Publications by authors named "Serge Amselem"

115 Publications

Impact of Gender on the Characteristics of Patients with Idiopathic Pulmonary Fibrosis Included in the RaDiCo-ILD Cohort.

Respiration 2021 Sep 2:1-12. Epub 2021 Sep 2.

Sorbonne Université, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Pneumologie Pédiatrique, Centre de Référence des Maladies Respiratoires Rares, Paris, France.

Background: There is growing evidence of gender-specific phenotypic differences among patients with idiopathic pulmonary fibrosis (IPF), which may affect patient outcomes.

Objectives: We present the characteristics of patients with IPF at inclusion in the French Rare Disease Cohort - Interstitial Lung Disease (RaDiCo-ILD) with the aim of characterizing gender-specific phenotypic differences.

Methods: Patients with IPF who were enrolled in the national, multicentre RaDiCo-ILD cohort were included. Demographic characteristics, comorbidities, health-related quality of life (HRQoL) scores, pulmonary function, chest imaging, and IPF treatment were collected at inclusion and described by gender.

Results: The cohort included 724 patients with IPF (54% of RaDiCo-ILD cohort), of whom 82.9% were male. The proportion of male and female patients with a prior history of smoking was 75.0% and 26.8%, respectively. Emphysema was present in 17.0% (95% confidence interval [CI]: 10.0, 24.0) of men and 5.4% (95% CI: 1.2, 9.6) of women. At inclusion, females had poorer HRQoL than males based on St. George's Respiratory Questionnaire scores (48.5 [95% CI: 43.9, 53.0] and 41.5 [39.4, 43.6], respectively). The mean forced vital capacity per cent predicted was 77.7% (95% CI: 76.2, 79.3) and 87.4% (83.4, 91.4) for males and females, respectively. Honeycombing on high-resolution computed tomography (HRCT) was present in 70.8% (95% CI: 61.0, 80.6) of males and 45.8% (95% CI: 35.1, 56.5) of females.

Conclusions: This analysis of patients with IPF at inclusion in the RaDiCo-ILD cohort provides evidence that comorbid emphysema, lung volume reduction, and honeycombing on HRCT are more common characteristics of males than females.
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http://dx.doi.org/10.1159/000518008DOI Listing
September 2021

Chronic hepatic involvement in the clinical spectrum of A20 haploinsufficiency.

Liver Int 2021 08 8;41(8):1894-1900. Epub 2021 Jun 8.

Department of Internal Medicine, CHU de Caen Normandie, Caen, France.

Background & Aims: Secondary to tumour necrosis factor-alpha induced protein 3 (TNFAIP3) mutations, A20 haploinsufficiency (HA20) is a recently described autoinflammatory disease with clinical features similar to those of Behçet's and Crohn's diseases but with a constantly expanding clinical spectrum. Here, we describe HA20 liver involvement in three new patients from the same family.

Methods: We retrospectively assessed clinical, biological and/or histological findings for eight patients over three generations of the same family with heterozygous mutations in the TNFAIP3 gene (c.259C > T, p.Arg87*).

Results: The eight patients exhibited the following: aphthous ulcers (8/8, bipolar in 7), autoimmune features (6/8, including 5 with definitive autoimmune disease diagnoses, ie, type I diabetes, Hashimoto thyroiditis, pernicious anaemia, and/or 5 with antinuclear antibodies ≥320), pustulosis/folliculitis (5/8), abdominal pain (4/8), arthralgia (3/8), enlarged cervical lymph nodes (3/8) and pericarditis (1/8). In addition, three patients (twin sisters and their grandmother aged 23 and 70 years, respectively) exhibited persistent mild hepatic cytolysis associated with splenomegaly (n = 3), hepatomegaly (n = 1) and/or liver atrophy (n = 1) on echography. We could not detect any other causes of chronic liver diseases. Liver biopsies from three patients displayed hepatic fibrosis, hepatocyte injury and/or CD4 /CD8 T lymphocyte infiltration, and patterns of inflammatory cells and NLRP3 or NF-κB immunostaining differed from the predominant neutrophil infiltration observed in skin or some digestive tract biopsies.

Conclusions: This study reinforces the dual involvement of innate and adaptive immunity in HA20 according to both acute and chronic injury and the organ involved and widens its clinical spectrum to include chronic hepatic involvement.
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http://dx.doi.org/10.1111/liv.14935DOI Listing
August 2021

Tumor necrosis factor receptor-1 assciated periodic syndrome (TRAPS) related AA amyloidosis: a national case series and systematic review.

Rheumatology (Oxford) 2021 Mar 14. Epub 2021 Mar 14.

Sorbonne University, GRC GRAASU, Department of Internal Medicine, APHP, Tenon Hospital, Paris, France.

Objectives: Tumor necrosis factor (TNF) receptor-1 associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder associated with mutations in the TNF receptor super family 1A (TNFRSF1A) gene. AA amyloidosis (AA) is the most severe complication of TRAPS. To study the occurrence and prognosis of AA in TRAPS, we conducted a retrospective study of all French cases and a systematic literature review.

Methods: This case series includes TRAPS patients followed by our center from 2000 to 2020 presenting with histologically confirmed AA. We conducted a systematic literature review on the PubMed and Embase databases for articles published up February 2021 following the PRISMA guidelines and using the keywords: amyloidoisis, amyloid, TNF receptor-associated periodic syndrome, TNF Receptor-associated Periodic Syndrome, Tumor necrosis factor receptor-associated periodic syndrome, TRAPS, TNFRSF1A, Familial Hibernian fever and Hibernian Familial Fever.

