Publications by authors named "Luigi D Notarangelo"

381 Publications

SARS-CoV-2 Spike Protein-Directed Monoclonal Antibodies May Ameliorate COVID-19 Complications in APECED Patients.

Front Immunol 2021 24;12:720205. Epub 2021 Aug 24.

Fungal Pathogenesis Section, LCIM, NIAID, NIH, Bethesda, MD, United States.

Patients with the monogenic immune dysregulatory syndrome autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by loss-of-function mutations in the autoimmune regulator () gene, uniformly carry neutralizing autoantibodies directed against type-I interferons (IFNs) and many develop autoimmune pneumonitis, both of which place them at high risk for life-threatening COVID-19 pneumonia. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein and block entry of SARS-CoV-2 in host cells. The use of bamlanivimab and etesevimab early during infection was associated with reduced COVID-19-associated hospitalization and death in patients at high risk for progressing to severe disease, which led the US Food and Drug Administration to issue an emergency use authorization for their administration in non-hypoxemic, non-hospitalized high-risk patients. However, the safety and efficacy of these mAbs has not been evaluated in APECED patients. We enrolled two siblings with APECED on an IRB-approved protocol (NCT01386437) and admitted them prophylactically at the NIH Clinical Center for evaluation of mild-to-moderate COVID-19. We assessed the safety and clinical effects of early treatment with bamlanivimab and etesevimab. The administration of bamlanivimab and etesevimab was well tolerated and was associated with amelioration of COVID-19 symptoms and prevention of invasive ventilatory support, admission to the intensive care, and death in both patients without affecting the production of antibodies to the nucleocapsid protein of SARS-CoV-2. If given early in the course of COVID-19 infection, bamlanivimab and etesevimab may be beneficial in APECED and other high-risk patients with neutralizing autoantibodies directed against type-I IFNs.
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http://dx.doi.org/10.3389/fimmu.2021.720205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421855PMC
September 2021

Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity.

J Allergy Clin Immunol 2021 Sep 4. Epub 2021 Sep 4.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address:

Background: SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients.

Objective: We sought to evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse events in a cohort of patients with IEIs.

Methods: Plasma was collected from 22 health care worker controls, 81 patients with IEIs, and 2 patients with thymoma; the plasma was collected before immunization, 1 to 6 days before the second dose of mRNA vaccine, and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson's Janssen vaccine. Anti-spike (anti-S) and anti-nucleocapsid antibody titers were measured by using a luciferase immunoprecipitation systems method. Information on T- and B-cell counts and use of immunosuppressive drugs was extracted from medical records, and information on vaccine-associated adverse events was collected after each dose.

Results: Anti-S antibodies were detected in 27 of 46 patients (58.7%) after 1 dose of mRNA vaccine and in 63 of 74 fully immunized patients (85.1%). A lower rate of seroconversion (7 of 11 [63.6%]) was observed in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Previous use of rituximab and baseline counts of less than 1000 CD3 T cells/mL and less than 100 CD19 B cells/mL were associated with lower anti-S IgG levels. No significant adverse events were reported.

Conclusion: Vaccinating patients with IEIs is safe, but immunogenicity is affected by certain therapies and gene defects. These data may guide the counseling of patients with IEIs regarding prevention of SARS-CoV-2 infection and the need for subsequent boosts.
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http://dx.doi.org/10.1016/j.jaci.2021.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418380PMC
September 2021

Treatment of Relapsing HPV Diseases by Restored Function of Natural Killer Cells.

N Engl J Med 2021 09;385(10):921-929

From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.).

Human papillomavirus (HPV) infections underlie a wide spectrum of both benign and malignant epithelial diseases. In this report, we describe the case of a young man who had encephalitis caused by herpes simplex virus during adolescence and currently presented with multiple recurrent skin and mucosal lesions caused by HPV. The patient was found to have a pathogenic germline mutation in the X-linked interleukin-2 receptor subunit gamma gene (), which was somatically reverted in T cells but not in natural killer (NK) cells. Allogeneic hematopoietic-cell transplantation led to restoration of NK cytotoxicity, with normalization of the skin microbiome and persistent remission of all HPV-related diseases. NK cytotoxicity appears to play a role in containing HPV colonization and the ensuing HPV-related hyperplastic or dysplastic lesions. (Funded by the National Institutes of Health and the Herbert Irving Comprehensive Cancer Center Flow Cytometry Shared Resources.).
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http://dx.doi.org/10.1056/NEJMoa2102715DOI Listing
September 2021

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.

