Showing papers by "Luisa Imberti published in 2020"
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University of Paris1, French Institute of Health and Medical Research2, Rockefeller University3, National Institutes of Health4, University of Tartu5, Lyon College6, Tartu University Hospital7, Utrecht University8, Vita-Salute San Raffaele University9, Yale University10, Pasteur Institute11, Collège de France12, University of Amsterdam13, McGill University Health Centre14, University of New South Wales15, Garvan Institute of Medical Research16, Ghent University Hospital17, University of Barcelona18, University of Vic19, Catalan Institution for Research and Advanced Studies20, Science for Life Laboratory21, Karolinska University Hospital22, Howard Hughes Medical Institute23, Aarhus University24, Aarhus University Hospital25, University of Milano-Bicocca26, University of Lorraine27, Karolinska Institutet28, Haukeland University Hospital29, University of Bergen30, Canadian Real Estate Association31, University of Brescia32, University of Pavia33
TL;DR: A means by which individuals at highest risk of life-threatening COVID-19 can be identified is identified, and the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical CO VID-19 is tested.
Abstract: Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or 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 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
1,913 citations
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TL;DR: The COVID Human Genetic Effort established to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance finds an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001.
Abstract: Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
1,659 citations
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TL;DR: It remains unknown whether the study of immune parameters at the time of admission to the hospital may help distinguish those who will progress to respiratory failure and will require admission to intensive care units (ICU) and possibly die, from those with moderate symptoms, who will not require invasive ventilation and will eventually recover.
Abstract: To the Editor: SARS-CoV-2 infection, first documented in Wuhan (China) at the end of 2019, rapidly spread to become a pandemic disease (COVID-19). The infection is highly contagious, and is characterized by a highly heterogeneous clinical phenotype, ranging from fully asymptomatic to severe disease and a high fatality rate [1]. While the reasons for such phenotypic heterogeneity remain ill-defined, some patterns have emerged. In particular, in individuals with severe clinical course, the disease often manifests in two waves [2]. In the first phase, patients present typical clinical symptoms of a respiratory tract infections, whereas in the second phase (approximately 8–12 days after onset of symptoms), sudden worsening of respiratory status occurs. At this stage, diffuse ground-glass opacities are observed on chest computed tomography. Lymphopenia, elevated D-dimer levels, and prolonged prothrombin time are common laboratory abnormalities in these critically ill patients [2, 3]. Although the infection has been documented in subjects of all ages, the mortality rate is particularly high among elderly (> 70 years) individuals. Pre-existing co-morbidities (such as diabetes, hypertension, and chronic lung disease) are associated with worse outcome. The mechanisms underlying worsening of the disease are object of intense investigation. Increased levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) have been documented in severely infected individuals [2–4]. Along with lymphopenia, these observations have led to hypothesize that dysregulation of immune responses may play an important role in the pathology of the disease. However, limited data are available on the immune status of COVID-19 patients. In particular, it remains unknown whether the study of immune parameters at the time of admission to the hospital may help distinguish those who will progress to respiratory failure and will require admission to intensive care units (ICU) and possibly die, from those with moderate symptoms, who will not require invasive ventilation and will eventually recover.
41 citations
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TL;DR: This study suggests that fingolimod-immunosuppressed patients, despite the low circulating lymphocytes, may rapidly expand antibody-secreting cells and mount an effective immune response that favors COVID-19 recovery after discontinuation.
19 citations
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TL;DR: Two siblings with novel ADA2 variants are described, expanding the mutational spectrum of ADA2 deficiency, and lymphoproliferation, persistence of large granular lymphocytes, T-cell perturbations, and activation of PI3K pathway are detectable in DADA2 patients without T-LGL leukemia.