Results: A total of 41 TRAPS with AA were studied: 3 new patients and 38 cases from the literature. AA diagnosis preceded that of TRAPS in 96% of cases, and 17/36 (47%) required renal replacement therapy. Death occurred in 5/36 (14%) with a median follow-up of 23 months. Effect of biologics on AA were available for 21 regimens in 19 patients: 10 improved renal function, 7 stabilized and 4 worsened. Four patients (36% of transplanted patients) relapse AA on kidney graft (only one under etanercept).

Conclusion: TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function.
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http://dx.doi.org/10.1093/rheumatology/keab252DOI Listing
March 2021

Association between familial Mediterranean fever and multiple sclerosis: A case series from the JIR cohort and systematic literature review.

Mult Scler Relat Disord 2021 May 10;50:102834. Epub 2021 Feb 10.

Sorbonne University; Internal Medicine Department; AP-HP; Hôpital Tenon; Paris; France; Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses Inflammatoire (CEREMAIA)-JIR Cohort; France. Electronic address:

Introduction: Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disorder; and leads to the uncontrolled production of interleukin (IL)-1β. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system; and its development seems to be partly correlated with IL-1β levels. It is hypothesized that FMF could be associated with MS. We aim to describe the features of patients displaying both diseases and to investigate the MEFV mutation rate in MS patients.

Methods: Patients with definite MS were retrieved from the cohort of FMF patients in the Reference Center for Rare Auto-inflammatory Diseases and Amyloidosis (CEREMAIA). We also performed a systematic literature review of articles from PubMed that were published from 1990 to 2020.

Results: Twenty-four patients were included in the case series: five patients (1.3%) from our cohort of 364 and 19 patients from the literature. The sex ratio was 2:1. The mean age at diagnosis of FMF was 19 years old; and that for MS was 29 years old. Seven studies investigating the MEFV mutation rate in MS patients were included. Three studies found a higher mutation rate in MS patients than in the control group.

Conclusion: FMF and MS features were comparable to those of patients with unrelated diseases; and MEFV mutation carriage was not positively correlated with MS. However; MS prevalence in FMF patients was higher than was expected in a healthy population. To a lesser extent; FMF prevalence in MS patients was higher than expected in a healthy population and the difference might not be significant. These data suggest that FMF could be associated with MS; and further studies are needed to investigate a potential causal association.
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http://dx.doi.org/10.1016/j.msard.2021.102834DOI Listing
May 2021

"Helicobacter pylori in familial mediterranean fever: A series of 120 patients from literature and from france".

Helicobacter 2021 Apr 15;26(2):e12789. Epub 2021 Feb 15.

Department of Internal Medicine, AP-HP, Tenon Hospital, Sorbonne University, Paris, France.

Introduction: Familial Mediterranean Fever (FMF), the most common monogenic auto-inflammatory disease, is characterized by recurrent febrile abdominal pain. Helicobacter pylori infection (HPI), one of the most frequent infections worldwide, can mimic an FMF attack.

Objectives: Identify FMF patients with HPI in a cohort of French FMF patients and the literature and identify features allowing to distinguish HPI from an FMF attack.

Methods: A retrospective study of all HPI cases was performed on the cohort of FMF patients fulfilling the Livneh criteria from the French Reference Center for rare Auto-Inflammatory Diseases and Amyloidosis (CEREMAIA). A systematic literature review of HPI in FMF patients was conducted according to the PRISMA guidelines.

Results: Eight French patients developed HPI, whose symptoms of epigastralgia, diarrhea, anorexia/weight loss, and nausea/vomiting differed from their typical abdominal FMF attacks. A total of 112 FMF patients with HPI have been described in the literature, including 61 adults. Diagnosis of HPI was made by gastroscopy (n = 43), labelled urea test (n = 55) or IgG serology by ELISA (n = 12). When performed, C-reactive protein was always elevated. Ten cases of interaction between colchicine and antibiotic therapy for HPI (clarithromycin (n = 9) and azithromycin (n = 1)) were reported.

Conclusion: We described a total of 120 patients with typical FMF and HPI. When FMF patients develop atypical abdominal symptoms, upper gastrointestinal endoscopy with biopsies is essential to eliminate underlying HPI. Untreated HPI can lead to misdiagnosis of colchicine resistance with inappropriate prescription of an interleukin-1 inhibitor at a non-negligible cost.
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http://dx.doi.org/10.1111/hel.12789DOI Listing
April 2021

Functional assessment and phenotypic heterogeneity of and mutations in interstitial lung diseases and lung cancer.

Eur Respir J 2020 12 24;56(6). Epub 2020 Dec 24.

Pulmonology Dept, Pasteur Hospital, Nice, France.

Introduction: Interstitial lung diseases (ILDs) can be caused by mutations in the and genes, which encode the surfactant protein (SP) complex SP-A. Only 11 or mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic or mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives.

Methods: The consequences of the 11 or mutations were analysed both , by studying the production and secretion of the corresponding mutated proteins and , by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented.

Results: For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic.

Discussion: This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic or mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.
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http://dx.doi.org/10.1183/13993003.02806-2020DOI Listing
December 2020

Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling.

J Exp Med 2020 11;217(11)

Immunity and Cancer Department, Institut Curie, Paris-Sciences-et-Lettres Research University, Institut National de la Santé et de la Recherche Médicale U932, Paris, France.

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.
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http://dx.doi.org/10.1084/jem.20200600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596811PMC
November 2020

TTC12 Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Unveil Distinct Dynein Assembly Mechanisms in Motile Cilia Versus Flagella.

Am J Hum Genet 2020 02 23;106(2):153-169. Epub 2020 Jan 23.

