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Primary hemophagocytic lymphohistiocytosis, a rare genetic immune disorder characterized by hyperinflammation, manifests in infancy and is associated with high mortality. In a study involving 34 children, an antibody to interferon-γ (emapalumab) produced responses in 65%; it served as a bridge to marrow transplantation in 70% of those who had received previous treatment.

ObjectivesMacrophage activation syndrome (MAS) is a severe, life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD). The objective of this study was to confirm the adequacy of an emapalumab dosing regimen in relation to interferon-γ (IFNγ) activity by assessing efficacy and safety. The efficacy outcome was MAS remission by week 8, based on clinical and laboratory criteria.MethodsWe studied emapalumab, a human anti-IFNγ antibody, administered with background glucocorticoids, in a prospective single-arm trial involving patients who had MAS secondary to sJIA or AOSD and had previously failed high-dose glucocorticoids, with or without anakinra and/or ciclosporin. The study foresaw 4-week treatment that could be shortened or prolonged based on investigator’s assessment of response. Patients entered a long-term (12 months) follow-up study.ResultsFourteen patients received emapalumab. All patients completed the trial, entered the long-term follow-up and were alive at the end of follow-up. The investigated dosing regimen, based on an initial loading dose followed by maintenance doses, was appropriate, as shown by rapid neutralisation of IFNγ activity, demonstrated by a prompt decrease in serum C-X-C motif chemokine ligand 9 (CXCL9) levels. By week 8, MAS remission was achieved in 13 of the 14 patients at a median time of 25 days. Viral infections and positive viral tests were observed.ConclusionsNeutralisation of IFNγ with emapalumab was efficacious in inducing remission of MAS secondary to sJIA or AOSD in patients who had failed high-dose glucocorticoids. Screening for viral infections should be performed, particularly for cytomegalovirus.Trial registration number NCT02069899 and NCT03311854.

Abdominal wall endometriosis (AWE) within the scar of a trocar insertion is seldom reported as a complication of laparoscopy. We describe the case of a 46 year-old woman suffering from uterine leiomyomas who underwent laparoscopic hysterectomy. One year later, she developed a painful abdominal wall mass, beneath the scar of suprapubic port-site trocar insertion. The diagnostic work-up, consisting in ultrasonography, magnetic resonance imaging and needle biopsy led to a diagnosis of AWE. Initially, a progestogen therapy was administered, obtaining relief from pain symptoms but insignificant reduction of lump’ size. Therefore, the patient underwent a laparotomic resection of the mass. Pathologic findings showed endometriotic tissue mixed with smooth muscle cells, leading to the diagnosis of extrauterine adenomyoma. Six months after surgery, neither AWE relapse nor incisional hernia was found. To our knowledge, no case of parasitic adenomyoma development in a trocar scar following a laparoscopy has been described before in literature.

Clinical evidence suggestive of a nonpituitary regulation of thyroid homeostasis in pregnancy seems to indicate that the placenta may function as an integrated control system, responding to feedback signals both from the fetal and the maternal compartments. This putative placental control system may be postulated to fulfill the critical role of ensuring an appropriate T4 environment for optimal fetal development through the synthesis and secretion of a placental thyroid stimulator. The aim of the study was to evaluate the thyroid stimulating activity (TSA) of human chorionic gonadotropin and to characterize different molecular forms of the hormone in relation to their ability to interact with thyroid tissue. The measurement of cAMP levels and I- uptake in FRTL-5 rat thyroid cells have been used as in vitro parameters indicating interactions with the TSH receptor and TSH-like biological activity of hCG and its isoforms. A dose-dependent response, paralleling that evoked by hTSH, was observed in a concentration range of 50-2,000 IU/ml of different preparations of hCG, 1 IU of hCG being equivalent to 0.13 μU of hTSH. TSA coeluted in a single peak with hCG immunoactivity at gel filtration and was not neutralized by monoclonal anti-hTSH antibodies indicating that it was not due to nonspecific protein or contamination by TSH. At chromatofocusing urinary hCG was resolved into six isoforms corresponding to pIs of 5.2, 4.9, 4.5, 4.0, 3.6 + some more acidic hCG-like material eluting in a final IM NaCl step. All the fractions were active in the TSH bioassay but the B/I ratio differed among hCG components ranging from 1.49±0.08 to 0.88±0.16, with the most basic component (pI 5.2) significantly more active and the most acidic component (1M NaC1) significantly less active than the unfractionated preparation. In parallel, hCG and TSH levels were measured in a longitudinal study of 32 normal pregnant women. In the 1st trimester samples, TSH levels were decreased and significantly correlated in a negative fashion with hCG levels (p<0.02). Seven 1st and 2nd trim, sera, out of ten cases studied, induced a significant increase in I- uptake, while no stimulation was obtained with post-partum sera. Although the response to 1st trim, samples was higher than to 2nd trim, sera, TSA was poorly correlated with hCG values when considering 1st and 2nd trimester individually. In these seven cases, a difference in the composition of circulating hCG was also observed between 1st and 2nd trim., with a shift towards more acidic forms at the earlier stage of gestation. This study has revealed a significant decrease of TSH levels in the 1st trimester of pregnancy when, however, the secretory activity of maternal thyroid gland is increased, supporting the view that the thyroid gland is not primarily TSH-driven in early pregnancy. hCG may represent the putative regulator of maternal thyroid function in pregnancy. In this context, hCG microheterogeneity may influence its thyrotropic activity, and the occurrence of different hCG isoforms may represent physiologically important steps in the control of the maternal thyroid.

