Hereditary C1 inhibitor deficiency is associated with high spontaneous amidase activity

International audiencefunction and antigenic C4 level) and contact phase activation (via amidase activity). Bradykinin is respon-sible for angioedema attacks and is produced from contact phase activation secondary to failed C1Inhcontrol.Objective: We aimed to compare the diagnostic performances of spontaneous amidase activity and anti-genic C4 level in C1Inh hereditary angioedema (C1Inh-HAE) patients.Methods: Samples from 185 C1Inh-HAE patients (81 men, 104 women; confirmed by SERPING1 genemutations) and from 99 blood donors (50 men, 49 women) were tested for C1Inh function, antigenic C4level and spontaneous amidase activity.Results: In the C1Inh-HAE group, antigenic C4 level was decreased (n = 135) and amidase activity wasincreased (n = 181). Receiver operating characteristic analyses showed higher diagnostic performancevalues for the spontaneous amidase assay compared to those of antigenic C4.Conclusion: The spontaneous amidase activity assay should replace antigenic C4 level testing and shouldbe tested alongside the C1Inh function for both AE screening and follow up of HAE patients

Classification and biological diagnostic of angioedema diseases

International audienceThe angioedema disease represents a situation associated with production or accumulation of kinins at the endothelial cell surface. A classification of the different forms of the disease can be proposed upon the bases of the metabolic failure, either from the increased proteolytic activities towards kininogens (decreased control by C1 Inhibitor, escape to this control) or from the kinin accumulation associated with the decreased catabolism. The diagnostic must describe the failure of the C1 Inhibitor control, the gain of function of the kinin-producing kininogenases or the decreased activities of the proteases needed for kinin catabolism (kininases)

Classification et diagnostic biologique des angioedèmes

National audienceThe angioedema disease represents a situation associated with production or accumulation of kinins at the endothelial cell surface. A classification of the different forms of the disease can be proposed upon the bases of the metabolic failure, either from the increased proteolytic activities towards kininogens (decreased control by C1 Inhibitor, escape to this control) or from the kinin accumulation associated with the decreased catabolism. The diagnostic must describe the failure of the C1 Inhibitor control, the gain of function of the kinin-producing kininogenases or the decreased activities of the proteases needed for kinin catabolism (kininases)

Classification et diagnostic biologique des angioedèmes

National audienceThe angioedema disease represents a situation associated with production or accumulation of kinins at the endothelial cell surface. A classification of the different forms of the disease can be proposed upon the bases of the metabolic failure, either from the increased proteolytic activities towards kininogens (decreased control by C1 Inhibitor, escape to this control) or from the kinin accumulation associated with the decreased catabolism. The diagnostic must describe the failure of the C1 Inhibitor control, the gain of function of the kinin-producing kininogenases or the decreased activities of the proteases needed for kinin catabolism (kininases)

Syndrome de Sneddon avec anticorps anti-mitochondries de type M5

International audienceAntimitochondrial type M5 antibodies (AMA-M5) are among the immunological abnormalities associated with Sneddon syndrome. Case A 45 year-old woman, hospitalized for diplopia and with a 20-year history of obstetrical accidents, internuclear ophthalmoplegia and livedo, was diagnosed with Sneddon syndrome associated with primary antiphospholipid syndrome (APS) aggravated by the presence of AMA-M5. Discussion AMA-M5 are immunological markers of APS to the same extent as antiphospholipid antibodies. This case demonstrates the interest of screening for AMA-M5 in cases of strong clinical suspicion of APS when the anticoagulant lupus test is normal and no anti-cardiolipin, anti-b2 glycoprotein I or antiprothrombin antibodies are found

Acylation of the lipid a region of a Klebsiella pneumoniae LPS controls the alternative pathway activation of human complement

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Phospholipase A2 Receptor–Related Membranous Nephropathy and Mannan-Binding Lectin Deficiency

International audienceMost patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against phospholipase A2 receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2

Characterisation of a new C1 inhibitor mutant in a patient with hepatocellular carcinoma.

International audienceA patient developed the first case of hepatocarcinoma associated with hereditary angioedema within the context of a 13-year long prophylactic danazol exposure. We sought to identify the molecular defect and to test the relative contribution to the development of hepatocarcinoma of intracellular accumulation of abnormal C1 inhibitor (C1-INH) protein. The de novo mutation c.878_881delTCTA was identified, leading to a premature stop codon. Monocyte C1-INH secretions of the patient and of her affected daughter were, respectively, 26 and 18% compared to controls. Mutant transcripts compatible with the 4bp deletion were detectable as a faint RT-PCR product both in interferon-stimulated monocytes and in liver tissue, whereas total C1-INH mRNA was found nearly half the amount recovered from normal subjects. In order to study the consequences at the protein level of the low expression of the mutant allele, we analysed the intracellular fate of mutant products. COS-7 cells were transiently transfected with a C1-INH expression minigene encoding the mutant protein. In pulse-chase experiments, a faint 75,000-M(r) band was detected only within 10min. Both the c.878_881delTCTA mutant transcript and the intracellular abnormal C1-INH protein are unstable. Our data therefore rule out the hypothesis of an accumulation of the mutant protein at levels relevant for the pathology and strengthen the link between the development of hepatocarcinoma and danazol exposure