Institut Cochin, Institut National de la Santé et de la Recherche Médicale, U1016), Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Paris 75014, France. Electronic address:

Cilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs and IDAs). Defects in ODAs and IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. PCD mutations in assembly factors have been shown to cause a combined ODA-IDA defect, affecting both cilia and flagella. We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia. Analyses of both primary cells from individuals carrying TTC12 mutations and human differentiated airway cells invalidated for TTC12 by a CRISPR-Cas9 approach revealed an IDA defect restricted to a subset of single-headed IDAs that are different in flagella and cilia, whereas TTC12 depletion in the ciliate Paramecium tetraurelia recapitulated the sperm phenotype. Overall, our study, which identifies TTC12 as a gene involved in PCD, unveils distinct dynein assembly mechanisms in human motile cilia versus flagella.
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http://dx.doi.org/10.1016/j.ajhg.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011118PMC
February 2020

NLRP3-associated autoinflammatory diseases: Phenotypic and molecular characteristics of germline versus somatic mutations.

J Allergy Clin Immunol 2020 04 6;145(4):1254-1261. Epub 2019 Dec 6.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), "Childhood genetic disorders", Paris, France; Département de Génétique Médicale, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address:

Background: NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) include conditions of various severities, due to germline or somatic mosaic NLRP3 mutations.

Objective: To identify mosaic- versus germline-specific NLRP3 mutations' characteristics, we reinterpreted all the mutations reported in NLRP3-AIDs and performed an in-depth study of 3 novel patients.

Methods: The pathogenicity of all reported mosaic/germline mutations was reassessed according to international recommendations and their location on the NLRP3 3-dimensional structure. Deep-targeted sequencing and NLRP3-inflammasome-activation assays were used to identify the disease-causing mutation in 3 patients.

Results: We identified, in 3 patients, mosaic mutations affecting the same NLRP3 amino acid (Glu569). This residue belongs to 1 of the 2 mosaic mutational hot spots that face each other in the core of the NLRP3 ATPase domain. The review of the 90 NLRP3 mutations identified in 277 patients revealed that those hot spots account for 68.5% of patients (37 of 54) with mosaic mutations. Glu569 is affected in 22% of the patients (12 of 54) with mosaic mutations and in 0.4% of patients (1 of 223) with germline mutations. Only 8 of 90 mutations were found in mosaic and germinal states. All of the germline mutations were associated with a severe phenotype. These data suggest that mutations found only in mosaic state could be incompatible with life if present in germinal state. None of the 5 most frequent germline mutations was identified in mosaic state. Mutations found only in germinal state could, therefore, be asymptomatic in mosaic state.

Conclusions: The phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations.
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http://dx.doi.org/10.1016/j.jaci.2019.11.035DOI Listing
April 2020

Pilot experience of multidisciplinary team discussion dedicated to inherited pulmonary fibrosis.

Orphanet J Rare Dis 2019 12 3;14(1):280. Epub 2019 Dec 3.

Service de Pneumologie A, DHU FIRE, Centre de Référence (Site Constitutif) Maladies Pulmonaires Rares, APHP, Hôpital Bichat, 46 rue Henri Huchard, 75877, Paris, CEDEX 18, France.

Background: Genetic testing is proposed for suspected cases of monogenic pulmonary fibrosis, but clinicians and patients need specific information and recommendation about the related diagnosis and management issues. Because multidisciplinary discussion (MDD) has been shown to improve accuracy of interstitial lung disease (ILD) diagnosis, we evaluated the feasibility of a genetic MDD (geneMDD) dedicated to the indication for and interpretation of genetic testing. The geneMDD group met monthly and included pediatric and adult lung specialists with ILD expertise, molecular and clinical geneticists, and one radiologist. Hematologists, rheumatologists, dermatologists, hepatologists, and pathologists were also invited to attend.

Results: Since 2016, physicians from 34 different centers in 7 countries have participated in the geneMDD. The medical files of 95 patients (53 males) have been discussed. The median age of patients was 43 years [range 0-77], 10 were ≤ 15 years old, and 6 were deceased at the time of the discussion. Among 85 analyses available, the geneMDD considered the rare gene variants pathogenic for 61: 37 variants in telomere-related genes, 23 variants in surfactant-related genes and 1 variant in MARS. Genetic counseling was offered for relatives of these patients. The geneMDD therapeutic proposals were as follows: antifibrotic drugs (n = 25), steroids or immunomodulatory therapy (n = 18), organ transplantation (n = 21), watch and wait (n = 21), or best supportive care (n = 4).

Conclusion: Our experience shows that a dedicated geneMDD is feasible regardless of a patient's age and provides a unique opportunity to adapt patient management and therapy in this very rare condition.
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http://dx.doi.org/10.1186/s13023-019-1256-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889342PMC
December 2019

The NLRP3 p.A441V Mutation in -AID Pathogenesis: Functional Consequences, Phenotype-Genotype Correlations and Evidence for a Recurrent Mutational Event.

ACR Open Rheumatol 2019 Jun 6;1(4):267-276. Epub 2019 Jun 6.

Sorbonne Université INSERM, Hôpital Trousseau Paris France.

Objective: To determine the molecular and cellular bases of autoinflammatory syndromes in a multigenerational French family with Muckle-Wells syndrome and in a patient originating from Portugal with familial cold autoinflammatory syndrome.