During starvation the transcriptional activation of catabolic processes is induced by the nuclear translocation and consequent activation of transcription factor EB (TFEB), a master modulator of autophagy and lysosomal biogenesis. However, how TFEB is inactivated upon nutrient refeeding is currently unknown. Here we show that TFEB subcellular localization is dynamically controlled by its continuous shuttling between the cytosol and the nucleus, with the nuclear export representing a limiting step. TFEB nuclear export is mediated by CRM1 and is modulated by nutrient availability via mTOR-dependent hierarchical multisite phosphorylation of serines S142 and S138, which are localized in proximity of a nuclear export signal (NES). Our data on TFEB nucleo-cytoplasmic shuttling suggest an unpredicted role of mTOR in nuclear export. On amino acid deprivation TFEB translocates from the cytoplasm to the nucleus. Here the authors identify a nuclear export signal in TFEB that is recognized by the exportin CRM1, and show that dual phosphorylation at S142 and S138 by mTOR accelerates export of TFEB.

Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism. Lysosomal storage disorders, characterized by altered metabolism of heparan sulfate, cause autistic symptoms followed by dementia in children. Here, the authors show that embryonic dopaminergic neurodevelopmental defects due to altered function of heparan sulfate cause autistic behaviours in mice.

Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3 . Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease. CLN3 mutations cause Batten disease, a devastating neurodegenerative lysosomal storage disease. Here, the authors discovered that CLN3 plays a crucial role in both trafficking of lysosomal proteins and autophagic lysosomal reformation.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) lead to accumulation of proteins aggregates in airways. Mutated CFTR promotes transglutaminases-mediated crosslinking of beclin 1, a positive regulator of autophagy, to induce accumulation of LC3-binding protein p62 and prevent autophagic degradation of aggregates. Accumulation of unwanted/misfolded proteins in aggregates has been observed in airways of patients with cystic fibrosis (CF), a life-threatening genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show how the defective CFTR results in defective autophagy and decreases the clearance of aggresomes. Defective CFTR-induced upregulation of reactive oxygen species (ROS) and tissue transglutaminase (TG2) drive the crosslinking of beclin 1, leading to sequestration of phosphatidylinositol-3-kinase (PI(3)K) complex III and accumulation of p62, which regulates aggresome formation. Both CFTR knockdown and the overexpression of green fluorescent protein (GFP)-tagged-CFTR F508del induce beclin 1 downregulation and defective autophagy in non-CF airway epithelia through the ROS–TG2 pathway. Restoration of beclin 1 and autophagy by either beclin 1 overexpression, cystamine or antioxidants rescues the localization of the beclin 1 interactome to the endoplasmic reticulum and reverts the CF airway phenotype in vitro , in vivo in Scnn1b -transgenic and Cftr F508del homozygous mice, and in human CF nasal biopsies. Restoring beclin 1 or knocking down p62 rescued the trafficking of CFTR F508del to the cell surface. These data link the CFTR defect to autophagy deficiency, leading to the accumulation of protein aggregates and to lung inflammation.

The mechanistic target of rapamycin complex 1 (mTORC1) is a key metabolic hub that controls the cellular response to environmental cues by exerting its kinase activity on multiple substrates 1 – 3 . However, whether mTORC1 responds to diverse stimuli by differentially phosphorylating specific substrates is poorly understood. Here we show that transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy 4 , 5 , is phosphorylated by mTORC1 via a substrate-specific mechanism that is mediated by Rag GTPases. Owing to this mechanism, the phosphorylation of TFEB—unlike other substrates of mTORC1, such as S6K and 4E-BP1— is strictly dependent on the amino-acid-mediated activation of RagC and RagD GTPases, but is insensitive to RHEB activity induced by growth factors. This mechanism has a crucial role in Birt–Hogg–Dubé syndrome, a disorder that is caused by mutations in the RagC and RagD activator folliculin ( FLCN ) and is characterized by benign skin tumours, lung and kidney cysts and renal cell carcinoma 6 , 7 . We found that constitutive activation of TFEB is the main driver of the kidney abnormalities and mTORC1 hyperactivity in a mouse model of Birt–Hogg–Dubé syndrome. Accordingly, depletion of TFEB in kidneys of these mice fully rescued the disease phenotype and associated lethality, and normalized mTORC1 activity. Our findings identify a mechanism that enables differential phosphorylation of mTORC1 substrates, the dysregulation of which leads to kidney cysts and cancer. Dysregulation of an mTORC1 substrate-specific mechanism leads to constitutive activation of TFEB, and promotes kidney cystogenesis and tumorigenesis in a mouse model of Birt–Hogg–Dubé syndrome.