Publications by authors named "Alain Fischer"

433 Publications

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

Is neutralization of IFN-γ sufficient to control inflammation in HLH?

Pediatr Blood Cancer 2021 Mar 6;68(3):e28886. Epub 2021 Jan 6.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

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http://dx.doi.org/10.1002/pbc.28886DOI Listing
March 2021

Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency.

J Clin Invest 2021 Feb;131(3)

Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.
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http://dx.doi.org/10.1172/JCI142434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843233PMC
February 2021

Different Clinical Presentations and Outcomes of Disseminated Varicella in Children With Primary and Acquired Immunodeficiencies.

Front Immunol 2020 5;11:595478. Epub 2020 Nov 5.

Service d'Immunologie et Hématologie Pédiatrique, Hôpital Necker Enfants Malades, AP-HP, Paris, France.

Primary infection with varicella-zoster virus (VZV) causes chickenpox, a benign and self-limited disease in healthy children. In patients with primary or acquired immunodeficiencies, primary infection can be life-threatening, due to rapid dissemination of the virus to various organs [lung, gastrointestinal tract, liver, eye, central nervous system (CNS)]. We retrospectively described and compared the clinical presentations and outcomes of disseminated varicella infection (DV) in patients with acquired (AID) (= 7) and primary (PID) (= 12) immunodeficiencies. Patients with AID were on immunosuppression (mostly steroids) for nephrotic syndrome, solid organ transplantation or the treatment of hemopathies, whereas those with PID had combined immunodeficiency (CID) or severe CID (SCID). The course of the disease was severe and fulminant in patients with AID, with multiple organ failure, no rash or a delayed rash, whereas patients with CID and SICD presented typical signs of chickenpox, including a rash, with dissemination to other organs, including the lungs and CNS. In the PID group, antiviral treatment was prolonged until immune reconstitution after bone marrow transplantation, which was performed in 10/12 patients. Four patients died, and three experienced neurological sequelae. SCID patients had the worst outcome. Our findings highlight substantial differences in the clinical presentation and course of DV between children with AID and PID, suggesting differences in pathophysiology. Prevention, early diagnosis and treatment are required to improve outcome.
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http://dx.doi.org/10.3389/fimmu.2020.595478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674974PMC
November 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

Outcome of chronic granulomatous disease - Conventional treatment vs stem cell transplantation.

Pediatr Allergy Immunol 2021 Apr 22;32(3):576-585. Epub 2020 Nov 22.

Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Charité Universitätsmedizin -Berlin University Hospital Center, Berlin, Germany.

Background: Hematopoietic stem cell transplantation (HSCT) can cure chronic granulomatous disease (CGD), but it remains debated whether all conventionally treated CGD patients benefit from HSCT.

Methods: We retrospectively analyzed 104 conventionally treated CGD patients, of whom 50 patients underwent HSCT.

Results: On conventional treatment, seven patients (13%) died after a median time of 16.2 years (interquartile range [IQR] 7.0-18.0). Survival without severe complications was 10 ± 3% (mean ± SD) at the age of 20 years; 85% of patients developed at least one infection, 76% one non-infectious inflammation. After HSCT, 44 patients (88%) were alive at a median follow-up of 2.3 years (IQR 0.8-4.9): Six patients (12%) died from infections. Survival after HSCT was significantly better for patients transplanted ≤8 years (96 ± 4%) or for patients without active complications at HSCT (100%). Eight patients suffered from graft failure (16%); six (12%) developed acute graft-vs-host disease requiring systemic treatment. Conventionally treated patients developed events that required medical attention at a median frequency of 1.7 (IQR 0.8-3.2) events per year vs 0 (IQR 0.0-0.5) in patients beyond the first year post-HSCT. While most conventionally treated CGD patients failed to thrive, catch-up growth after HSCT in surviving patients reached the individual percentiles at the age of diagnosis of CGD.

Conclusion: Chronic granulomatous disease patients undergoing HSCT until 8 years of age show excellent survival, but young children need more intense conditioning to avoid graft rejection. Risks and benefits of HSCT for adolescents and adults must still be weighed carefully.
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http://dx.doi.org/10.1111/pai.13402DOI Listing
April 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

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

J Allergy Clin Immunol 2021 Feb 24;147(2):520-531. Epub 2020 Sep 24.

Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, Australia. Electronic address:

Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.

Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.

Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.

Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jaci.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832563PMC
February 2021

Nocardiosis Associated with Primary Immunodeficiencies (Nocar-DIP): an International Retrospective Study and Literature Review.

J Clin Immunol 2020 11 12;40(8):1144-1155. Epub 2020 Sep 12.

Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker -Pasteur, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades University Hospital, Université de Paris, Paris, France.

Purpose: Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID).

Methods: This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed.

Results: Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0-56) years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis of Nocardia infection was 20 (2-257) days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency.

Conclusions: Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.
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http://dx.doi.org/10.1007/s10875-020-00866-8DOI Listing
November 2020

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

J Crohns Colitis 2021 03;15(3):517-518

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944498PMC
March 2021

Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection.

J Exp Med 2020 11;217(11)

Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, Imagine Institute, Paris, France.

Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.
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http://dx.doi.org/10.1084/jem.20192262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596820PMC
November 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

A 23-Year Follow-Up of a Patient with Gain-of-Function IkB-Alpha Mutation and Stable Full Chimerism After Hematopoietic Stem Cell Transplantation.

J Clin Immunol 2020 08 2;40(6):927-933. Epub 2020 Jul 2.

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Piazza S. Onofrio 4, Rome, Italy.

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http://dx.doi.org/10.1007/s10875-020-00780-zDOI Listing
August 2020

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

J Clin Immunol 2020 Jul;40(5):786-787

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

The original version of the article contained error regarding the presentation of the institutional authors in the PDF and html versions.
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http://dx.doi.org/10.1007/s10875-020-00793-8DOI Listing
July 2020

Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series.

J Clin Immunol 2020 07 19;40(5):752-762. Epub 2020 Jun 19.

Pediatric Immuno-Hematology and Rheumatology Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades University Hospital, Paris, France.

Background: X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype.

Methods: We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types.

Results: The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well.

Conclusion: This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.
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http://dx.doi.org/10.1007/s10875-020-00791-wDOI Listing
July 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

Resistance of children to Covid-19. How?

Authors:
Alain Fischer

Mucosal Immunol 2020 07 28;13(4):563-565. Epub 2020 May 28.

Collège de France, Paris, France.

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http://dx.doi.org/10.1038/s41385-020-0303-9DOI Listing
July 2020

[What is the fair price of innovative therapy?]

Med Sci (Paris) 2020 Apr 1;36(4):389-393. Epub 2020 May 1.

I3h Institute, Université libre de Bruxelles, Belgique.

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http://dx.doi.org/10.1051/medsci/2020059DOI Listing
April 2020

Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome.

J Allergy Clin Immunol 2020 11 18;146(5):1165-1179.e11. Epub 2020 Apr 18.

Milan Unit, Institute for Genetic and Biomedical Research (IRGB) National Research Council (CNR), Milan, Italy; Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy. Electronic address:

Background: Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS).

Objective: The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified.

Methods: We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2 (Rag2) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt.

Results: We show that memory/activated T cells from patients with OS and from the Rag2 mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad T1/T2/T17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2 mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2 mice results in increased frequency of Ccr4 splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by T1 effector T cells.

Conclusions: These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS.
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http://dx.doi.org/10.1016/j.jaci.2020.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649331PMC
November 2020

Kinesin-1 regulates antigen cross-presentation through the scission of tubulations from early endosomes in dendritic cells.

Nat Commun 2020 04 14;11(1):1817. Epub 2020 Apr 14.

Université de Paris, Imagine Institute, Laboratory of Molecular basis of altered immune homeostasis, INSERM UMR1163, F-75015, Paris, France.