Methods: Sequencing of exon 3 was performed in all accessible patients. Microsatellite and whole-genome single nucleotide polymorphism genotyping was used i) to test the intrafamilial segregation of the identified variant and ii) to look for a founder effect. Functional analyses included the study of i) apoptosis-associated speck-like protein containing a CARD (ASC) speck formation in HEK293T cells (stably expressing ASC-green fluorescent protein and pro-caspase 1-FLAG) transiently expressing the wild-type or mutated NLRP3 protein, ii) levels of IL-1β secreted from transfected THP-1 cells, and iii) inflammasome-related gene expression and cytokine secretion from monocytes isolated from patients in crisis (probands from the two families), related patients out of crisis, and from controls.

Results: The same heterozygous mutation (c.1322C>T, p.A441V) located in the NACHT domain, segregating with the disease within the first family, was identified in the two families. This mutation was found to be associated with different core haplotypes. NLRP3-A441V led to increased ASC speck formation and high levels of secreted IL-1β. Monocyte inflammasome-related gene expression and cytokine secretion, which were within the normal range in patients out of crisis, were found to be differentially regulated between the two probands, correlating with their phenotypic status.

Conclusion: These molecular and cellular findings, which indicate a recurrent mutational event, clearly demonstrate the pathogenicity of the p.A441V missense mutation in -associated autoinflammatory disease and point to the interest of studying patients' primary cells to assess disease activity.
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http://dx.doi.org/10.1002/acr2.1039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857991PMC
June 2019

Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia.

J Med Genet 2020 04 26;57(4):237-244. Epub 2019 Nov 26.

Universite Paris-Est, Faculte de Médecine, INSERM (Institut National pour la Santé et la Recherche Médicale) UMR_S955, Equipe 13, CNRS (Centre National pour la Recherche Scientifique), ERL 7000, Creteil, France.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder resulting in abnormal ciliary motility/structure, extremely heterogeneous at genetic and ultrastructural levels. We aimed, in light of extensive genotyping, to identify specific and quantitative ciliary beating anomalies, according to the ultrastructural phenotype.

Methods: We prospectively included 75 patients with PCD exhibiting the main five ultrastructural phenotypes (n=15/group), screened all corresponding PCD genes and measured quantitative beating parameters by high-speed video-microscopy (HSV).

Results: Sixty-eight (91%) patients carried biallelic mutations. Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved. ODA defect induces a residual beating with dramatically low ciliary beat frequency (CBF) related to increased recovery stroke and pause durations, especially in case of mutations. IDA defect with microtubular disorganisation induces a low percentage of beating cilia with decreased beating angle and, in case of mutations, a relatively conserved mean CBF with a high maximal CBF. Central complex defect induces nearly normal beating parameters, regardless of the gene involved, and a gyrating motion in a minority of ciliated edges, especially in case of mutations. PCD with normal ultrastructure exhibits heterogeneous HSV values, but mostly an increased CBF with an extremely high maximal CBF.

Conclusion: Quantitative HSV analysis in PCD objectives beating anomalies associated with specific ciliary ultrastructures and genotypes. It represents a promising approach to guide the molecular analyses towards the best candidate gene(s) to be analysed or to assess the pathogenicity of the numerous sequence variants identified by next-generation-sequencing.
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http://dx.doi.org/10.1136/jmedgenet-2019-106424DOI Listing
April 2020

Use of ruxolitinib in COPA syndrome manifesting as life-threatening alveolar haemorrhage.

Thorax 2020 01 30;75(1):92-95. Epub 2019 Oct 30.

Inserm UMR_S933, INSERM and Sorbonne Université, Paris, France

COPA (coatomer subunit α) syndrome is a newly recognised cause of interstitial lung disease in children and adults, frequently associated with arthritis and renal dysfunction. We report a 11-year-old girl with disease limited to major pulmonary haemosiderosis manifesting at the age of 2 years, due to a heterozygous p.(Arg233His) mutation in Her interferon (IFN) signature was elevated (10.312 and 12.429, healthy <2.466), as was the level of serum IFNα (211 fg/mL, healthy <10 fg/mL). STAT1 phosphorylation in T lymphocytes and monocytes was increased as compared with healthy controls. Based on these results she was treated with the JAK1/2 inhibitor ruxolitinib, which resulted in reduction in IFN signalling and appeared to be associated with partial though incomplete decrease in the severity of her pulmonary disease. Patients with alveolar haemorrhage of unknown origin should be considered for screening. Functional tests can help to personalise patient therapy.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213892DOI Listing
January 2020

Somatic Mosaic NLRP3 Mutations and Inflammasome Activation in Late-Onset Chronic Urticaria.

J Invest Dermatol 2020 04 9;140(4):791-798.e2. Epub 2019 Sep 9.

Sorbonne Université, INSERM, Hôpital Trousseau, Maladies génétiques d'expression pédiatrique, Paris, France; Unité Fonctionnelle de génétique moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Paris, France. Electronic address:

Chronic urticaria is a common skin disorder with heterogeneous causes. In the absence of physical triggers, chronic urticarial rash is called idiopathic or spontaneous. The objective of this study was to identify the molecular and cellular bases of a disease condition displayed by two unrelated patients aged over 60 years who presented for two decades with a chronic urticaria resistant to standard therapy that occurred in the context of systemic inflammation not triggered by cold. In both patients, a targeted sequencing approach using a next generation technology identified somatic mosaic mutations in NLRP3, a gene encoding a key inflammasome component. The study of several of both patients' cell types showed that, despite the late onset of the disease, NLRP3 mutations were not found to be restricted to myelomonocytic cells. Rather, the data obtained strongly suggested that the mutational event occurred very early, during embryonic development. As shown by functional studies, the identified mutations-an in-frame deletion and a recurrent NLRP3 missense mutation-have a gain-of-function effect on NLRP3-inflammasome activation. Consistently, a complete remission was obtained in both patients with anti-IL-1 receptor antagonists. This study unveils that in late-onset chronic urticaria, the search for autoinflammatory markers and somatic mosaic NLRP3 mutations may have important diagnostic and therapeutic consequences.
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http://dx.doi.org/10.1016/j.jid.2019.06.153DOI Listing
April 2020

Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele.

