Publications by authors named "Frederic Rieux-Laucat"

109 Publications

Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.

Haematologica 2021 Jan 14. Epub 2021 Jan 14.

Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE), Bordeaux, France; Pediatric Oncology Hematology Unit, University Hospital, Plurithématique CIC (CICP), Centre d'Investigation Clinique (CIC) 1401, INSERM Bordeaux.

Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IMs). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 (6.8-50.0) years and the median follow-up period was 11.3 (5.1-38.0) years. At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IMs increased with age: at 20 years old, 74% had at least one clinical cIM. A wide range of cIMs occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IMs. The number of cIMs was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio, 1.4; 95% confidence interval, 1.15-1.60; p = 0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 (1.7-31.5) years, and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, longterm outcomes of pES showed remission of cytopenias but frequent IMs linked to high secondline treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.
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http://dx.doi.org/10.3324/haematol.2020.271106DOI Listing
January 2021

Life-Saving, Dose-Adjusted, Targeted Therapy in a Patient with a STAT3 Gain-of-Function Mutation.

J Clin Immunol 2021 Jan 11. Epub 2021 Jan 11.

Pediatric Immunohematology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), 149 rue de Sèvres, F-75015, Paris, France.

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http://dx.doi.org/10.1007/s10875-020-00914-3DOI Listing
January 2021

Immunologic evaluation and genetic defects of apoptosis in patients with autoimmune lymphoproliferative syndrome (ALPS).

Crit Rev Clin Lab Sci 2020 Dec 23:1-30. Epub 2020 Dec 23.

Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.

Apoptosis plays an important role in controlling the adaptive immune response and general homeostasis of the immune cells, and impaired apoptosis in the immune system results in autoimmunity and immune dysregulation. In the last 25 years, inherited human diseases of the Fas-FasL pathway have been recognized. Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity, characterized clinically by nonmalignant and noninfectious lymphoproliferation, autoimmunity, and increased risk of lymphoma due to a defect in lymphocyte apoptosis. The laboratory hallmarks of ALPS are an elevated percentage of T-cell receptor αβ double negative T cells (DNTs), elevated levels of vitamin B12, soluble FasL, IL-10, IL-18 and IgG, and defective Fas-mediated apoptosis. In order of frequency, the genetic defects associated with ALPS are germinal and somatic ALPS-FAS, ALPS-FASLG, ALPS-CASP10, ALPS-FADD, and ALPS-CASP8. Partial disease penetrance and severity suggest the combination of germline and somatic mutations as well as other risk factor genes. In this report, we summarize human defects of apoptosis leading to ALPS and defects that are known as ALPS-like syndromes that can be clinically similar to, but are genetically distinct from, ALPS. An efficient genetic and immunological diagnostic approach to patients suspected of having ALPS or ALPS-like syndromes is essential because this enables the establishment of specific therapeutic strategies for improving the prognosis and quality of life of patients.
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http://dx.doi.org/10.1080/10408363.2020.1855623DOI Listing
December 2020

Generation of an iPSC line (IMAGINi011-A) from a patient carrying a STING mutation.

Stem Cell Res 2020 Dec 2;50:102107. Epub 2020 Dec 2.

Université de Paris, Imagine Institute, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR U1163, F-75015 Paris, France. Electronic address:

Mutation in STING1gene, which encodes stimulator of type I IFN gene (STING) leads to its constitutive activation and thereby to a severe vasculopathy and sometimes a lupus-like disease. We generated induced pluripotent stem cells (iPSCs) from a patient carrying a rare heterozygous variant c.463G > A (resulting in a p.V155M substitution) in STING1. Cells from this patient, which were reprogrammed by non-integrative viral transduction, had normal karyotype, expressed pluripotency markers and were able to differentiate into the three germ cell layers.
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http://dx.doi.org/10.1016/j.scr.2020.102107DOI Listing
December 2020

Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients.

J Allergy Clin Immunol Pract 2021 Feb 18;9(2):803-818.e11. Epub 2020 Nov 18.

Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France; Université de Paris, Imagine Institute, Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Paris, France. Electronic address:

Background: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).

Objective: To describe a cohort of patients with SAVI.

Methods: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.

Results: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.

Conclusion: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
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http://dx.doi.org/10.1016/j.jaip.2020.11.007DOI Listing
February 2021

Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

Nat Commun 2020 10 21;11(1):5341. Epub 2020 Oct 21.

Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 24 boulevard du Montparnasse, 75015, Paris, France.

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.
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http://dx.doi.org/10.1038/s41467-020-18925-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578789PMC
October 2020

Autoantibodies against type I IFNs in patients with life-threatening COVID-19.

Authors:
Paul Bastard Lindsey B Rosen Qian Zhang Eleftherios Michailidis Hans-Heinrich Hoffmann Yu Zhang Karim Dorgham Quentin Philippot Jérémie Rosain Vivien Béziat Jérémy Manry Elana Shaw Liis Haljasmägi Pärt Peterson Lazaro Lorenzo Lucy Bizien Sophie Trouillet-Assant Kerry Dobbs Adriana Almeida de Jesus Alexandre Belot Anne Kallaste Emilie Catherinot Yacine Tandjaoui-Lambiotte Jeremie Le Pen Gaspard Kerner Benedetta Bigio Yoann Seeleuthner Rui Yang Alexandre Bolze András N Spaan Ottavia M Delmonte Michael S Abers Alessandro Aiuti Giorgio Casari Vito Lampasona Lorenzo Piemonti Fabio Ciceri Kaya Bilguvar Richard P Lifton Marc Vasse David M Smadja Mélanie Migaud Jérome Hadjadj Benjamin Terrier Darragh Duffy Lluis Quintana-Murci Diederik van de Beek Lucie Roussel Donald C Vinh Stuart G Tangye Filomeen Haerynck David Dalmau Javier Martinez-Picado Petter Brodin Michel C Nussenzweig Stéphanie Boisson-Dupuis Carlos Rodríguez-Gallego Guillaume Vogt Trine H Mogensen Andrew J Oler Jingwen Gu Peter D Burbelo Jeffrey I Cohen Andrea Biondi Laura Rachele Bettini Mariella D'Angio Paolo Bonfanti Patrick Rossignol Julien Mayaux Frédéric Rieux-Laucat Eystein S Husebye Francesca Fusco Matilde Valeria Ursini Luisa Imberti Alessandra Sottini Simone Paghera Eugenia Quiros-Roldan Camillo Rossi Riccardo Castagnoli Daniela Montagna Amelia Licari Gian Luigi Marseglia Xavier Duval Jade Ghosn John S Tsang Raphaela Goldbach-Mansky Kai Kisand Michail S Lionakis Anne Puel Shen-Ying Zhang Steven M Holland Guy Gorochov Emmanuelle Jouanguy Charles M Rice Aurélie Cobat Luigi D Notarangelo Laurent Abel Helen C Su Jean-Laurent Casanova

Science 2020 10 24;370(6515). Epub 2020 Sep 24.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
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http://dx.doi.org/10.1126/science.abd4585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857397PMC
October 2020

Corrigendum to: Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study.

J Crohns Colitis 2020 Sep 8. Epub 2020 Sep 8.

INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France.

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http://dx.doi.org/10.1093/ecco-jcc/jjaa164DOI Listing
September 2020

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.

Science 2020 08 13;369(6504):718-724. Epub 2020 Jul 13.

Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP, APHP-CUP, Hôpital Cochin, F-75014 Paris, France.

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.
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http://dx.doi.org/10.1126/science.abc6027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402632PMC
August 2020

Letter to the Editor: Coexistence of Autoimmune Lymphoproliferative Syndrome and Familial Mediterranean Fever.

Iran J Immunol 2020 06;17(2):172-174

Department of Pediatric Hematology, Dr. Behçet Uz Children's Hospital, Izmir, Turkey.

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http://dx.doi.org/10.22034/iji.2020.85774.1725DOI Listing
June 2020

STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice.

Cell Rep 2020 06;31(11):107771

Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address:

STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer's patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β7 progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.
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http://dx.doi.org/10.1016/j.celrep.2020.107771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372600PMC
June 2020

Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing.

J Allergy Clin Immunol 2021 Feb 10;147(2):734-737. Epub 2020 Jun 10.

University of Paris, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1163, Imagine Institute, Paris, France; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children-Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM-UMR 1163, Paris, France; Pediatric Immuno-Hematology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France; French National Reference Center for Primary Immune Deficiencies, Le Centre de Référence Déficits Immunitaires Héréditaires, Necker Hospital for Sick Children, AP-HP, Paris, France.