Sci Immunol 2021 08;6(62)

Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such variants ( = 3.5 × 10). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (=2, 5 and 38 years), or moderate (=1, 5 years), severe (=1, 27 years), or critical (=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious variants in the male general population is < 6.5x10 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
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http://dx.doi.org/10.1126/sciimmunol.abl4348DOI Listing
August 2021

Autoantibodies neutralizing type I IFNs are present in 4% of uninfected individuals over 70 years old and account for 20% of COVID-19 deaths.

Sci Immunol 2021 08;6(62)

Joint Research Unit, Hospices Civils de Lyon-bio Mérieux, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France; International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.
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http://dx.doi.org/10.1126/sciimmunol.abl4340DOI Listing
August 2021

IFNγR1 deficiency presenting with visceral leishmaniasis and Mycobacterium Avium infections mimicking HLH.

Pediatr Allergy Immunol 2021 Aug 18. Epub 2021 Aug 18.

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

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http://dx.doi.org/10.1111/pai.13653DOI Listing
August 2021

Poor T-cell receptor β repertoire diversity early posttransplant for severe combined immunodeficiency predicts failure of immune reconstitution.

J Allergy Clin Immunol 2021 Aug 9. Epub 2021 Aug 9.

Division of Allergy, Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, Calif; Smith Cardiovascular Research Institute, San Francisco, Calif; UCSF Benioff Children's Hospital, San Francisco, Calif. Electronic address:

Background: Development of a diverse T-cell receptor β (TRB) repertoire is associated with immune recovery following hematopoietic cell transplantation (HCT) for severe combined immunodeficiency (SCID). High-throughput sequencing of the TRB repertoire allows evaluation of clonotype dynamics during immune reconstitution.

Objectives: We investigated whether longitudinal analysis of the TRB repertoire would accurately describe T-cell receptor diversity and illustrate the quality of T-cell reconstitution following HCT or gene therapy for SCID.

Methods: We used high-throughput sequencing to study composition and diversity of the TRB repertoire in 27 infants with SCID at 3, 6, and 12 months and yearly posttreatment(s). Total RNA from peripheral blood was used as template to amplify TRB rearrangements.

Results: TRB sequence analysis showed poor diversity at 3 months, followed by significant improvement by 6 months after cellular therapies. Kinetics of development of TRB diversity were similar in patients with a range of underlying gene defects. However, in patients with RAG and DCLRE1C defects, HCT with no conditioning or immune suppression only resulted in lower diversity than did HCT with conditioning. HCT from a matched donor correlated with higher diversity than did HCT from a mismatched donor. Naive CD4 T-cell count at 6 months post-HCT correlated with higher TRB diversity. A Shannon index of diversity of 5.2 or lower 3 months after HCT predicted a need for a second intervention.

Conclusions: TRB repertoire after hematopoietic cell therapies for SCID provides a quantitative and qualitative measure of diversity of T-cell reconstitution and permits early identification of patients who may require a second intervention.
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http://dx.doi.org/10.1016/j.jaci.2021.07.029DOI Listing
August 2021

BTK inhibitors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): A systematic review.

Clin Immunol 2021 09 2;230:108816. Epub 2021 Aug 2.

Laboratory of Clinical Immunology and Microbiology, Fungal Pathogenesis Section, NIAID, NIH, Bethesda, MD, USA.

Introduction: The Bruton tyrosine kinase (BTK) regulates B cell and macrophage signaling, development, survival, and activation. Inhibiting BTK has been hypothesized to ameliorate lung injury in patients with severe COVID-19, however clinical outcome data is inconclusive.

Objective: To evaluate the clinical outcomes of BTK inhibitors (BTKinibs) in patients with COVID-19.

Evidence Review: We searched PubMed, Embase, and Web of Science:Core on December 30, 2020. Clinical studies with at least 5 COVID-19 patients treated with BTKinibs were included. Case reports and reviews were excluded.

Findings: 125 articles were identified, 6 of which met inclusion criteria. The most common clinical outcomes measured were oxygen requirements (4/6) and hospitalization rate or duration (3/6). Three studies showed decreased oxygen requirements in patients who started or continued BTKinibs. All three studies that evaluated hospitalization rate or duration found favorable outcomes in those on BTKinibs.

Conclusions And Relevance: BTKinib use was associated with decreased oxygen requirements and decreased hospitalization rates and duration.
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http://dx.doi.org/10.1016/j.clim.2021.108816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327577PMC
September 2021

Neutralizing type-I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID-19.

Immunol Cell Biol 2021 Jul 26. Epub 2021 Jul 26.