Hum Mutat 2020 01 15;41(1):115-121. Epub 2019 Sep 15.

INSERM UMR_S933, Sorbonne Université, U.F. de Génétique moléculaire (AP-HP), Hôpital Armand-Trousseau, Paris, France.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North-African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi-allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North-African patients. This mutation is estimated to date back at least 1,400-1,750 years ago. The identification of this major allele allowed us to suggest a cost-effective genetic diagnostic strategy in North-African patients with PCD.
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http://dx.doi.org/10.1002/humu.23905DOI Listing
January 2020

Bi-allelic missense mutations in a patient with childhood ILD who reached adulthood.

ERJ Open Res 2019 Jul 22;5(3). Epub 2019 Jul 22.

2nd Pulmonary Medicine Dept, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens, Athens, Greece.

http://bit.ly/2LzMNOE.
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http://dx.doi.org/10.1183/23120541.00066-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646961PMC
July 2019

Extreme Short Stature and Severe Neurological Impairment in a 17-Year-Old Male With Untreated Combined Pituitary Hormone Deficiency Due to Mutation.

Front Endocrinol (Lausanne) 2019 27;10:381. Epub 2019 Jun 27.

Ha'Emek Medical Center, Pediatric Endocrine Institute, Afula, Israel.

POU1F1 is an essential transcription factor for the differentiation, proliferation and survival of somatotrophs, lactotrophs, and thyrotrophs. Mutations in the gene are characterized by growth hormone (GH), thyrotropin, and prolactin deficiencies, commonly presenting with growth retardation and central hypothyroidism. Since the first report in 1992, more than 25 mutations have been identified in . We describe a 17-year-old male who presented to our Pediatric Endocrinology clinic with extreme short stature (height 81.7 cm, -9.3 SD), cognitive impairment, deaf-mutism, and neurological disabilities. L-thyroxine supplemental therapy, which had been initiated at the age of 6 months but ceased due to non-compliance, was reintroduced at presentation. GH therapy was initiated at 19 years of age, resulting in 42 cm linear growth, to a final height of 124 cm. Sequencing of revealed a previously described homozygous insertion mutation-c.580_581insT, p (Thr194Ilefs7)-in exon 4 causing a frameshift that introduces a stop codon 7 amino acids downstream, leading to a severely truncated protein lacking the homeodomain. This case report sheds light on the natural history of untreated patients with mutations and raises awareness for early diagnosis and adequate treatment of central congenital hypothyroidism and GH deficiency.
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http://dx.doi.org/10.3389/fendo.2019.00381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610292PMC
June 2019

Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations.

Hum Mutat 2019 11 6;40(11):2033-2043. Epub 2019 Aug 6.

Genetic Department, INSERM UMR_S933, Hôpital Trousseau, Sorbonne Université, AP-HP, Paris, France.

Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.
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http://dx.doi.org/10.1002/humu.23847DOI Listing
November 2019

Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia.

Am J Hum Genet 2019 07 6;105(1):198-212. Epub 2019 Jun 6.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale U933, Hôpital Trousseau, Paris 75012, France; Assistance Publique-Hôpitaux de Paris, Département de Génétique Médicale, Hôpital Trousseau, Paris 75012, France.

Motile cilia and sperm flagella share an evolutionarily conserved axonemal structure. Their structural and/or functional defects are associated with primary ciliary dyskinesia (PCD), a genetic disease characterized by chronic respiratory-tract infections and in which most males are infertile due to asthenozoospermia. Among the well-characterized axonemal protein complexes, the outer dynein arms (ODAs), through ATPase activity of their heavy chains (HCs), play a major role for cilia and flagella beating. However, the contribution of the different HCs (γ-type: DNAH5 and DNAH8 and β-type: DNAH9, DNAH11, and DNAH17) in ODAs from both organelles is unknown. By analyzing five male individuals who consulted for isolated infertility and displayed a loss of ODAs in their sperm cells but not in their respiratory cells, we identified bi-allelic mutations in DNAH17. The isolated infertility phenotype prompted us to compare the protein composition of ODAs in the sperm and ciliary axonemes from control individuals. We show that DNAH17 and DNAH8, but not DNAH5, DNAH9, or DNAH11, colocalize with α-tubulin along the sperm axoneme, whereas the reverse picture is observed in respiratory cilia, thus explaining the phenotype restricted to sperm cells. We also demonstrate the loss of function associated with DNAH17 mutations in two unrelated individuals by performing immunoblot and immunofluorescence analyses on sperm cells; these analyses indicated the absence of DNAH17 and DNAH8, whereas DNAH2 and DNALI, two inner dynein arm components, were present. Overall, this study demonstrates that mutations in DNAH17 are responsible for isolated male infertility and provides information regarding ODA composition in human spermatozoa.
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http://dx.doi.org/10.1016/j.ajhg.2019.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612517PMC
July 2019

Expression of SAA1, SAA2 and SAA4 genes in human primary monocytes and monocyte-derived macrophages.

PLoS One 2019 17;14(5):e0217005. Epub 2019 May 17.

Sorbonne Université, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicale, Paris, France.