13 citations
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TL;DR: A viral exposure signature predictive of COVID-19-related disease severity linked to patient survival is developed by applying a machine-learning-based strategy.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic respiratory infectious disease COVID-19. However, clinical manifestations and outcomes differ significantly among COVID-19 patients, ranging from asymptomatic to extremely severe, and it remains unclear what drives these disparities. Here, we studied 159 hospitalized Italian patients with pneumonia from the NIAID-NCI COVID-19 Consortium using a phage-display method to characterize circulating antibodies binding to 93,904 viral peptides encoded by 1,276 strains of human viruses. SARS-CoV-2 infection was associated with a marked increase in individual's immune memory antibody repertoires linked to trajectories of disease severity from the longitudinal analysis also including anti-spike protein antibodies. By applying a machine-learning-based strategy, we developed a viral exposure signature predictive of COVID-19-related disease severity linked to patient survival. These results provide a basis for understanding the roles of memory B-cell repertoires in COVID-19-related symptoms as well as a predictive tool for monitoring its clinical severity.
7 citations
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TL;DR: The data suggest that a good level of thymic activity can compensate the deleterious effects of past periods without cART, if HIV replication is suppressed for a sufficient time.
Abstract: Perinatally HIV-infected patients face the consequences of both chronic infection effects per se and long-term combination antiretroviral therapy (cART) on immunosenescence Aims of our study were to evaluate which factors independently contribute to immunosenescence in HIV-infected young adults with a very different HIV infection duration (perinatally HIV-infected young individuals -pHIVy- and age-matched non perinatally HIV-infected youths -npHIVy), after durable efficient cART We considered low thymic and bone marrow output, respectively evaluated by quantifying T-cell receptor excision circles (TRECs), K-deleting recombination excision circles (KRECs), and shorter telomeres lenght (TL) as surrogate biomarkers of immunosenescence Twenty-one pHIVy and 19 npHIVy (with a mean HIV duration of 3-8 years) were included; mean age was 27 years for both groups Immunosenescence biomarkers were comparable between pHIVy and npHIVy (despite longer HIV-infection, higher frequency of AIDS events, past cART-free periods and concomitant chronic viral infections in pHIVy) At the multivariate analysis, CD4+ was the only variable independently associated with TRECs and TL Our data suggest that a good level of thymic activity can compensate the deleterious effects of past periods without cART, if HIV replication is suppressed for a sufficient time
6 citations
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TL;DR: This observational study indicated that different age-related changes of the new T and B lymphocyte production could be one of the reasons for the emergence of adverse events not otherwise observed in clinical trials; thus, caution is advised when choosing disease-modifying therapies for multiple sclerosis patients.
Abstract: Patients with multiple sclerosis exhibit the same qualitative and quantitative changes in immune system cells observed in aging. In the last 20 years, multiple sclerosis patients have shown an increase in life expectancy and average age, but clinical trial inclusion criteria typically exclude patients over the age of 55 years. Therefore, disease-modifying therapies are likely administered to patients older than those enrolled in clinical trials. In order to investigate whether disease-modifying therapies for multiple sclerosis induce modifications to the immune system that may have (super)additive effects resulting in an acceleration of immunosenescence, we quantified the number of T-cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs). These molecules are contained in new T and B lymphocytes released by the thymus and bone marrow and are considered molecular age-related markers. The markers of aging were measured by a multiplex quantitative real-time PCR assay in 122 patients who had started therapy with interferon-beta (IFN-β), fingolimod, alemtuzumab, or natalizumab. Samples were obtained before the therapy and at 6 and 12 months of treatment. Comparisons between the variables were performed by a non-parametric statistical analysis. In therapy-naive patients, a significant and direct correlation was found between a lower number of newly produced T and B cells and older age. Although disease-modifying therapies induced different changes (both increases and decreases) in the production of new T and B lymphocytes, 12 months of therapy with IFN-β or natalizumab did not affect the correlations found at baseline between the release of lymphocytes containing TRECs or KRECs and age. On the contrary, in patients treated with alemtuzumab, both correlations were lost, while in fingolimod-treated patients, only the correlation between TRECs and age disappeared. This observational study indicated that different age-related changes of the new T and B lymphocyte production could be one of the reasons for the emergence, in the real-world setting, of adverse events not otherwise observed in clinical trials; thus, caution is advised when choosing disease-modifying therapies for multiple sclerosis patients.
