Publications by authors named "Ottavia M Delmonte"

28 Publications

  • Page 1 of 1

SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.

Blood 2021 Apr 19. Epub 2021 Apr 19.

NIAID, National Institutes of Health, Bethesda, Maryland, United States.

SAM and SH3 domain-containing 3 (SASH3), also called SH3-containing Lymphocyte Protein (SLY1) is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction cascades in lymphocytes. The SASH3 gene is located on the X-chromosome. Here, we identified three novel SASH3 deleterious variants in four unrelated male patients with a history of combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopenias. Patients exhibited CD4+ T cell lymphopenia, decreased T cell proliferation and cell cycle progression, and increased T cell apoptosis in response to mitogens. In vitro T-cell differentiation of CD34+ cells and molecular signatures of rearrangements at the T-cell receptor alpha (TRA) locus were indicative of impaired thymocyte survival. These patients also manifested neutropenia and B and NK cell lymphopenia. Lentivirus-mediated transfer of the SASH3 cDNA corrected protein expression, in vitro proliferation and signaling in SASH3-deficient Jurkat and patient-derived T cells. These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in Sly1-/- and Sly1D/Dmutant mice, highlighting an important role of SASH3 in human lymphocyte function and survival.
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http://dx.doi.org/10.1182/blood.2020008629DOI Listing
April 2021

Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19.

Cell 2021 04 10;184(7):1836-1857.e22. Epub 2021 Feb 10.

Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA; NIH Center for Human Immunology, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address:

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56CD16 NK cells linked positively to circulating interleukin (IL)-15. CD8 T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.
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http://dx.doi.org/10.1016/j.cell.2021.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874909PMC
April 2021

Gene Editing Rescues In vitro T Cell Development of RAG2-Deficient Induced Pluripotent Stem Cells in an Artificial Thymic Organoid System.

J Clin Immunol 2021 Mar 1. Epub 2021 Mar 1.

Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, DIR, NIAID, NIH, 10 Center Drive, Bldg. 10 CRC, Room 5-3950, Bethesda, MD, 20892-1456, USA.

Severe combined immune deficiency (SCID) caused by RAG1 or RAG2 deficiency is a genetically determined immune deficiency characterized by the virtual absence of T and B lymphocytes. Unless treated with hematopoietic stem cell transplantation (HSCT), patients with RAG deficiency succumb to severe infections early in life. However, HSCT carries the risk of graft-versus-host disease. Moreover, a high rate of graft failure and poor immune reconstitution have been reported after unconditioned HSCT. Expression of the RAG genes is tightly regulated, and preclinical attempts of gene therapy with heterologous promoters have led to controversial results. Using patient-derived induced pluripotent stem cells (iPSCs) and an in vitro artificial thymic organoid system as a model, here we demonstrate that gene editing rescues the progressive T cell differentiation potential of RAG2-deficient cells to normal levels, with generation of a diversified T cell repertoire. These results suggest that targeted gene editing may represent a novel therapeutic option for correction of this immunodeficiency.
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http://dx.doi.org/10.1007/s10875-021-00989-6DOI Listing
March 2021

Gut Microbiota-Host Interactions in Inborn Errors of Immunity.

Int J Mol Sci 2021 Jan 31;22(3). Epub 2021 Jan 31.

Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, USA.

Inborn errors of immunity (IEI) are a group of disorders that are mostly caused by genetic mutations affecting immune host defense and immune regulation. Although IEI present with a wide spectrum of clinical features, in about one third of them various degrees of gastrointestinal (GI) involvement have been described and for some IEI the GI manifestations represent the main and peculiar clinical feature. The microbiome plays critical roles in the education and function of the host's innate and adaptive immune system, and imbalances in microbiota-immunity interactions can contribute to intestinal pathogenesis. Microbial dysbiosis combined to the impairment of immunosurveillance and immune dysfunction in IEI, may favor mucosal permeability and lead to inflammation. Here we review how immune homeostasis between commensals and the host is established in the gut, and how these mechanisms can be disrupted in the context of primary immunodeficiencies. Additionally, we highlight key aspects of the first studies on gut microbiome in patients affected by IEI and discuss how gut microbiome could be harnessed as a therapeutic approach in these diseases.
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http://dx.doi.org/10.3390/ijms22031416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866830PMC
January 2021

An immune-based biomarker signature is associated with mortality in COVID-19 patients.