Circulating serum amyloid A (SAA) is increased in various inflammatory conditions. The human SAA protein family comprises the acute phase SAA1/SAA2, known to activate a large set of innate and adaptive immune cells, and the constitutive SAA4. The liver synthesis of SAA1/SAA2 is well-established but there is still an open debate on extrahepatic SAA expression especially in macrophages. We aimed to investigate the ability of human primary monocytes and monocyte-derived macrophages to express SAA1, SAA2 and SAA4 at both the transcriptional and protein levels, as previous studies almost exclusively dealt with monocytic cell lines. Monocytes and derived macrophages from healthy donors were stimulated under various conditions. In parallel with SAA, pro-inflammatory IL1A, IL1B and IL6 cytokine expression was assessed. While LPS alone was non-effective, a combined LPS/dexamethasone treatment induced SAA1 and to a lesser extent SAA2 transcription in human monocytes and macrophages. In contrast, as expected, pro-inflammatory cytokine expression was strongly induced following stimulation with LPS, an effect which was dampened in the presence of dexamethasone. Furthermore, in monocytes polarized towards a pro-inflammatory M1 phenotype, SAA expression in response to LPS/dexamethasone was potentiated; a result mainly seen for SAA1. However, a major discrepancy was observed between SAA mRNA and intracellular protein levels under the experimental conditions used. Our results demonstrate that human monocytes and macrophages can express SAA genes, mainly SAA1 in response to an inflammatory environment. While SAA is considered as a member of a large cytokine network, its expression in the monocytes-macrophages in response to LPS-dexamethasone is strikingly different from that observed for classic pro-inflammatory cytokines. As monocytes-macrophages are major players in chronic inflammatory diseases, it may be hypothesized that SAA production from macrophages may contribute to the local inflammatory microenvironment, especially when macrophages are compactly organized in granulomas as in sarcoidosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217005PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524798PMC
January 2020

Monoclonal Gammopathy, Arthralgias, and Recurrent Fever Syndrome: A New Autoinflammatory Syndrome?

J Rheumatol 2019 11 15;46(11):1535-1539. Epub 2019 Mar 15.

From the Sorbonne Université, AP-HP, Hôpital Tenon, Service de Médecine Interne, Centre de Référence des Maladies Auto-inflammatoires et des Amyloses d'Origine Inflammatoire (CEREMAIA); Service d'Immuno-hélatologie, Hôpital St. Louis; INSERM UMRS-933, et Laboratoire de Génétique, Hôpital Trousseau, AP-HP, Faculté de Médecine, Sorbonne Université, Paris; Service de Médecine Interne, Centre Hospitalier d'Auxerre, Auxerre; Service de Médecine Interne, Centre Hospitalier Universitaire (CHU) Henri Mondor; and Service d'Immunologie Clinique, Hôpital St. Louis, Paris, France.

Objective: To describe a new autoinflammatory syndrome with recurrent fever and monoclonal gammopathy that differs from Schnitzler syndrome.

Methods: We conducted a retrospective study of patients with monoclonal gammopathy and recurrent fever of unknown origin.

Results: Five patients were studied; median age at onset of symptoms was 44 years. Median frequency of fever attacks was 6 episodes per year. In the absence of treatment, the median duration of fevers was 3 days.

Conclusion: This new autoinflammatory syndrome is defined by an association among monoclonal gammopathy, arthralgias, and recurrent fever.
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http://dx.doi.org/10.3899/jrheum.181204DOI Listing
November 2019

Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.

Am J Hum Genet 2019 02 18;104(2):229-245. Epub 2019 Jan 18.

Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887_890delTAAG (p.Val296Glyfs13), in exon 5; this frameshift introduces a stop codon in amino acid 308 of the growth arrest-specific protein 2-like 2 (GAS2L2). Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867_343+1207del; p.?) starting in exon 5. Both individuals had clinical features of PCD but normal ciliary axoneme structure. In this research, using human nasal cells, mouse models, and X.laevis embryos, we show that GAS2L2 is abundant at the apical surface of ciliated cells, where it localizes with basal bodies, basal feet, rootlets, and actin filaments. Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern. These results were recapitulated in Gas2l2 mouse tracheal epithelial cell (mTEC) cultures and in X. laevis embryos treated with Gas2l2 morpholinos. In mice, the absence of Gas2l2 caused neonatal death, and the conditional deletion of Gas2l2 impaired mucociliary clearance (MCC) and led to mucus accumulation. These results show that a pathogenic variant in GAS2L2 causes a genetic defect in ciliary orientation and impairs MCC and results in PCD.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372263PMC
February 2019

Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens.

Nat Commun 2018 12 17;9(1):5338. Epub 2018 Dec 17.

University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France.

Mutations in the nucleotide-binding oligomerization domain protein 12 (NLRP12) cause recurrent episodes of serosal inflammation. Here we show that NLRP12 efficiently sequesters HSP90 and promotes K48-linked ubiquitination and degradation of NOD2 in response to bacterial muramyl dipeptide (MDP). This interaction is mediated by the linker-region proximal to the nucleotide-binding domain of NLRP12. Consequently, the disease-causing NLRP12 R284X mutation fails to repress MDP-induced NF-κB and subsequent activity of the JAK/STAT signaling pathway. While NLRP12 deficiency renders septic mice highly susceptible towards MDP, a sustained sensing of MDP through NOD2 is observed among monocytes lacking NLRP12. This loss of tolerance in monocytes results in greater colonization resistance towards Citrobacter rodentium. Our data show that this is a consequence of NOD2-dependent accumulation of inflammatory mononuclear cells that correlates with induction of interferon-stimulated genes. Our study unveils a relevant process of tolerance towards the gut microbiota that is exploited by an attaching/effacing enteric pathogen.
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http://dx.doi.org/10.1038/s41467-018-07750-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297353PMC
December 2018

Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus.