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

Type-I interferons (IFNs) mediate antiviral activity and have emerged as important immune mediators during coronavirus disease 19 (COVID-19). Several lines of evidence suggest that impaired type-I IFN signaling may predispose to severe COVID-19. However, the pathophysiologic mechanisms that contribute to illness severity remain unclear. In this study, our goal was to gain insight into how type-I IFNs influence outcomes in patients with COVID-19. To achieve this goal, we compared clinical outcomes between 26 patients with neutralizing type-I IFN autoantibodies (AAbs) and 192 patients without AAbs who were hospitalized for COVID-19 at three Italian hospitals. The presence of circulating AAbs to type-I IFNs was associated with an increased risk of admission to the intensive care unit and a delayed time to viral clearance. However, survival was not adversely affected by the presence of type-I IFN AAbs. Our findings provide further support for the role of type-I IFN AAbs in impairing host antiviral defense and promoting the development of critical COVID-19 pneumonia in severe acute respiratory syndrome coronavirus 2-infected individuals.
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http://dx.doi.org/10.1111/imcb.12495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444766PMC
July 2021

Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

Cell 2021 Jul 1;184(14):3812-3828.e30. Epub 2021 Jul 1.

Zahedan University of Medical Sciences, 054 Zahedan, Iran.

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4 T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4 T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.
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http://dx.doi.org/10.1016/j.cell.2021.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329841PMC
July 2021

Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.

Front Immunol 2021 15;12:669943. Epub 2021 Jun 15.

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.

Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.
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http://dx.doi.org/10.3389/fimmu.2021.669943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239840PMC
June 2021

Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.

Nat Med 2021 Sep 28;27(9):1646-1654. Epub 2021 Jun 28.

Department of Virology, Cochin Hospital, University of Paris, Paris, France.

The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2 γδ T, mucosal-associated invariant T and CD56 natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT CD4CD8 double-negative αβ T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.
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http://dx.doi.org/10.1038/s41591-021-01388-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446316PMC
September 2021

Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia.

J Clin Invest 2021 08;131(15)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

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http://dx.doi.org/10.1172/JCI152474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321559PMC
August 2021

Nodular regenerative hyperplasia in X-linked agammaglobulinemia: An underestimated and severe complication.

J Allergy Clin Immunol 2021 Jun 1. Epub 2021 Jun 1.

Liver Diseases Branch, National Institute of Diabetes and Digestive & Kidney Diseases, NIH, Bethesda, Md. Electronic address:

Background: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited.

Objectives: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA.

Methods: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons.

Results: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per μL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002).

Conclusions: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.
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http://dx.doi.org/10.1016/j.jaci.2021.05.028DOI Listing
June 2021

CRISPR-targeted MAGT1 insertion restores XMEN patient hematopoietic stem cells and lymphocytes.

Blood 2021 Jun 4. Epub 2021 Jun 4.

National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, United States.

'X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus-infection and N-linked glycosylation defect' (XMEN) disease is a recently described primary immunodeficiency marked by defective T and Natural Killer (NK) cells. Potentially curative hematopoietic stem cell transplant is associated with high mortality rates. We sought to develop an ex vivo targeted gene therapy approach for XMEN patients using CRISPR/Cas9/adeno-associated vector (AAV) to insert a therapeutic MAGT1 gene at the constitutive locus under the regulation of the endogenous promoter. Clinical translation of CRISPR/Cas9/AAV-targeted gene editing (GE) is hampered by low engraftable GE hematopoietic stem/progenitor cells (HSPCs). Here, we optimized GE conditions by transient enhancement of homology-directed repair while suppressing AAV-associated DNA damage response to achieve highly efficient (>60%) genetic correction in engrafting XMEN HSPCs in transplanted mice. Restored MAGT1-glycosylation function in human NK and CD8+ T cells restored NKG2D expression and function in XMEN lymphocytes for potential treatment of infections, and corrected HSPCs for long-term gene therapy, thus offering two efficient therapeutic options for XMEN poised for clinical translation.
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http://dx.doi.org/10.1182/blood.2021011192DOI Listing
June 2021

International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome.

J Allergy Clin Immunol 2021 May 24. Epub 2021 May 24.

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

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).

Objectives: This study sought to characterize HCT outcomes in APDS.

Methods: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.

Results: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT.

Conclusions: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
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http://dx.doi.org/10.1016/j.jaci.2021.04.036DOI Listing
May 2021

HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related auto-inflammatory disease.

Blood 2021 05 21. Epub 2021 May 21.

