Hemophagocytic lymphohistiocytosis: Overview and diagnostic procedure. A case induced by anexpansion of monoclonal EBV-negative NK cells

Las causas más comunes de linfohistiocitosis hemofagocítica (HLH) sonexpansiones 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 decélulas 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 unamutación de nueva descripción en RAB27A, con albinismo parcial, fiebre persistente, hepatoesplenomegalia, adenopatías y citopenias al diagnóstico. Nose 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 manteníanintacta su actividad asesina y secretaban grandes cantidades de IFN-γ. Aldiagnóstico 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 deIFN-γ como la causa más probable del episodio de HLH en una paciente conGS2. Tras el trasplante de médula ósea de su hermana HLA-idéntica, las cifrasy el fenotipo de las células NK recobraron la normalidad (AU)

Clonal natural killer (NK) and T cell expansions induced by EpsteinBarr virus (EBV) and genetic alterations compromising NK cell killing arethe most common causes of hemophagocytic lymphohistocytosis (HLH).Generally, HLH is induced by an immune dysfunction where hypercytokinemia develops into reactive hemophagocytosis. In this work wereview the causes of HLH and describe a case of a monoclonal expansionof EBV-negative NK cells associated to HLH in a seventeen-month-oldgirl 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/µland progressively increased to pre-therapy levels by week 28. X-chromosome inactivation assay demonstrated NK cell monoclonality. NK cellssustained 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) wereelevated. In conclusion, we describe a monoclonal expansion of EBV-negative NK cells highly secretory of IFN-γ as the most probable cause of HLHepisode in a patient with Griscelli syndrome type-2. NK cell count recovered normal levels and phenotype after bone marrow transplantationfrom her HLA identical sister (AU)

Impact of recipient HLA-C in liver transplant: a protective effect of HLA-Cw*07 on acute rejection.

The involvement of the human leukocyte antigen (HLA) in liver graft acceptance is controversial, but the frequency of acute rejection (AR) remains high in spite of the use of the modern immunosuppressive agents. The present study was aimed at determining whether an association exists between liver recipient HLA-C polymorphism and AR development that could influence graft acceptance. Four hundred and forty-six liver recipients and 473 controls were studied within the framework of a collaborative study carried out by the Spanish Transplant Immunotolerance Group (RED-GIT). HLA-A and -B were typed by the standard microlymphocytotoxicity technique, and HLA-C by polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP). A statistically significant decrease in the HLA-Cw*07 allele frequency was found in liver recipients suffering AR episodes compared to those without AR (NAR). Studies regarding the possible influence of the Asn80 and Lys80 epitopes showed that the Asn80 epitope also could be associated with AR. However, further analysis considering Asn80 alleles others than HLA-Cw*07, confirmed that the apparent protective effect of the Asn80 epitope was actually from the HLA-Cw*07 allele. In conclusion, the HLA-Cw*07 allele carried by the liver recipient is negatively associated with AR development, and could be considered a predictive factor for liver graft acceptance.

TGF-beta1 gene polymorphism in liver graft recipients.

Cytokines are known to be important mediators during liver graft outcome and their gene polymorphism could affect the overall expression and secretion of cytokines. In this retrospective study, we analyzed the effect of TGF-beta1 polymorphism in 150 liver allograft recipients. Genotyping PCR-SSP were performed for TGF-beta1 gene (codon 10T/C and 25C/G). TGF-beta1 polymorphism at codon 10 and 25 correlate borderline with liver graft acceptance and when the combination between codon 10 and 25 was analyzed, it revealed that T/T G/C genotype and the TC haplotype were significantly associated with graft acceptance (p<0.05). TGF-beta1 high secretor phenotype was also increased in the acute rejection group close to significance (p=0.06). In conclusion, these findings show a correlation between TGF-beta1 gene polymorphism and liver graft acceptance.