Type I interferon-mediated autoinflammation due to DNase II deficiency

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans

Caractérisation des plasmocytes médullaires par cytométrie de flux 8 couleurs dans les gammapathies monoclonales

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Intérêt diagnostique et pronostique de la cytométrie en flux multiparamétrique 8 couleurs dans la prise en charge du myélome

Objectif: Evaluer l intérêt diagnostique et pronostique de la cytométrie en flux (CMF) multiparamétrique dans la prise en charge du myélome (MM). Patients et méthodes: Nous avons analysé les marqueurs antigéniques CD38, CD138, CD45, CD56, CD19, CD20, CD24, CD28, CD117, c-kappa, c-lambda et b2-microglobuline par CMF 8 couleurs sur les plasmocytes médullaires de patients atteints de MM et MGUS. Pour une évaluation rapide de la t(4 ;14), l expression protéique de FGFR3 a été étudiée par CMF et corrélée à l expression des transcrits FGFR3 et IGH/MMSET. Résultats: Nos résultats montrent que l immunophénotypage des plasmocytes par CMF s intègre facilement aux pratiques courantes d un laboratoire d hématologie. La caractérisation et la quantification précise des plasmocytes anormaux sont utiles au diagnostic de MM. Par ailleurs, FGFR3 et la b2-microglobuline membranaire représentent des marqueurs pronostiques intéressants. Pour le dépistage de la t(4 ;14), les résultats obtenus en biologie moléculaire et CMF sont le plus souvent concordants, suggérant une utilisation de la CMF pour détecter une surexpression de FGFR3 et l utilisation complémentaire de la PCR en temps réel sur les cellules mononucléées médullaires pour déceler les cas de t(4 ;14)+ sans surexpression de FGFR3. Conclusion: Bien que l immunophénotypage par CMF soit indispensable dans la prise en charge des hémopathies malignes, il n est pas couramment réalisé dans celle du MM. Son intérêt clinique est pourtant clairement établi pour le diagnostic, le pronostic et le suivi de la maladie résiduelle du MM.Purpose: To analyse the diagnostic and prognostic utility of multiparameter flow cytometry (MFC) for the management of patients with multiple myeloma (MM). Patients and methods: We have analysed the antigenic markers CD38, CD138, CD45, CD56, CD19, CD20, CD24, CD28, CD117, c-kappa, c-lambda and b2-microglobulin, assessed by 8-colours MFC, on plasma cells from MM and MGUS patients. For a rapid assessment of the t(4;14), plasma cells were studied by MFC to detect FGFR3 protein expression and results were compared to real-time PCR of the FGFR3 and IGH/MMSET transcripts. Results: Our results show that MFC immunophenotyping of plasma cells can be easily applied in haematology laboratories. Characterization and enumeration of aberrant plasma cells are useful for diagnosis of MM. b2-microglobulin and FGFR3 assessed by MFC could represent interesting prognostic markers. Results obtained by MFC and real time PCR are correlated and suggest that MFC can detect FGFR3 expression on plasma cells and FGFR3 and IGH/MMSET transcripts can be analysed on bone marrow mononuclear cells. Conclusion: Although MFC immunophenotyping is mandatory in the clinical management of haematological malignancies, it is not routinely applied for MM. However, MFC immunophenotyping has an obvious clinical relevance in diagnosis, prognostic and minimal residual disease monitoring of MM.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Adult T-Cell Leukemia/Lymphoma in a Caucasian Patient After Sexual Transmission of Human T-Cell Lymphotropic Virus Type 1.

International audienceAdult T-cell leukemia/lymphoma (ATLL), a T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1), develops in the majority of cases in individuals who were infected with HTLV-1 as young children, by their mother during prolonged breastfeeding. We report the case of a Caucasian French man, whose parents were HTLV-1-seronegative and who developed ATLL after HTLV-1 sexual transmission by a Cameroonian woman. This hypothesis was corroborated by genotyping of the patient's virus, which revealed an HTLV-1B strain, found only in Central Africa, especially in Cameroon. Thus, ATLL may develop after HTLV-1 infection during adulthood, outside breastfeeding

A French National Survey on Clotting Disorders in Mastocytosis.

Mastocytosis is characterized by a clonal mast cell proliferation with organ infiltration and uncontrolled degranulation. Although not characteristic and poorly explained, some patients develop clotting abnormalities. We retrospectively identified patients with established diagnosis of mastocytosis and related clotting abnormalities (clinical and/or biological) using the national French Reference Centre for Mastocytosis database. From our cohort of 14 adult patients with clotting abnormalities (median age 46 years [range 26-75]), 4 had a presentation suggestive of a primary hemostasis disorder alone (by their symptoms and/or abnormal clotting tests [PFA, von Willebrand's disease [vWD] screening]) and 10 had a laboratory impairment of secondary hemostasis. Among these, 7 had bleeds characteristic of a coagulation cascade disorder (severe/life-threatening in 5 and mild in 2 patients). Clotting abnormalities were of variable severity, typically related to intense crisis of degranulation, such as anaphylactic reactions, and/or to severe organ infiltration by mast cells. Importantly, classical hemostatic management with platelet transfusion, fresh frozen plasma, or vitamin K infusions was unsuccessful, as opposed to the use of agents inhibiting mast cell activity, particularly steroids. This illustrates the crucial role of mast cell mediators such as tryptase and heparin, which interfere both with primary (mainly via inhibition of von Willebrand factor) and secondary hemostasis. There was interestingly an unusually high number of aggressive mastocytosis (particularly mast cell leukemia) and increased mortality in the group with secondary hemostasis disorders (n = 5, 36% of the whole cohort). Mast cell degranulation and/or high tumoral burden induce both specific biologic antiaggregant and anticoagulant states with a wide clinical spectrum ranging from asymptomatic to life-threatening bleeds. Hemostatic control is achieved by mast cell inhibitors such as steroids

Perls' Stain Guidelines from the French-Speaking Cellular Hematology Group (GFHC).

In order to standardize cellular hematology practices, the French-speaking Cellular Hematology Group (Groupe Francophone d'Hématologie Cellulaire, GFHC) focused on Perls' stain. A national survey was carried out, leading to the proposal of recommendations on insoluble iron detection and quantification in bone marrow. The criteria presented here met with a "strong professional agreement" and follow the suggestions of the World Health Organization's classification of hematological malignancies

X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene

BACKGROUND: We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. OBJECTIVE: We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. METHODS: We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. RESULTS: We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8(+) T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. CONCLUSION: Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency