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Research paper thumbnail of The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis

Haematologica, Jan 28, 2015

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and labora... more Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. This includes patients with primary immunodeficiencies, in whom pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistio...

Research paper thumbnail of Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency

Blood, Jan 7, 2014

Accumulation of CD3(+) T-cell receptor (TCR)αβ(+)CD4(-)CD8(-) double-negative T cells (DNT) is a ... more Accumulation of CD3(+) T-cell receptor (TCR)αβ(+)CD4(-)CD8(-) double-negative T cells (DNT) is a hallmark of autoimmune lymphoproliferative syndrome (ALPS). DNT origin and differentiation pathways remain controversial. Here we show that human ALPS DNT have features of terminally differentiated effector memory T cells reexpressing CD45RA(+) (TEMRA), but are CD27(+)CD28(+)KLRG1(-) and do not express the transcription factor T-bet. This unique phenotype was also detected among CD4(+) or CD8(+) ALPS TEMRA cells. T-cell receptor β deep sequencing revealed a significant fraction of shared CDR3 sequences between ALPS DNT and both CD4(+) and CD8(+)TEMRA cells. Moreover, in ALPS patients with a germ line FAS mutation and somatic loss of heterozygosity, in whom biallelic mutant cells can be tracked by absent Fas expression, Fas-negative T cells accumulated not only among DNT, but also among CD4(+) and CD8(+)TEMRA cells. These data indicate that in human Fas deficiency DNT cannot only derive f...

Research paper thumbnail of Late-onset hemophagocytic lymphohistiocytosis (HLH) in an adult female with Griscelli syndrome type 2 (GS2)

Annals of Hematology, 2014

Research paper thumbnail of Novel Patient with Late-Onset Familial Hemophagocytic Lymphohistiocytosis with STXBP2 Mutations Presenting with Autoimmune Hepatitis, Neurological Manifestations and Infections Associated with Hypogammaglobulinemia

Journal of Clinical Immunology, 2014

Research paper thumbnail of First characterization of platelet secretion defect in patients with familial hemophagocytic lymphohistiocytosis type 3 (FHL-3)

Research paper thumbnail of The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2

Blood, 2013

Genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocy... more Genetic disorders of lymphocyte cytotoxicity predispose patients 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. Because 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. After infection with lymphocytic choriomeningitis virus, 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 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. HPS2 confers a risk for HLH that is lower than in Griscelli or Chediak-Higashi syndrome, probably because of a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.

Research paper thumbnail of β2-Microglobulin deficiency causes a complex immunodeficiency of the innate and adaptive immune system

Journal of Allergy and Clinical Immunology, 2015

Research paper thumbnail of The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis

Haematologica, Jan 28, 2015

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and labora... more Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. This includes patients with primary immunodeficiencies, in whom pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistio...

Research paper thumbnail of Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency

Blood, Jan 7, 2014

Accumulation of CD3(+) T-cell receptor (TCR)αβ(+)CD4(-)CD8(-) double-negative T cells (DNT) is a ... more Accumulation of CD3(+) T-cell receptor (TCR)αβ(+)CD4(-)CD8(-) double-negative T cells (DNT) is a hallmark of autoimmune lymphoproliferative syndrome (ALPS). DNT origin and differentiation pathways remain controversial. Here we show that human ALPS DNT have features of terminally differentiated effector memory T cells reexpressing CD45RA(+) (TEMRA), but are CD27(+)CD28(+)KLRG1(-) and do not express the transcription factor T-bet. This unique phenotype was also detected among CD4(+) or CD8(+) ALPS TEMRA cells. T-cell receptor β deep sequencing revealed a significant fraction of shared CDR3 sequences between ALPS DNT and both CD4(+) and CD8(+)TEMRA cells. Moreover, in ALPS patients with a germ line FAS mutation and somatic loss of heterozygosity, in whom biallelic mutant cells can be tracked by absent Fas expression, Fas-negative T cells accumulated not only among DNT, but also among CD4(+) and CD8(+)TEMRA cells. These data indicate that in human Fas deficiency DNT cannot only derive f...

Research paper thumbnail of Late-onset hemophagocytic lymphohistiocytosis (HLH) in an adult female with Griscelli syndrome type 2 (GS2)

Annals of Hematology, 2014

Research paper thumbnail of Novel Patient with Late-Onset Familial Hemophagocytic Lymphohistiocytosis with STXBP2 Mutations Presenting with Autoimmune Hepatitis, Neurological Manifestations and Infections Associated with Hypogammaglobulinemia

Journal of Clinical Immunology, 2014

Research paper thumbnail of First characterization of platelet secretion defect in patients with familial hemophagocytic lymphohistiocytosis type 3 (FHL-3)

Research paper thumbnail of The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2

Blood, 2013

Genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocy... more Genetic disorders of lymphocyte cytotoxicity predispose patients 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. Because 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. After infection with lymphocytic choriomeningitis virus, 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 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. HPS2 confers a risk for HLH that is lower than in Griscelli or Chediak-Higashi syndrome, probably because of a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.

Research paper thumbnail of β2-Microglobulin deficiency causes a complex immunodeficiency of the innate and adaptive immune system

Journal of Allergy and Clinical Immunology, 2015

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