Fighting autoinflammation in FIRES: The role of interleukins and early immunomodulation

Febrile infection-related epilepsy syndrome (FIRES) is a challenging condition with unfavorable outcome in most cases. Preliminary evidence suggests that some interleukins, in particular IL-1 Receptor Antagonist (IL-1RA), could be elevated due to a functional deficiency of anti-inflammatory pathways. Therefore, treatment strategies acting on innate immunity could represent a targeted treatment. We describe the case of an 11-year-old child with super-refractory status epilepticus (SE), lasting more than two months. After being treated aggressively with antiseizure medications, anesthetics and empiric treatment for autoimmune encephalitis without success, she responded to anakinra and ketogenic diet. Escalation of the therapy was supported by the finding of a very high serum level of IL-1RA. This immunomodulatory approach allowed to discharge the child from intensive care 48 days after the SE onset. After more than one year follow-up the patient has moderate intellectual disability but with good language skills; she is seizure free and without motor deficits. This case suggests that serum IL-1RA serum levels may help to support treatment escalation. Moreover, anakinra and ketogenic diet represent encouraging immunomodulatory strategies which deserve further studies and could potentially have a synergistic effect. Finally, structured neuropsychological testing is an important outcome measure that will help to define the effectiveness of different treatment strategies

Most cleaved anti-müllerian hormone binds its receptor in human follicular fluid but little is competent in serum

Context: Anti-Müllerian hormone (AMH) is an important clinical marker for diagnosing and assessing the reproductive status and/or disorders in men and women. Most studies have not distinguished between levels of inactive AMH precursor and the cleaved noncovalent complex that binds the AMH type II receptor (AMHRII) and initiates signaling. Objective: The objective of the study was to measure the levels of AMH cleavage and bioactivity in human body fluids. Design, Setting, and Patients: AMH cleavage levels and bioactivity were measured in the serum of six boys and in the follicular fluid and serum of nine control women and 13 women with the polycystic ovary syndrome (PCOS). Main Outcome Measures: AMH cleavage levels were measured by capturing AMH with an anti- AMH antibody, followed by Western blotting. The bioactivity of cleaved AMH was assessed with an ELISA that measures the levels of AMH capable of binding AMHRII. Results: PCOS women have an elevated level of AMH cleavage in their follicular fluid (24% vs 8% in controlwomen),andmostofthecleavedAMHcanbindAMHRII.Higherlevels of cleavage areobserved in female (60%) and male (79%) serum, but very little of the cleaved AMH can bind AMHRII. Conclusions: These results support an autocrine role for AMH in the pathophysiology of PCOS in the follicle. In addition,theyindicate thatAMHundergoesinteractions or structuralchangesaftercleavage that prevent receptor binding, meaning, unexpectedly, that the level of cleaved AMH in biological fluids does not always reflect the level of bioactive AMH.Fil: Pierre, Alice. Inserm; Francia. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaFil: Racine, Chrystèle. Inserm; Francia. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaFil: Rey, Rodolfo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Fanchin, Renato. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaFil: Taieb, Joëlle. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaFil: Cohen Tannoudji, Joëlle. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaFil: Carmillo, Paul. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Pepinsky, R. Blake. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Cate, Richard L.. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaFil: Di Clemente, Nathalie. Inserm; Francia. Université Paris Diderot - Paris 7; Francia. Centre National de la Recherche Scientifique; Franci

Potential role of OERP as early marker of Mild Cognitive Impairment

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Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta.

International audienceTGF-β family ligands are translated as prepropeptide precursors and are processed into mature C-terminal dimers that signal by assembling a serine/threonine kinase receptor complex containing type I and II components. Many TGF-β ligands are secreted in a latent form that cannot bind their receptor, due to the pro-region remaining associated with the mature ligand in a noncovalent complex after proteolytic cleavage. Here we show that anti-Müllerian hormone (AMH), a TGF-β family ligand involved in reproductive development, must be cleaved to bind its type II receptor (AMHRII), but dissociation of the pro-region from the mature C-terminal dimer is not required for this initial interaction. We provide direct evidence for this interaction by showing that the noncovalent complex binds to a soluble form of AMHRII in an ELISA format and to AMHRII immobilized on Sepharose. Binding of the noncovalent complex to Sepharose-coupled AMHRII induces dissociation of the pro-region from the mature C-terminal dimer, whereas no dissociation occurs after binding to immobilized AMH antibodies. The pro-region cannot be detected after binding of the AMH noncovalent complex to AMHRII expressed on COS cells, indicating that pro-region dissociation may occur as a natural consequence of receptor engagement on cells. Moreover, the mature C-terminal dimer is more active than the noncovalent complex in stimulating Sma- and Mad-related protein activation, suggesting that pro-region dissociation contributes to the assembly of the active receptor complex. AMH thus exemplifies a new mechanism for receptor engagement in which interaction with the type II receptor promotes pro-region dissociation to generate mature ligand

Sequencing and Analysis of JC Virus DNA From Natalizumab-Treated PML Patients

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients is linked to JC virus (JCV) infection. JCV sequence variation and rearrangements influence viral pathogenicity and tropism. To better understand PML development, we analyzed viral DNA sequences in blood, CSF and/or urine of natalizumab-treated PML patients. METHODS: Using biofluid samples from 17 natalizumab-treated PML patients, we sequenced multiple isolates of the JCV noncoding control region (NCCR), VP1 capsid coding region, and the entire 5 kb viral genome. RESULTS: Analysis of JCV from multiple biofluids revealed that individuals were infected with a single genotype. Across our patient cohort, multiple PML-associated NCCR rearrangements and VP1 mutations were present in CSF and blood, but absent from urine-derived virus. NCCR rearrangements occurred in CSF of 100% of our cohort. VP1 mutations were observed in blood or CSF in 81% of patients. Sequencing of complete JCV genomes demonstrated that NCCR rearrangements could occur without VP1 mutations, but VP1 mutations were not observed without NCCR rearrangement. CONCLUSIONS: These data confirm that JCV in natalizumab-PML patients is similar to that observed in other PML patient groups, multiple genotypes are associated with PML, individual patients appear to be infected with a single genotype, and PML-associated mutations arise in patients during PML development