JCI Insight 2021 01 11;6(1). Epub 2021 Jan 11.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.
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http://dx.doi.org/10.1172/jci.insight.144455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821609PMC
January 2021

Complete Absence of CD3γ Protein Expression Is Responsible for Combined Immunodeficiency with Autoimmunity Rather than SCID.

J Clin Immunol 2021 Feb 19;41(2):482-485. Epub 2020 Nov 19.

Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1007/s10875-020-00918-zDOI Listing
February 2021

POLD1 Deficiency Reveals a Role for POLD1 in DNA Repair and T and B Cell Development.

J Clin Immunol 2021 Jan 2;41(1):270-273. Epub 2020 Nov 2.

Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 5-3950, 10 Center Dr, Bethesda, MD, 20892, USA.

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http://dx.doi.org/10.1007/s10875-020-00903-6DOI Listing
January 2021

Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility.

J Exp Med 2021 Feb;218(2)

Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.

NF-κB2/p100 (p100) is an inhibitor of κB (IκB) protein that is partially degraded to produce the NF-κB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or IκB function of mutated p100 is unclear. Here, we studied mice bearing mutations in the p100 degron, a domain that harbors most of the clinically recognized mutations and is required for signal-dependent p100 degradation. Distinct mutations caused graded increases in p100-degradation resistance. Severe p100-degradation resistance, due to inheritance of one highly degradation-resistant allele or two subclinical alleles, caused thymic medullary hypoplasia and autoimmune disease, whereas the absence of p100 and p52 did not. We inferred a similar mechanism occurs in humans, as the T cell receptor repertoires of affected humans and mice contained a hydrophobic signature of increased self-reactivity. Autoimmunity in autosomal dominant NFKB2 syndrome arises largely from defects in nonhematopoietic cells caused by the IκB function of degradation-resistant p100.
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http://dx.doi.org/10.1084/jem.20200476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595743PMC
February 2021

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

Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels.

medRxiv 2020 Aug 4. Epub 2020 Aug 4.

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,015 samples (from 827 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 83.8% [95% CI = 77.6-89.4]; Day 8-14 = 92.4% [87.6-96.6]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 96.7% [93.0-99.2]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in vaccine development as well as clinical diagnostics and monitoring.
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http://dx.doi.org/10.1101/2020.07.31.20165647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418734PMC
August 2020

A large-scale database of T-cell receptor beta (TCRβ) sequences and binding associations from natural and synthetic exposure to SARS-CoV-2.

Res Sq 2020 Aug 4. Epub 2020 Aug 4.

We describe the establishment and current content of the ImmuneCODE™ database, which includes hundreds of millions of T-cell Receptor (TCR) sequences from over 1,400 subjects exposed to or infected with the SARS-CoV-2 virus, as well as over 135,000 high-confidence SARS-CoV-2-specific TCRs. This database is made freely available, and the data contained in it can be downloaded and analyzed online or offline to assist with the global efforts to understand the immune response to the SARS-CoV-2 virus and develop new interventions.
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http://dx.doi.org/10.21203/rs.3.rs-51964/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418738PMC
August 2020

Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia.

Blood Adv 2020 06;4(12):2611-2616

Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.

The study of early T-cell development in humans is challenging because of limited availability of thymic samples and the limitations of in vitro T-cell differentiation assays. We used an artificial thymic organoid (ATO) platform generated by aggregating a DLL4-expressing stromal cell line (MS5-hDLL4) with CD34+ cells isolated from bone marrow or mobilized peripheral blood to study T-cell development from CD34+ cells of patients carrying hematopoietic intrinsic or thymic defects that cause T-cell lymphopenia. We found that AK2 deficiency is associated with decreased cell viability and an early block in T-cell development. We observed a similar defect in a patient carrying a null IL2RG mutation. In contrast, CD34+ cells from a patient carrying a missense IL2RG mutation reached full T-cell maturation, although cell numbers were significantly lower than in controls. CD34+ cells from patients carrying RAG mutations were able to differentiate to CD4+CD8+ cells, but not to CD3+TCRαβ+ cells. Finally, normal T-cell differentiation was observed in a patient with complete DiGeorge syndrome, consistent with the extra-hematopoietic nature of the defect. The ATO system may help determine whether T-cell deficiency reflects hematopoietic or thymic intrinsic abnormalities and define the exact stage at which T-cell differentiation is blocked.
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http://dx.doi.org/10.1182/bloodadvances.2020001730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322962PMC
June 2020

Immune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency.

