syndrome type 2 (HPS-2), a rare genetic disease characterized byalbinism, platelet defects, and recurrent infections. Likewise, pearl mice, which lack functional AP-3, show several HPS-2 defects. The AP-3 absence results in defective TLR trafficking and signaling in dendritic cells (DC), but its effect on the efficiency of the in vivo antiviral response is unclear. We evaluated the impact of AP-3 deficiency on the distribution of DC subsets, interferon (IFN) production, and the susceptibility to murine cytomegalovirus (MCMV) infection. Pearl mice showed a distribution and frequency of conventional (cDC) and plasmacytoid DC (pDC) similar to that of wild-type mice both before and afterMCMV infection.Moreover, pearl mice controlled MCMV infection even at high virus doses and showed a normal production of IFN-a. Since pDC, but not cDC, from pearl mice showed an impaired IFN-a and tumor necrosis factor-a production in response to prototypic DNA (MCMV and Herpes Simplex virus) or RNA (Vesicular Stomatitis virus) viruses in vitro, it is likely that MCMV infection can be controlled in vivo independently of an efficient production of IFN-a by pDC, and that the AP-3 complex has a minimal impact on protective antiviral responses.Journal of Interferon & Cytokine Research 03/2015; 35(3):232-238. DOI:10.1089/jir.2013.0110 · 3.90 Impact Factor