Am J Hum Genet 2018 12 21;103(6):984-994. Epub 2018 Nov 21.

Genetics and Genomic Medicine Programme, University College London, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK. Electronic address:

Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288320PMC
December 2018

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

N Engl J Med 2018 12 20;379(23):2209-2219. Epub 2018 Oct 20.

From Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bichat-Claude Bernard, Departments of Rheumatology (P.-A.J., E.E., S. Ottaviani, P.D.), Genetics (C.K., C. Boileau), Pulmonology A (R.B., B.C.), Pulmonology B (G.T.), and Radiology (M.-P.D.), Département Hospitalo-Universitaire Fibrose Inflammation Remodelage, INSERM Unité Mixte de Recherche (UMR) 1152, Université Paris Diderot (P.-A.J., C.K., R.B., G.T., B.C., P.D.), Arthritis Recherche et Développement (P.-A.J.), AP-HP, Hôpital Lariboisière, Service de Rhumatologie (A. Frazier, P.R.), INSERM, UMR 1132 (P.R.), AP-HP, Hôpital Cochin, Service de Rhumatologie A, and INSERM, Unité 1016, UMR 8104 (Y.A.), AP-HP, Hôpital Tenon, Service de Pneumologie (H.L.), AP-HP, Service de Pneumologie Pédiatrique et Centre de Référence des Maladies Respiratoires Rares, and INSERM UMR S933 (N.N., S.A., A.C.), and AP-HP, Département de Génétique, Hôpital Trousseau (S.A.), Paris, Centre Hospitalier Régional Universitaire (CHRU) de Lille, Service de Pneumologie et Immuno-Allergologie, Centre de Compétence des Maladies Pulmonaires Rares, Fédératif Hospitalo-Universitaire Immune-Mediated Inflammatory Diseases and Targeted Therapies (L.W.-S., B.W.), and Centre Hospitalier Universitaire (CHU) de Lille, Service de Rhumatologie (R.-M.F.), Lille, the Departments of Pulmonology (H.N., D.V.) and Rheumatology (N.S.-K., M.-C.B.), Hôpital Avicenne, AP-HP, INSERM UMR 1125 (N.S.-K., M.-C.B.), and Université Paris 13, Sorbonne Paris Cité (N.S.-K., M.-C.B.), Bobigny, the Department of Pulmonology, CHRU Tours, Tours (S.M.-A.), CHRU de Strasbourg, Service de Rhumatologie, Hôpital de Hautepierre, INSERM UMR S1109, and Laboratoire d'Immuno-Rhumatologie Moléculaire, Centre de Recherche en Histoire des Idées, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg (J. Sibilia), Service de Pneumologie (C.D.) and Service de Rhumatologie (C.R., T.S.), CHU de Bordeaux, and ImmunoConcEpT, Centre National de la Recherche Scientifique UMR 5164 (C.R., T.S.), Bordeaux, CHU Clermont-Ferrand, Service de Rhumatologie, Institut National de la Recherche Agronomique (INRA), UMR 1019, Unité de Nutrition Humaine, Centre de Recherche en Nutrition Humaine Auvergne, Clermont-Ferrand (M.S.), and Hospices Civils de Lyon, Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, and INRA, UMR 754, Université Claude Bernard Lyon 1, Lyon, (V.C.) - all in France; the Departments of Medicine (J.S.L., E.D., K.D., A.D.W., A. Fischer, M.I.S., M.H., D.A.S.) and Immunology and Microbiology (D.A.S.), University of Colorado School of Medicine, Aurora, and the Departments of Biomedical Research (T.F.) and Medicine (J.J. Solomon), National Jewish Health, Denver - both in Colorado; the Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba (H.F., S. Oka, N.T.), and the Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Sagamihara (H.F., S. Oka, S.T.) - both in Japan; the Department of Epidemiology, Harvard T.H. Chan School of Public Health (S.G.), and the Department of Medicine, Brigham and Women's Hospital (T.D., I.O.R.), Boston, and the Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge (S.G.) - all in Massachusetts; the Interstitial Lung Disease and Rheumatology Unit (J.R.-S., M.I.G.-P., M.M., I.B.-R.) and the HLA Laboratory (R.F.-V., E.A.-O.), Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City; the 2nd Pulmonary Medicine Department (E.M., S.A.P.) and the Rheumatology and Clinical Immunology Unit, 4th Department of Internal Medicine (T.K., D.B.), University Hospital of Athens "Attikon," National and Kapodistrian University of Athens, Athens, and the Department of Respiratory Medicine and the Laboratory of Molecular and Cellular Pneumonology, Faculty of Medicine, University of Crete, Crete (K.A.) - both in Greece; St. Antonius ILD Center of Excellence, St. Antonius Ziekenhuis, Nieuwegein, the Netherlands (C.H.M.M., J.V., Y.A.M., J.C.G.); the Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China (Y.W.); the Divisions of Pulmonary and Critical Care Medicine (J.H.R.) and Rheumatology (E.L.M.), Mayo Clinic College of Medicine and Science, Rochester, MN; the Colton Center for Autoimmunity, New York University School of Medicine, New York (T.B.N.); the Department of Medicine, McGill University, Montreal (D.A.); the Department of Medicine, University of California, San Francisco, San Francisco (A.G., P.W.); and Data Tecnica International, Glen Echo, and the Laboratory of Neurogenetics, National Institute on Aging, Bethesda - both in Maryland (C. Blauwendraat, M.A.N.).

Background: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA.

Methods: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls.

Results: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone.