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http://dx.doi.org/10.1016/j.jaci.2020.05.046DOI Listing
February 2021

Germline TET2 loss of function causes childhood immunodeficiency and lymphoma.

Blood 2020 Aug;136(9):1055-1066

Primary Immunodeficiency Group, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom.

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.
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http://dx.doi.org/10.1182/blood.2020005844DOI Listing
August 2020

Two neurologic facets of CTLA4-related haploinsufficiency.

Neurol Neuroimmunol Neuroinflamm 2020 07 4;7(4). Epub 2020 Jun 4.

From the Department of Neurology (X.A., C.C.-D., P.L.), Montpellier University Hospital, INSERM, Univ Montpellier, Montpellier; Internal Medicine Department (R.G.), Caremeau University Hospital, Nimes; Department of Paediatrics (E.J.), Montpellier University Hospital, INSERM, Univ Montpellier; Médecine interne multi-organes (P.R., P.G.), Montpellier University Hospital, INSERM, Univ Montpellier; Department of Immunology (C.L., P.P., T.V.), Montpellier University Hospital, INSERM, Univ Montpellier; Internal Medicine Department (J.F.V.), Bordeaux University Hospital, Univ Bordeaux; Department of Neuroradiology (N.M.C.), Montpellier University Hospital, INSERM, Univ Montpellier; Université de Paris (F.R.-L., C.B.), Imagine institute, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Paris; and Laboratory of Molecular Genetics (M.K., C.G.), Montpellier University Hospital, INSERM, Univ Montpellier, France.

Objective: To describe the clinical and radiologic neurologic characteristics of patients with cytotoxic T-lymphocyte antigen-4 () haploinsufficiency.

Methods: Three patients from 2 families had neurologic manifestations in the context of haploinsufficiency. Their clinical and MRI findings are presented.

Results: A 16-year-old boy with a previous diagnosis of combined immunodeficiency presented with severe recurrent episodes of headaches, motor deficit, and seizures associated with waxing and waning gadolinium-enhancing FLAIR cortical/juxtacortical hyperintensities. His sister, who also had combined immunodeficiency, had a brain MRI when she was aged 13 years due to recent headaches and transient right hemianopsia. It revealed a gadolinium-enhancing left occipital white matter hyperintensity. Another 49-year-old woman had progressive visual loss and cerebellar ataxia in the context of recurrent pulmonary infections. All 3 patients were found to have inherited haploinsufficiency. Patient 1's general condition and neurologic manifestations were completely controlled with abatacept (CTLA4-Ig).

Conclusions: These cases suggest that in addition to the variable clinical penetrance and wide spectrum of haploinsufficiency, its neurologic spectrum is broad, ranging from recurrent tumefactive lesions to progressive deficits including cerebellar ataxia and optic atrophy with leukoencephalopathy. These phenotypes must be recognized, and should lead to a complete immunologic workup, because potentially effective targeted immunotherapy exists.
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http://dx.doi.org/10.1212/NXI.0000000000000751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286662PMC
July 2020

Autoimmune Lymphoproliferative Syndrome Presenting with Invasive Streptococcus pneumoniae Infection.

J Clin Immunol 2020 04 6;40(3):543-546. Epub 2020 Mar 6.

Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute ; INSERM UMR 1163, Paris Descartes Sorbonne Paris Cité University, Paris, France.

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http://dx.doi.org/10.1007/s10875-020-00765-yDOI Listing
April 2020

After 95 years, it's time to eRASe JMML.

Blood Rev 2020 09 16;43:100652. Epub 2020 Jan 16.

Université de Paris, Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, F-75015 Paris, France. Electronic address:

Juvenile myelomonocytic leukaemia (JMML) is a rare clonal disorder of early childhood. Constitutive activation of the RAS pathway is the initial event in JMML. Around 90% of patients diagnosed with JMML carry a mutation in the PTPN11, NRAS, KRAS, NF1 or CBL genes. It has been demonstrated that after this first genetic event, an additional somatic mutation or epigenetic modification is involved in disease progression. The available genetic and clinical data have enabled researchers to establish relationships between JMML and several clinical conditions, including Noonan syndrome, Ras-associated lymphoproliferative disease, and Moyamoya disease. Despite scientific progress and the development of more effective treatments, JMML is still a deadly disease: the 5-year survival rate is ~50%. Here, we report on recent research having led to a better understanding of the genetic and molecular mechanisms involved in JMML.
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http://dx.doi.org/10.1016/j.blre.2020.100652DOI Listing
September 2020

Fatal Hypogammaglobulinemia 3 Years after Rituximab in a Patient with Immune Thrombocytopenia: An Underlying Genetic Predisposition?