Blood 2020 02;135(9):610-619

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Traditionally, primary immune deficiencies have been defined based on increased susceptibility to recurrent and/or severe infections. However, immune dysregulation, manifesting with autoimmunity or hyperinflammatory disease, has emerged as a common feature. This is especially true in patients affected by combined immune deficiency (CID), a group of disorders caused by genetic defects that impair, but do not completely abolish, T-cell function. Hypomorphic mutations in the recombination activating genes RAG1 and RAG2 represent the prototype of the broad spectrum of clinical and immunological phenotypes associated with CID. The study of patients with RAG deficiency and with other forms of CID has revealed distinct abnormalities in central and peripheral T- and B-cell tolerance as the key mechanisms involved in immune dysregulation. Understanding the pathophysiology of autoimmunity and hyperinflammation in these disorders may also permit more targeted therapeutic interventions.
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http://dx.doi.org/10.1182/blood.2019000923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046604PMC
February 2020

Novel Missense Mutation inSP110Associated with Combined Immunodeficiency and Advanced Liver Disease Without VOD.

J Clin Immunol 2020 01 13;40(1):236-239. Epub 2019 Nov 13.

Division of Allergy and Immunology, St. Joseph's University Medical Center, Paterson, NJ, USA.

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http://dx.doi.org/10.1007/s10875-019-00715-3DOI Listing
January 2020

Disseminated and Congenital Toxoplasmosis in a Mother and Child With Activated PI3-Kinase δ Syndrome Type 2 (APDS2): Case Report and a Literature Review of Toxoplasma Infections in Primary Immunodeficiencies.

Front Immunol 2019 14;10:77. Epub 2019 Feb 14.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States.

Phosphoinositide 3-kinase (PI3K) plays an integral role in lymphocyte function. Mutations in and , encoding the PI3K p110δ and p85α subunits, respectively, cause increased PI3K activity and result in immunodeficiency with immune dysregulation. We describe here the first cases of disseminated and congenital toxoplasmosis in a mother and child who share a pathogenic mutation in and review the mechanisms underlying susceptibility to severe infection in activated PI3Kδ syndrome (APDS) and in other forms of primary immunodeficiency.
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http://dx.doi.org/10.3389/fimmu.2019.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413717PMC
December 2019

Flow cytometry: Surface markers and beyond.

J Allergy Clin Immunol 2019 02 28;143(2):528-537. Epub 2018 Aug 28.

Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Md.

Flow cytometry is a routinely available laboratory method to study cells in suspension from a variety of human sources. Application of this technology as a clinical laboratory method has evolved from the identification of cell-surface proteins to characterizing intracellular proteins and providing multiple different techniques to assess specific features of adaptive and innate immune function. This expanded menu of flow cytometric testing approaches has increased the utility of this platform in characterizing and diagnosing disorders of immune function.
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http://dx.doi.org/10.1016/j.jaci.2018.08.011DOI Listing
February 2019

RAG Deficiency: Two Genes, Many Diseases.

J Clin Immunol 2018 08 25;38(6):646-655. Epub 2018 Jul 25.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

Purpose: To review the clinical and laboratory spectrum of RAG gene defects in humans, and discuss the mechanisms underlying phenotypic heterogeneity, the basis of immune dysregulation, and the current and perspective treatment modalities.

Methods: Literature review and analysis of medical records RESULTS: RAG gene defects in humans are associated with a surprisingly broad spectrum of clinical and immunological phenotypes. Correlation between in vitro recombination activity of the mutant RAG proteins and the clinical phenotype has been observed. Altered T and B cell development in this disease is associated with defects of immune tolerance. Hematopoietic cell transplantation is the treatment of choice for the most severe forms of the disease, but a high rate of graft failure has been observed.