Dendritic cells (DCs) constitute a specialized population of immune cells that present exogenous antigen (Ag) on major histocompatibility complex (MHC) class I molecules to initiate CD8 + T cell responses against pathogens and tumours. Although cross-presentation depends critically on the trafficking of Ag-containing intracellular vesicular compartments, the molecular machinery that regulates vesicular transport is incompletely understood. Here, we demonstrate that mice lacking Kif5b (the heavy chain of kinesin-1) in their DCs exhibit a major impairment in cross-presentation and thus a poor in vivo anti-tumour response. We find that kinesin-1 critically regulates antigen cross-presentation in DCs, by controlling Ag degradation, the endosomal pH, and MHC-I recycling. Mechanistically, kinesin-1 appears to regulate early endosome maturation by allowing the scission of endosomal tubulations. Our results highlight kinesin-1's role as a molecular checkpoint that modulates the balance between antigen degradation and cross-presentation.
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http://dx.doi.org/10.1038/s41467-020-15692-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156633PMC
April 2020

Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Imagine Institute, Paris, France.

Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.
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http://dx.doi.org/10.1172/jci.insight.133880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141395PMC
March 2020

Clonal tracking in gene therapy patients reveals a diversity of human hematopoietic differentiation programs.

Blood 2020 04;135(15):1219-1231

Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA.

In gene therapy with human hematopoietic stem and progenitor cells (HSPCs), each gene-corrected cell and its progeny are marked in a unique way by the integrating vector. This feature enables lineages to be tracked by sampling blood cells and using DNA sequencing to identify the vector integration sites. Here, we studied 5 cell lineages (granulocytes, monocytes, T cells, B cells, and natural killer cells) in patients having undergone HSPC gene therapy for Wiskott-Aldrich syndrome or β hemoglobinopathies. We found that the estimated minimum number of active, repopulating HSPCs (which ranged from 2000 to 50 000) was correlated with the number of HSPCs per kilogram infused. We sought to quantify the lineage output and dynamics of gene-modified clones; this is usually challenging because of sparse sampling of the various cell types during the analytical procedure, contamination during cell isolation, and different levels of vector marking in the various lineages. We therefore measured the residual contamination and corrected our statistical models accordingly to provide a rigorous analysis of the HSPC lineage output. A cluster analysis of the HSPC lineage output highlighted the existence of several stable, distinct differentiation programs, including myeloid-dominant, lymphoid-dominant, and balanced cell subsets. Our study evidenced the heterogeneous nature of the cell lineage output from HSPCs and provided methods for analyzing these complex data.
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http://dx.doi.org/10.1182/blood.2019002350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146019PMC
April 2020

Antibody-coated microbiota in nasopharynx of healthy individuals and IVIg-treated patients with hypogammaglobulinemia.

J Allergy Clin Immunol 2020 06 16;145(6):1686-1690.e4. Epub 2020 Jan 16.

Innate Immunity Unit, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.01.002DOI Listing
June 2020

A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency.

Haematologica 2021 Feb 1;106(2):404-411. Epub 2021 Feb 1.

Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest,Assistance Publique.

Severe combined immunodeficiencies (SCIDs) constitute a heterogeneous group of life-threatening genetic disorders that typically present in the first year of life. They are defined by the absence of autologous T cells and the presence of an intrinsic or extrinsic defect in the B-cell compartment. In three newborns presenting with frequent infections and profound leukopenia, we identified a private, heterozygous mutation in the RAC2 gene (p.G12R). This mutation was de novo in the index case, who had been cured by hematopoietic stem cell transplantation but had transmitted the mutation to her sick daughter. Biochemical assays showed that the mutation was associated with a gain of function. The results of in vitro differentiation assays showed that RAC2 is essential for the survival and differentiation of hematopoietic stem/progenitor cells. Therefore, screening for RAC2 gain-of-function mutations should be considered in patients with a SCID phenotype and who lack a molecular diagnosis.
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http://dx.doi.org/10.3324/haematol.2019.230250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849581PMC
February 2021

Gene therapy for severe combined immunodeficiencies and beyond.

J Exp Med 2020 01;217(2)

Unité de Technologies Chimiques et Biologiques pour la Santé, UMR8258 Centre National de la Recherche Scientifique - U1267 Institut National de la Santé et de la Recherche Médicale, Faculté de Pharmacie de Paris, Université Paris Descartes, Paris, France.

Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott-Aldrich syndrome, while further applications are pending. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.
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http://dx.doi.org/10.1084/jem.20190607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041706PMC
January 2020

Primary immunodeficiency-related bronchiectasis in adults: comparison with bronchiectasis of other etiologies in a French reference center.

Respir Res 2019 Dec 4;20(1):275. Epub 2019 Dec 4.

Service de Pneumologie, Hôpital Foch, Suresnes, France.

Background: Bronchiectasis is a heterogeneous disease depending on etiology. It represents the most frequent non-infectious pulmonary complication of primary immunodeficiencies (PID). We investigated whether bronchiectasis associated with PID had a distinct course in comparison to bronchiectasis of other causes.

Methods: Retrospective single-center study of adult patients diagnosed with non-cystic fibrosis bronchiectasis with more than 5 years of follow-up and at least 4 pulmonary functional tests available at one year apart. They were divided into three groups: PID- related bronchiectasis, idiopathic/post infectious-related bronchiectasis and other causes of bronchiectasis. Respiratory functional data and clinical outcomes were compared.

Results: Of 329 patients with bronchiectasis diagnosed in Foch Hospital (Suresnes, France), 98 patients fulfilled the selected criteria (20 PID-related cases, 39 idiopathic or post-infectious cases, and 39 cases with other causes). Median time of follow-up was 9.5 years. Groups were similar concerning initial characteristics (female 70.4%, never smokers 59.2%, mild severity bronchiectasis according to the FACED score and median FEV1 at diagnosis 73.5% predicted values [Q1-Q3: 53.75-90.5]), except PID patients who were younger (median age of 51.5 vs 62 years, p = 0.02). Eighty-five percent of PID patients received immunoglobulin substitution (median trough level was measured at 10.5 g/dl [10;10.92]). Global median FEV1 annual decline was 25.03 ml/year [8.16;43.9] and 19.82 ml/year [16.08;48.02] in the PID patients group. Forty-five percent of patients had bacterial colonization, pneumoniae occurred in 56% of patients and median exacerbation annual rate was 0.8 [0.3-1.4]. Hemoptysis occurred in 31.6% of patients. Global mortality rate was 11.2%. We did not record any significant difference for all clinical and functional outcomes between patients with PID and other etiologies. The median decline in FEV1 was similar in the three groups.

Conclusions: The course of PID-related bronchiectasis was similar to bronchiectasis of other causes. Provided that patients receive immunoglobulin replacement, the course of PID-related bronchiectasis seems to be independent of the underlying immune disorder.
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http://dx.doi.org/10.1186/s12931-019-1242-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894192PMC
December 2019

Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency.

Front Immunol 2019 7;10:2592. Epub 2019 Nov 7.

Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Paris, France.

Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause very early onset inflammatory bowel diseases (VOIBD) or multiple intestinal atresia associated with immune deficiency of various severities, ranging from combined immune deficiency to mild lymphopenia. In this manuscript, we report the clinical, biological and molecular features of a patient born from consanguineous parents, presenting with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO). Genetic screening revealed the novel c.974G>A (p.R325Q) mutation in homozygosity in the gene. The patient's phenotype differs significantly from that previously associated with TTC7A deficiency in humans. It becomes closer to the one reported in the ttc7a-deficient mice that invariably develop a proliferative lymphoid and myeloid disorder. Functional studies showed that the extreme variability in the clinical phenotype couldn't be explained by the cellular phenotype. Indeed, the patient's TTC7A mutation, as well as the murine-ttc7 mutant, have the same functional impact on protein expression, DNA instability and chromatin compaction, as the other mutations that lead to classical TTC7A-associated phenotypes. Co-inheritance of genetic variants may also contribute to the unique nature of the patient's phenotype. The present case report shows that the clinical spectrum of TTC7A deficiency is much broader than previously suspected. Our findings should alert the physicians to consider screening of mutations in patients with lymphoproliferative syndrome and hypergammaglobulinemia and/or chronic intestinal pseudo-obstruction.
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http://dx.doi.org/10.3389/fimmu.2019.02592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853864PMC
September 2020