Case Reports Immunol 2019 28;2019:2543038. Epub 2019 Dec 28.

INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Paris Descartes-Sorbonne, Paris Cité University, Imagine Institute, Paris, France.

We report the case of a young woman who developed, 3 years after stopping Rituximab (RTX) prescribed for immune thrombocytopenia (ITP), a severe immunodeficiency leading to fatal pulmonary Epstein-Barr virus-positive diffuse large B-cell lymphoma. Genetic analysis led us to identify four missense mutations known to affect immune-deficiency-associated genes (FAS-ligand () gene (p.G167R); perforin-1 ( (p.R55C) gene; the Bloom syndrome RecQ-Like helicase () gene and the Moesin () (p.A122T) gene). The heterozygous mutation in the gene, not present in the Genome Aggregation Database or ClinVar database, could suggest atypical Autoimmune LymphoProliferative Syndrome and its role in this patient's immunodepression is discussed. This observation strengthens the role of gene mutation in severe clinical phenotypes of primary immune deficiency and raises new questions about the genetic background of ITP occurring in young people in a context of immunodeficiency.
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http://dx.doi.org/10.1155/2019/2543038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949674PMC
December 2019

Comment on: Monogenic mimics of Behçet's disease in the young.

Rheumatology (Oxford) 2020 11;59(11):e109-e111

Department of Paediatric Immunology-Haematology and Rheumatology, Necker University Hospital - AP-HP.

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http://dx.doi.org/10.1093/rheumatology/kez543DOI Listing
November 2020

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

Authors:
Hélène Coignard-Biehler Nizar Mahlaoui Benoit Pilmis Vincent Barlogis Pauline Brosselin Nathalie De Vergnes Marianne Debré Marion Malphettes Pierre Frange Emilie Catherinot Isabelle Pellier Isabelle Durieu Antoinette Perlat Bruno Royer Alain Le Quellec Eric Jeziorski Alain Fischer Olivier Lortholary Laurent Aaron Daniel Adoue Claire Aguilar Nathalie Aladjidi Alexandre Alcais Zahir Amoura Philippe Arlet Corinne Armari-Alla Brigitte Bader-Meunier Sophie Bayart Yves Bertrand Boris Bienvenu Stéphane Blanche Damien Bodet Bernard Bonnotte Raphaël Borie Patrick Boutard Claire Briandet Jean-Paul Brion Jacques Brouard Sarah Cohen-Beaussant Laurence Costes Louis-Jean Couderc Pierre Cougoul Virginie Courteille Geneviève de Saint Basile Catherine Devoldere Anne Deville Jean Donadieu Eric Dore Fabienne Dulieu Christine Edan Natacha Entz-Werle Claire Fieschi Amandine Forestier Fanny Fouyssac Vincent Gajdos Lionel Galicier Virginie Gandemer Martine Gardembas Catherine Gaud Gaelle Guillerm Eric Hachulla Mohamed Hamidou Olivier Hermine Cyrille Hoarau Sébastien Humbert Arnaud Jaccard Serge Jacquot Jean-Philippe Jais Roland Jaussaud Pierre-Yves Jeandel Kamila Kebaili Anne-Sophie Korganow Olivier Lambotte Fanny Lanternier Claire Larroche Anne-Sophie Lascaux Emmanuelle Le Moigne Vincent Le Moing Yvon Lebranchu Marc Lecuit Guillaume Lefevre Richard Lemal Valérie Li Thiao Te Aude Marie-Cardine Nicolas Martin Silva Agathe Masseau Christian Massot Françoise Mazingue Etienne Merlin Gérard Michel Frédéric Millot Béatrice Monlibert Fabrice Monpoux Despina Moshous Luc Mouthon Martine Munzer Bénédicte Neven Raphaëlle Nove-Josserand Eric Oksenhendler Marie Ouachée-Chardin Caroline Oudot Anne Pagnier Jean-Louis Pasquali Marlène Pasquet Yves Perel Capucine Picard Christophe Piguet Dominique Plantaz Johan Provot Pierre Quartier Frédéric Rieux-Laucat Pascal Roblot Pierre-Marie Roger Pierre-Simon Rohrlich Hervé Rubie Valéry Salle Françoise Sarrot-Reynauld Amélie Servettaz Jean-Louis Stephan Nicolas Schleinitz Felipe Suarez Laure Swiader Sophie Taque Caroline Thomas Olivier Tournilhac Caroline Thumerelle François Tron Jean-Pierre Vannier Jean-François Viallard

J Clin Immunol 2019 10 10;39(7):702-712. Epub 2019 Aug 10.

Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.

Purpose: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles.

Methods: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included.

Results: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04).

Conclusion: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.
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http://dx.doi.org/10.1007/s10875-019-00658-9DOI Listing
October 2019

Monogenic lupus: Dissecting heterogeneity.

Autoimmun Rev 2019 Oct 8;18(10):102361. Epub 2019 Aug 8.

CIRI, Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Inserm, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, CNRS, UMR5308, Lyon, France; Pediatric Nephrology, Rheumatology, Dermatology Unit, Hospices Civils de Lyon, France; National Referee Centre for Rheumatic and AutoImmune and Systemic diseases in childrEn (RAISE), France. Electronic address:

Systemic lupus erythematosus (SLE) is a severe lifelong multisystem autoimmune disease characterized by the presence of autoantibodies targeting nuclear autoantigens, increased production of type I interferon and B cell abnormalities. Clinical presentation of SLE is extremely heterogeneous and different groups of disease are likely to exist. Recently, childhood-onset SLE (cSLE) cases have been linked to single gene mutations, defining the concept of monogenic or Mendelian lupus. Genes associated with Mendelian lupus can be grouped in at least three functional categories. First, complement deficiencies represent the main cause of monogenic lupus and its components are involved in the clearance of dying cells, a mechanism also called efferocytosis. Mutations in extracellular DNASE have been also identified in cSLE patients and represent additional causes leading to defective clearance of nucleic acids and apoptotic bodies. Second, the study of Aicardi-Goutières syndromes has introduced the concept of type-I interferonopathies. Bona fide lupus syndromes have been associated to this genetic condition, driven by defective nucleic acids metabolism or innate sensors overactivity. Interferon signalling anomalies can be detected and monitored during therapies, such as Janus-kinase (JAK) inhibitors. Third, tolerance breakdown can occur following genetic mutations in B and/or T cell expressing key immunoregulatory molecules. Biallelic mutations in PRKCD are associated to lupus and lymphoproliferative diseases as PKC-δ displays proapoptotic activity and is crucial to eliminate self-reactive transitional B cells. Here we review the literature of the emerging field of Mendelian lupus and discuss the physiopathological learning from these inborn errors of immunity. In addition, clinical and biological features are highlighted as well as specific therapies that have been tested in these genetic contexts.
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http://dx.doi.org/10.1016/j.autrev.2019.102361DOI Listing
October 2019

Life-threatening pulmonary interstitial lung disease complicating pediatric nonhumoral immunodeficiencies.

J Allergy Clin Immunol Pract 2019 Sep - Oct;7(7):2456-2458.e4. Epub 2019 Apr 3.

Department of Paediatric Allergy & Immunology, Lydia Becker Institute of Immunology & Inflammation, University of Manchester, Manchester, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.03.034DOI Listing
October 2020

Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes.

Blood 2019 07 2;134(1):9-21. Epub 2019 Apr 2.

Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, Unité Mixte de Recherche (UMR) 1163, INSERM, Paris, France.

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (, , , , , , , , and ), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.
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http://dx.doi.org/10.1182/blood-2018-11-887141DOI Listing
July 2019

Neurological Involvement in Childhood Evans Syndrome.

J Clin Immunol 2019 02 22;39(2):171-181. Epub 2019 Jan 22.

Centre de Référence National des Cytopénies Autoimmunes de l'Enfant (CEREVANCE), University Hospital of Bordeaux, Bordeaux, France.

Purpose: Immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are associated in the definition of Evans syndrome (ES). The occurrence of neurological involvement in this population is poorly described and suggests an underlying primary immunodeficiency (PID). We aimed to describe the clinical manifestations, evolution, and PID profiles of these patients.

Methods: OBS'CEREVANCE is a French, nationwide prospective cohort that includes children with chronic ITP, AIHA, and ES. Patients with a neurological involvement were described. Centralized radiological and pathological reviews and genetic analyses were performed.