Conclusions: Phenotypic heterogeneity of RAG gene defects in humans may represent a diagnostic challenge. There is a need to improve treatment for severe, early-onset forms of the disease. Optimal treatment modalities for patients with delayed-onset disease presenting with autoimmunity and/or inflammation remain to be defined.
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http://dx.doi.org/10.1007/s10875-018-0537-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643099PMC
August 2018

Disrupted N-linked glycosylation as a disease mechanism in deficiency of ADA2.

J Allergy Clin Immunol 2018 10 21;142(4):1363-1365.e8. Epub 2018 Jun 21.

Division of Immunology, Boston Children's Hospital, Boston, Mass; Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Mass.

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http://dx.doi.org/10.1016/j.jaci.2018.05.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175612PMC
October 2018

Patients with mutations reveal a role for human CD3γ in T diversity and suppressive function.

Blood 2018 05 13;131(21):2335-2344. Epub 2018 Apr 13.

Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, , , and gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor β (TRB) repertoire in regulatory T cells (Ts), conventional CD4 (T), and CD8 T cells from 6 patients with mutations and healthy controls. T function was assessed by studying its ability to suppress proliferation of T cells. T cells of patients with defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of T cells from patients with deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.
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http://dx.doi.org/10.1182/blood-2018-02-835561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969384PMC
May 2018

First Case of X-Linked Moesin Deficiency Identified After Newborn Screening for SCID.

J Clin Immunol 2017 05 4;37(4):336-338. Epub 2017 Apr 4.

Immune Deficiency Genetics Section, Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10 CRC, Room 5-3950, 10 Center Drive, MSC 1456, Bethesda, MD, 20892, USA.

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http://dx.doi.org/10.1007/s10875-017-0391-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082367PMC
May 2017

B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice.

Blood 2012 Mar 1;119(12):2819-28. Epub 2012 Feb 1.

Children's Hospital, Division of Immunology and Manton Center for Orphan Disease Research, Boston, MA, USA.

Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell-intrinsic mechanisms critically contribute to WAS-associated autoimmunity.
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http://dx.doi.org/10.1182/blood-2011-09-379412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327460PMC
March 2012

Immunomodulatory effects of two HIV protease inhibitors, Saquinavir and Ritonavir, on lymphocytes from healthy seronegative individuals.

Immunol Lett 2007 Aug 30;111(2):111-5. Epub 2007 Jul 30.

Department of Pediatrics, University of Turin, Piazza Polonia 94, 10126 Torino Turin, Italy.

Unlabelled: Immunological and clinical benefits of highly active antiretroviral therapy (HAART) do not always correlate with its efficacy in controlling HIV replication. This could be due to biological effects on the cell of retroviral agents.

Design: To this view we evaluated possible direct immunomodulatory effects of two HIV protease inhibitors, such as Saquinavir (SQ) and Ritonavir (RIT).

Methods: In particular we assessed the PHA- and anti-CD3-driven T cell proliferation, mixed lymphocyte reaction (MLR) and cytokine production on PBMCs from HIV-uninfected subjects incubated with increasing concentrations (2, 5, 10 and 20 microM) of SQ or RIT.

Results: Treatment of PBMCs with RIT resulted in a dose-dependent reduction of lymphoproliferative responses. Such an effect was also marked with SQ. MLR was significantly reduced in a concentration-dependent fashion after incubation with either drug. The percentages of stimulated PBMCs and mostly of CD4+ cells expressing TNF-alpha, IL-2 and IFN-gamma were also reduced by SQ or RIT.

Conclusion: At therapeutic doses both SQ and RIT exhibit potent immunomodulatory activity, which may contribute to correct the HIV-driven cytokine dysregulation and account for some clinical and immunological benefits of therapy in patients with virologic failure. In view of autoreactive immunopathology occurring in AIDS, these direct biologic effects raise intriguing speculations on anti-HIV strategy.
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http://dx.doi.org/10.1016/j.imlet.2007.06.003DOI Listing
August 2007