Baylor College of Medicina, United States.

Inborn errors of immunity that present with concomitant immunodeficiency and auto-inflammation are therapeutically challenging; furthermore, complexity is added when they are caused by mutations in genes that encode for proteins expressed beyond immune cells. The ubiquitin-proteasome system is the main intracellular proteolytic machinery and participates in most cellular processes by degrading ubiquitinated proteins. Mutations in proteasome subunits resulting in proteasome deficiency cause a severe auto-inflammatory disease characterized by chronic auto-inflammation neutrophilic dermatosis and fever, collectively referred to as Proteasome Associated Auto-inflammatory Syndromes (PRAAS). POMP is a chaperone for proteasome assembly and AD mutations in POMP cause a form of PRAAS with prominent immunodeficiency referred to as POMP-related auto-inflammation and immune dysregulation (PRAID) manifesting with recurrent, severe and opportunistic infections in addition to inflammatory features that are characteristic for all PRAAS disorders, most importantly early-onset neutrophilic dermatosis. JAK inhibitors partially control the disease in individuals with PRAAS, however life-threatening, recurrent and opportunistic infections in patients with POMP mutations limit immunosuppressive therapies and prompted consideration of hematopoietic stem cell transplant (HSCT). We describe successful HSCT in two patients with POMP deficiency. Despite POMP being ubiquitously expressed, the immunologic and auto-inflammatory phenotype were both ameliorated through HSCT which suggests that the clinical and immunological features of PRAID are predominantly derived from a proteasome defect in hematopoietic cells. To our knowledge, these are the first patients with a form of PRAAS cured by HSCT, opening new therapeutic possibilities for these diseases.
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http://dx.doi.org/10.1182/blood.2021011005DOI Listing
May 2021

Robust Antibody and T Cell Responses to SARS-CoV-2 in Patients with Antibody Deficiency.

J Clin Immunol 2021 08 13;41(6):1146-1153. Epub 2021 May 13.

Center for Cancer and Immunology Research, Children's Research Institute, Children's National Hospital, Washington, DC, USA.

Immunocompromised patients, including those with inborn errors of immunity (IEI), may be at increased risk for severe or prolonged infections with SARS-CoV-2 (Zhu et al. N Engl J Med. 382:727-33, 2020; Guan et al. 2020; Minotti et al. J Infect. 81:e61-6, 2020). While antibody and T cell responses to SARS-CoV-2 structural proteins are well described in healthy convalescent donors, adaptive humoral and cellular immunity has not yet been characterized in patients with antibody deficiency (Grifoni et al. Cell. 181:1489-1501 e1415, 2020; Burbelo et al. 2020; Long et al. Nat Med. 26:845-8, 2020; Braun et al. 2020). Herein, we describe the clinical course, antibody, and T cell responses to SARS-CoV-2 structural proteins in a cohort of adult and pediatric patients with antibody deficiencies (n = 5) and controls (related and unrelated) infected with SARS-CoV-2. Five patients within the same family (3 with antibody deficiency, 2 immunocompetent controls) showed antibody responses to nucleocapsid and spike proteins, as well as SARS-CoV-2 specific T cell immunity at days 65-84 from onset of symptoms. No significant difference was identified between immunocompromised patients and controls. Two additional unrelated, adult patients with common variable immune deficiency were assessed. One did not show antibody response, but both demonstrated SARS-CoV-2-specific T cell immunity when evaluated 33 and 76 days, respectively, following SARS-CoV-2 diagnosis. This report is the first to show robust T cell activity and humoral immunity against SARS-CoV-2 structural proteins in some patients with antibody deficiency. Given the reliance on spike protein in most candidate vaccines (Folegatti et al. Lancet. 396:467-78, 2020; Jackson et al. N Engl J Med. 383:1920-31, 2020), the responses are encouraging. Additional studies will be needed to further define the timing of onset of immunity, longevity of the immune response, and variability of response in immunocompromised patients.
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http://dx.doi.org/10.1007/s10875-021-01046-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117127PMC
August 2021

Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients with RAG1/2 Mutations: First Cases Series from Mexico and Description of Two Novel Mutations.

J Clin Immunol 2021 Aug 5;41(6):1291-1302. Epub 2021 May 5.

Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mexico.