Results: On October 2016, eight patients (7/181 ES, 1/371 AIHA, and 0/615 ITP) were identified, all male, with a median age (range) at cytopenia onset of 11.5 years (1.6-15.8). Neurological symptoms appeared with a median delay of 6 years (2.5-18) after cytopenia and were polymorphic: seizures (n = 4), cranial nerve palsy (n = 2), Brown-Sequard syndrome (n = 2), intracranial pressure (n = 2), vertigo (n = 1), and/or sensory neuropathy (n = 1). Magnetic resonance imaging (MRI) showed inflammatory lesions, confirmed by pathology for five patients with macrophagic or lymphoplasmocytic infiltrates. All patients had other relevant immunopathological manifestations: pulmonary nodules (n = 6), lymphoproliferation (n = 4), abnormal immunophenotype (n = 8), and hypogammaglobulinemia (n = 7). Treatment consisted of steroids that improved symptomatology and MRI. Five patients relapsed and three had an asymptomatic radiological progression. A PID was identified in 3/8 patients: 22q11.2 microdeletion (n = 1) and CTLA deficiency (n = 2).

Conclusion: Neurological involvement is a rare and severe late event in the course of childhood ES, which can reveal an underlying PID. Imaging and pathology examination highlight a causative immune dysregulation that may guide targeted therapeutic strategies.
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http://dx.doi.org/10.1007/s10875-019-0594-3DOI Listing
February 2019

FAS and RAS related Apoptosis defects: From autoimmunity to leukemia.

Immunol Rev 2019 01;287(1):50-61

Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Paris, France.

The human adaptive immune system recognizes almost all the pathogens that we encounter and all the tumor antigens that may arise during our lifetime. Primary immunodeficiencies affecting lymphocyte development or function therefore lead to severe infections and tumor susceptibility. Furthermore, the fact that autoimmunity is a frequent feature of primary immunodeficiencies reveals a third function of the adaptive immune system: its self-regulation. Indeed, the generation of a broad repertoire of antigen receptors (via a unique strategy of random somatic rearrangements of gene segments in T cell and B cell receptor loci) inevitably creates receptors with specificity for self-antigens and thus leads to the presence of autoreactive lymphocytes. There are many different mechanisms for controlling the emergence or action of autoreactive lymphocytes, including clonal deletion in the primary lymphoid organs, receptor editing, anergy, suppression of effector lymphocytes by regulatory lymphocytes, and programmed cell death. Here, we review the genetic defects affecting lymphocyte apoptosis and that are associated with lymphoproliferation and autoimmunity, together with the role of somatic mutations and their potential involvement in more common autoimmune diseases.
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http://dx.doi.org/10.1111/imr.12720DOI Listing
January 2019

Efficacy of Ruxolitinib Therapy in a Patient With Severe Enterocolitis Associated With a STAT3 Gain-of-Function Mutation.

Gastroenterology 2019 03 15;156(4):1206-1210.e1. Epub 2018 Dec 15.

Inserm UMR1163, Intestinal Immunity, Institut Imagine, Paris, France; Université Paris Descartes Sorbonne Paris Cité, Paris, France; AP-HP, Gastroenterology, Hôpital Cochin, Paris, France. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2018.11.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433619PMC
March 2019

Monitoring Disease Activity in Systemic Lupus Erythematosus With Single-Molecule Array Digital Enzyme-Linked Immunosorbent Assay Quantification of Serum Interferon-α.

Arthritis Rheumatol 2019 05;71(5):756-765

Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.

Objective: No simple or standardized assay is available to quantify interferon-α (IFNα) in routine clinical practice. Single-molecule array (Simoa) digital enzyme-linked immunosorbent assay (ELISA) technology enables direct IFNα quantification at attomolar (femtogram per milliliter [fg/ml]) concentrations. This study was undertaken to assess IFNα digital ELISA diagnostic performances to monitor systemic lupus erythematosus (SLE) activity.

Methods: IFNα concentrations in serum samples from 150 consecutive SLE patients in a cross-sectional study were determined with digital ELISA and a functional biologic activity assay (bioassay). According to their Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) flare composite scores, patients were divided into groups with inactive SLE (SLEDAI score of <4 or clinical SLEDAI score of 0) or active SLE (SLEDAI score of ≥4 or clinical SLEDAI score of >0), and into groups with no flare or mild/moderate flare or severe flare.