Conclusions: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).
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http://dx.doi.org/10.1056/NEJMoa1801562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371965PMC
December 2018

Clinical and multi-omics cross-phenotyping of patients with autoimmune and autoinflammatory diseases: the observational TRANSIMMUNOM protocol.

BMJ Open 2018 08 30;8(8):e021037. Epub 2018 Aug 30.

Immunology, Immunopathology, Immunotherapy (i3), Sorbonne Université, INSERM, Paris, France.

Introduction: Autoimmune and autoinflammatory diseases (AIDs) represent a socioeconomic burden as the second cause of chronic illness in Western countries. In this context, the TRANSIMMUNOM clinical protocol is designed to revisit the nosology of AIDs by combining basic, clinical and information sciences. Based on classical and systems biology analyses, it aims to uncover important phenotypes that cut across diagnostic groups so as to discover biomarkers and identify novel therapeutic targets.

Methods And Analysis: TRANSIMMUNOM is an observational clinical protocol that aims to cross-phenotype a set of 19 AIDs, six related control diseases and healthy volunteers . We assembled a multidisciplinary cohort management team tasked with (1) selecting informative biological (routine and omics type) and clinical parameters to be captured, (2) standardising the sample collection and shipment circuit, (3) selecting omics technologies and benchmarking omics data providers, (4) designing and implementing a multidisease electronic case report form and an omics database and (5) implementing supervised and unsupervised data analyses.

Ethics And Dissemination: The study was approved by the institutional review board of Pitié-Salpêtrière Hospital (ethics committee Ile-De-France 48-15) and done in accordance with the Declaration of Helsinki and good clinical practice. Written informed consent is obtained from all participants before enrolment in the study. TRANSIMMUNOM's project website provides information about the protocol (https://www.transimmunom.fr/en/) including experimental set-up and tool developments. Results will be disseminated during annual scientific committees appraising the project progresses and at national and international scientific conferences.

Discussion: Systems biology approaches are increasingly implemented in human pathophysiology research. The TRANSIMMUNOM study applies such approach to the pathophysiology of AIDs. We believe that this translational systems immunology approach has the potential to provide breakthrough discoveries for better understanding and treatment of AIDs.

Trial Registration Number: NCT02466217; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-021037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119447PMC
August 2018

Photoaging and skin cancer: Is the inflammasome the missing link?

Mech Ageing Dev 2018 06 12;172:131-137. Epub 2018 Mar 12.

Sorbonne Université, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Département de Génétique médicale, Paris, F-75012, France. Electronic address:

Photoaging and epithelial skin tumorigenesis are complex processes triggered mainly by UV radiation from chronic sun exposure. This leads to DNA damage and reactive oxygen species (ROS) production, which initiate an inflammatory response that alters cell structure and function. Changes in cell homeostasis and ROS production activate intracellular multiprotein platforms called inflammasomes. Inflammasomes nucleate around cytoplasmic receptors mainly of the NLR (nucleotide-binding domain and leucine-rich repeat) family and regulate caspase-1-dependant secretion of pro-inflammatory interleukin (IL)1β and IL18 cytokines, and an inflammatory form of death named pyroptosis. NLRP1 inflammasomes have taken centre stage in skin biology, as mutations in NLRP1 underlie the genetic etiology of dermatological diseases and increase the susceptibility to skin cancer. Targeting inflammasome(s) might be an important approach to improve skin inflammation, photoaging and reduce the risk of epithelial skin tumorigenesis. In this context, we discuss the potential implication of NLRP1 and NLRP3 inflammasomes.
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http://dx.doi.org/10.1016/j.mad.2018.03.003DOI Listing
June 2018

Inflammasome biology, molecular pathology and therapeutic implications.

Pharmacol Ther 2018 07 18;187:133-149. Epub 2018 Feb 18.

Sorbonne Université, INSERM, UMR_S 933, Assistance Publique Hôpitaux de Paris, Département de Génétique médicale, Hôpital Trousseau, Paris, F-75012, France. Electronic address:

Inflammasomes are intracellular multiprotein signaling complexes, mainly present in myeloid cells. They commonly assemble around a cytoplasmic receptor of the nucleotide-binding leucine-rich repeat containing receptor (NLR) family, although other cytoplasmic receptors like pyrin have been shown to form inflammasomes. The nucleation of the multiprotein scaffolding platform occurs upon detection of a microbial, a danger or a homeostasis pattern by the receptor that will, most commonly, associate with the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) through homotypic domain interactions resulting in recruitment of procaspase-1. This will lead to the autoproteolytic activation of caspase-1, which regulates the secretion of proinflammatory IL1β and IL18 cytokines and pyroptosis, a caspase-1-mediated form of cell death. Pyroptosis occurs through cleavage of Gasdermin D, a membrane pore forming protein. Recently, non-canonical inflammasomes have been described, which directly sense intracellular pathogens through caspase-4 and -5 in humans, leading to pyroptosis. Inflammasomes are important in host defense; however, a deregulated activity is associated with a number of inflammatory, immune and metabolic disorders. Furthermore, mutations in inflammasome receptor coding genes are causal for an increasing number of rare autoinflammatory diseases. Biotherapies targeting the products of inflammasome activation as well as molecules that directly or indirectly inhibit inflammasome nucleation and activation are promising therapeutic areas. This review discusses recent advances in inflammasome biology, the molecular pathology of several inflammasomes, and current therapeutic approaches in autoinflammatory diseases and in selected common multifactorial inflammasome-mediated disorders.
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http://dx.doi.org/10.1016/j.pharmthera.2018.02.011DOI Listing
July 2018
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