Mutations in recombinase activating genes 1 and 2 (RAG1/2) result in human severe combined immunodeficiency (SCID). The products of these genes are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Mutations resulting in null-recombination activity in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with hypomorphic mutations may develop leaky SCID, including Omenn syndrome (OS). A group of previously unrecognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here, we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two variants that had not been associated with immunodeficiency. This study represents the first case series of RAG1- or RAG2-deficient patients from Mexico and Latin America.
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http://dx.doi.org/10.1007/s10875-021-01052-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319791PMC
August 2021

Skewed TCR Alpha, but not Beta, Gene Rearrangements and Lymphoma Associated with a Pathogenic TRAC Variant.

J Clin Immunol 2021 Aug 28;41(6):1395-1399. Epub 2021 Apr 28.

Paediatric Allergy Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education & Research, Sector 12, Chandigarh, 160012, India.

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http://dx.doi.org/10.1007/s10875-021-01047-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316983PMC
August 2021

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.

J Exp Med 2021 07;218(7)

Pediatric Medicine Unit, University Hospital of Besançon, Besançon, France.

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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http://dx.doi.org/10.1084/jem.20210554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077172PMC
July 2021

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

Blood 2021 Apr 19. Epub 2021 Apr 19.

Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, 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

BTK inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): A Systematic Review.

Res Sq 2021 Mar 22. Epub 2021 Mar 22.

NIAID, NIH, Bethesda.

ImportanceThe Bruton tyrosine kinase (BTK) regulates B cell and macrophage signaling, development, survival, and activation. BTK inhibition was shown to protect against lethal influenza-induced acute lung injury in mice. Inhibiting BTK has been hypothesized to ameliorate lung injury in patients with severe coronavirus disease 2019 (COVID-19). ObjectiveTo evaluate the use of BTK inhibitors (BTKinibs) during COVID-19 and assess how they may affect patient outcomes.Evidence ReviewWe searched PubMed, Embase, and Web of Science: Core on December 30, 2020. Clinical studies with at least 5 COVID-19 patients treated with BTKinibs were included. Case reports and reviews were excluded.FindingsOne hundred twenty-five articles were identified, 6 of which met inclusion criteria. Sample size ranged from 6 to 126 patients. Patient populations included subjects hospitalized with COVID-19 (6/6) and admitted to the intensive care unit (5/6). Patient age ranged between 35 and 98 years. Four studies included patients already receiving BTKinibs for their lymphoproliferative disease, 1 for Waldenstrom's macroglobulinemia and 3 for chronic lymphocytic leukemia (CLL). The most common clinical outcomes measured were oxygen requirements (4/6) and hospitalization rate or duration (3/6). Differences in standard-of-care reflected the date of study and pre-existing conditions in the various patient cohorts. Full-dose acalabrutinib was evaluated in 2 studies, one study evaluated full-dose ibrutinib, and another study evaluated both ibrutinib and acalabrutinib. The remainder 2 studies described outcomes in CLL patients on multiple BTKinibs and other CLL-targeted treatments. Three studies showed decreased oxygen requirements in patients who started or continued BTKinibs. All three studies that evaluated hospitalization rate or duration found favorable outcomes in those on BTKinibs. Conclusions and RelevanceBTKinib use was associated with decreased oxygen requirements and decreased hospitalization rates and duration. However, randomized clinical trials are needed to validate the beneficial effects of BTKinibs for acute SARS-CoV-2 infection.
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http://dx.doi.org/10.21203/rs.3.rs-319342/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010740PMC
March 2021

Inhibition of HECT E3 ligases as potential therapy for COVID-19.

Cell Death Dis 2021 03 24;12(4):310. Epub 2021 Mar 24.

Infection, Antimicrobials, Modelling, Evolution (IAME), INSERM, UMRS1137, University of Paris, Paris, France.

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.
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http://dx.doi.org/10.1038/s41419-021-03513-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987752PMC
March 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

RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches.

Eur J Immunol 2021 05 22;51(5):1028-1038. Epub 2021 Mar 22.

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

The RAG1 and RAG2 proteins initiate the process of V(D)J recombination and therefore play an essential role in adaptive immunity. While null mutations in the RAG genes cause severe combined immune deficiency with lack of T and B cells (T B SCID) and susceptibility to life-threatening, early-onset infections, studies in humans and mice have demonstrated that hypomorphic RAG mutations are associated with defects of central and peripheral tolerance resulting in immune dysregulation. In this review, we provide an overview of the extended spectrum of RAG deficiencies and their associated clinical and immunological phenotypes in humans. We discuss recent advances in the mechanisms that control RAG expression and function, the effects of perturbed RAG activity on lymphoid development and immune homeostasis, and propose novel approaches to correct this group of disorders.
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http://dx.doi.org/10.1002/eji.202048880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325549PMC
May 2021
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