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    ABSTRACT: Clonal natural killer (NK) and T cell expansions induced by Epstein- Barr virus (EBV) and genetic alterations compromising NK cell killing are the most common causes of hemophagocytic lymphohistocytosis (HLH). Generally, HLH is induced by an immune dysfunction where hypercytokinemia develops into reactive hemophagocytosis. In this work we review the causes of HLH and describe a case of a monoclonal expansion of EBV-negative NK cells associated to HLH in a seventeen-month-old girl suffering of Griscelli syndrome type-2 with novel RAB27A mutation and showing partial albinism, persistent fever, hepatosplenomegaly, adenopaties and cytopenias. At diagnosis, no evidence of active viral infections, including EBV, was found. Expansion of NK cells (5300/μl in peripheral blood) CD2+CD7+CD8+CD16+CD56+CD94+CD158a/h+CD158b/j–Perforin+ Granzyme B+ was found. After treatment (HLH-2004 protocol: Cyclosporin, Etoposide and Dexamethasone), NK cell count fell to 850/μl and progressively increased to pre-therapy levels by week 28. X-chromosome inactivation assay demonstrated NK cell monoclonality. NK cells sustained a strong killing and secreted high amounts of IFN-γ. At diagnosis, serum levels of sIL-2R (36,8 ng/ml) and IFN-γ (400 pg/ml) were elevated. In conclusion, we describe a monoclonal expansion of EBV-negative NK cells highly secretory of IFN-γ as the most probable cause of HLH episode in a patient with Griscelli syndrome type-2. NK cell count recovered normal levels and phenotype after bone marrow transplantation from her HLA identical sister.ResumenLas causas más comunes de linfohistiocitosis hemofagocítica (HLH) son expansiones clonales de células NK y T, inducidas por EBV, así como las alteraciones genéticas que comprometen la actividad asesina de las NKs. Generalmente, HLH se desencadena por una disfunción inmune en la que se desarrolla hipercitoquinemia. En este trabajo se resumen las causas más comunes de HLH y se presenta un caso en el que una expansión monoclonal de células NK, EBV-negativas, se asocia a HLH en una paciente aquejada de Síndrome de Griscelli tipo-2 (GS2). Se trata de una niña de 17 meses con una mutación de nueva descripción en RAB27A, con albinismo parcial, fiebre persistente, hepatoesplenomegalia, adenopatías y citopenias al diagnóstico. No se detectaron evidencias de infecciones virales activas, incluida EBV. Se detectó una expansión de células NKs (5300/μl) CD2+CD7+CD8+CD16+CD56+ CD94+CD158a/h+CD158b/j–Perforin+Granzyme-B+. Tras el tratamiento (Protocolo HLH-2004: Cyclosporina, Etoposido y Dexametasona), la cifra de células NK se redujo a 850/μl y que aumentaron progresivamente hasta alcanzar niveles similares al diagnóstico. El ensayo de inactivación del cromosoma X demostró monoclonalidad de células NK. Dichas células mantenían intacta su actividad asesina y secretaban grandes cantidades de IFN-γ. Al diagnóstico los niveles séricos de sIL-2R (36.8 ng/ml) e IFN-γ (400 pg/ml) estaban elevados. En conclusión, se describe un caso de una expansión monoclonal de células NK, EBV-negativas, que secretan grandes cantidades de IFN-γ como la causa más probable del episodio de HLH en una paciente con GS2. Tras el trasplante de médula ósea de su hermana HLA-idéntica, las cifras y el fenotipo de las células NK recobraron la normalidad.
    Inmunologia 07/2009; 28(3):135–146. DOI:10.1016/S0213-9626(09)70037-X
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    ABSTRACT: Hemophagocytic lymphohistiocytosis is a multisystem inflammation, generated by the uncontrolled and excessive activation of cytotoxic T lymphocytes and natural killer cells. Severe immunodeficiency and generalized macrophage activation can often be detected in the background of this life threatening disorder. It is classified as a primary immunodeficiency. Functional abnormalities of the perforin protein or defects in granule secretory mechanisms are caused by gene mutations in most cases. Diagnostic criteria of hemophagocytic lymphohistiocytosis are the following: fever, splenomegaly, cytopenias affecting at least two of the 3 lineages in peripheral blood, hypertriglyceridemia and hyperferritinemia, elevated serum level of soluble interleukin-2 receptor (sCD25), hypofibrinogenemia, hemophagocytosis in bone marrow and decreased cytotoxic T cell and natural killer cell activity. In this case report the authors summarize the utility of functional flow cytometry in the diagnosis of hemophagocytic lymphohistiocytosis. Using flow cytometry, elevated intracellular perforin content, decreased killing activity of cytotoxic T cells and natural killer cells, and impaired cell surface expression of CD107a (LAMP1 protein) from in vitro stimulated blood lymphocytes were detected. Abnormal secretion of perforin was also demonstrated. Genetic testing revealed mutation of the MUNC 13-4 gene, which confirmed the base of the abnormal flow cytometric findings. This case report demonstrates the value of functional flow cytometry in the rapid diagnosis of genetically determined hemophagocytic lymphohistiocytosis, a condition in which early diagnosis is critical for optimal management. The authors emphasize the significance of functional flow cytometry in the differential diagnosis of immunodeficiencies. Orv. Hetil., 2014, 155(10), 389-395.
    Orvosi Hetilap 03/2014; 155(10):389-95. DOI:10.1556/OH.2014.29790
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