Results: Based on serum samples from healthy blood donors, the abnormal serum IFNα level threshold value was 136 fg/ml. Next, using receiver operating characteristic curves for an SLE patient series that was widely heterogeneous in terms of disease activity and organ involvement, the threshold IFNα value associated with active disease was determined to be 266 fg/ml. The digital ELISA-assessed serum IFNα level was a better biomarker of disease activity than the Farr assay because its specificity, likelihood ratio for positive results, and positive predictive value better discerned active SLE or flare from inactive disease. The digital ELISA was more sensitive than the bioassay for detecting low-abnormal serum IFNα concentrations and identifying patients with low disease activity.

Conclusion: Direct serum IFNα determination with a highly sensitive assay might improve monitoring of clinical SLE activity and selection of the best candidates for anti-IFNα treatment.
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http://dx.doi.org/10.1002/art.40792DOI Listing
May 2019

Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds.

PLoS One 2018 26;13(10):e0205826. Epub 2018 Oct 26.

INSERM, UMR1163 and Institut Imagine, Laboratory of Intestinal Immunity, Paris, France.

Mutations in interleukin-10 receptor (IL-10R) genes are one cause of very early-onset inflammatory bowel disease with perianal lesions, which can be cured by hematopoietic stem cell transplantation. Using a functional test, which assesses responsiveness of peripheral monocytes to IL-10, we identified three unrelated Portuguese patients carrying two novel IL-10RB mutations. In the three patients, sequencing of genomic DNA identified the same large deletion of exon 3 which precluded protein expression. This mutation was homozygous in two patients born from consanguineous families and heterozygous in the third patient born from unrelated parents. Microsatellite analysis of the IL10RB genomic region revealed a common haplotype in the three Portuguese families pointing to a founder deletion inherited from a common ancestor 400 years ago. In the third patient, surface expression of IL-10R was normal but signaling in response to IL-10 was impaired. Complementary DNA sequencing and next-generation sequencing of IL10RB locus with custom-made probes revealed a ≈ 6 Kb duplication encompassing the exon 6 which leads to a frameshift mutation and a loss of the TYK2-interacting Box 2 motif. Altogether, we describe two novel copy number variations in IL10RB, one with founder effect and one preserving cell surface expression but abolishing signaling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205826PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203366PMC
April 2019

Chronic granulomatous skin lesions leading to a diagnosis of TAP1 deficiency syndrome.

Pediatr Dermatol 2018 Nov 6;35(6):e375-e377. Epub 2018 Sep 6.

Department of Dermatology, Rennes University Hospital, Rennes, France.

Transporter associated with antigen processing (TAP) is essential for the stabilization and surface expression of major histocompatibility complex class I molecules of all nucleated cells. TAP deficiency syndrome, also known as bare lymphocyte syndrome type I, is a rare primary immunodeficiency disorder. We report a case of TAP1 deficiency revealed by skin lesions long before the occurrence of respiratory infectious manifestations.
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http://dx.doi.org/10.1111/pde.13676DOI Listing
November 2018

The Autoimmune Lymphoproliferative Syndrome with Defective FAS or FAS-Ligand Functions.

J Clin Immunol 2018 07 17;38(5):558-568. Epub 2018 Jun 17.

Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163-Institut Imagine, 24 boulevard du Montparnasse, 75015, Paris, France.

The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia. The genetic etiology of the ALPS was described in 1995 by the discovery of the FAS gene mutations. The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic defects of this apoptosis pathway, such as FADD and CASPASE 8 deficiencies. The ALPS-FAS was the first description of a monogenic cause of autoimmunity, but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients. The recognition of these genetic diseases brought new information on the role of this apoptotic pathway in controlling the adaptive immune response in humans.
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http://dx.doi.org/10.1007/s10875-018-0523-xDOI Listing
July 2018

Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice.

J Allergy Clin Immunol 2019 02 23;143(2):712-725.e5. Epub 2018 May 23.

CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; UFR Sciences Pharmaceutiques, Université de Strasbourg, Illkirch-Graffenstaden, France. Electronic address:

Background: Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts.

Objective: The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system.

Methods: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in human patients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-α/β receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded.

Results: In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B- and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency.

Conclusions: STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent.
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http://dx.doi.org/10.1016/j.jaci.2018.04.034DOI Listing
February 2019