5 citations
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TL;DR: The percentage of natural regulatory T cells increased after 6, 12, and 24 months of interferon-β treatment, characterized by the expansion of central and effector memory regulatory T-cell subsets.
Abstract: The mechanisms underlying the therapeutic activity of interferon-β in multiple sclerosis are still not completely understood. In the present study, we evaluated the short and long-term effects of interferon-β treatment on different subsets of regulatory T cells in relapsing–remitting multiple sclerosis patients biologically responsive to treatment because of mixovirus resistance protein A inducibility. In this prospective longitudinal study, subsets of natural regulatory T cells (naive, central memory and effector memory) and inducible regulatory T cells (Tr1), as well as in vitro-induced regulatory T cells (Tr1-like cells), were simultaneously quantified by flow cytometry in samples prepared from 148 therapy-naive multiple sclerosis patients obtained before and after 6, 12, 18, and 24 months of interferon-β-1a treatment. mRNA for interleukin-10 and Tr1-related genes (CD18, CD49b, and CD46, together with Cyt-1 and Cyt-2 CD46-associated isoforms) were quantified in Tr1-like cells. Despite profound inter-individual variations in the modulation of all regulatory T-cell subsets, the percentage of natural regulatory T cells increased after 6, 12, and 24 months of interferon-β treatment. This increase was characterized by the expansion of central and effector memory regulatory T-cell subsets. The percentage of Tr1 significantly enhanced at 12 months of therapy and continued to be high at the subsequent evaluation points. Patients experiencing relapses displayed a higher percentage of naive regulatory T cells and a lower percentage of central memory regulatory T cells and of Tr1 before starting interferon-β therapy. In addition, an increase over time of central memory and of Tr1 was observed only in patients with stable disease. However, in vitro-induced Tr1-like cells, prepared from patients treated for 24 months, produced less amount of interleukin-10 mRNA compared with pre-treatment Tr1-like cells. Interferon-β induces the expansion of T regulatory subsets endowed with a high suppressive activity, especially in clinically stable patients. The overall concurrent modulation of natural and inducible regulatory T-cell subsets might explain the therapeutic effects of interferon-β in multiple sclerosis patients.
4 citations
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TL;DR: While it has been reported that SARS-CoV-2 is cleared without significant problems by the majority of people with MS or other autoimmune diseases on immunotherapy, these data indicate that treatment with anti-CD20 mAb may significantly alter humoral responses to the virus.
1 citations
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TL;DR: If confirmed in other patients, SF2/ASF evaluation could be a new and early biomarker of natalizumab-associated PML risk, allowing an 18–24-month interval before PML onset (presently ~ 5 months), in which clinicians could evaluate other risk factors and change therapy.
Abstract: Natalizumab is effective against relapsing-remitting multiple sclerosis (MS) but increases the risk of progressive multifocal leukoencephalopathy (PML), which is caused by the activation of the JCV polyomavirus. SF2/ASF (splicing factor2/alternative splicing factor) is a potent cellular inhibitor of JCV replication and large T-antigen (T-Ag) expression. We reported that SF2/ASF levels in blood cells increase during the first year of natalizumab therapy and decrease thereafter, inversely related to T-Ag expression, and suggested a correlation with JCV reactivation. Here, we report SF2/ASF levels of longitudinal blood samples of two patients undergoing natalizumab therapy, who developed PML while monitored, in comparison to natalizumab-treated controls and to one-off PML samples. After 6 months of therapy, SF2/ASF levels of the two cases were reduced, instead of increased, and their overall SF2/ASF levels were lower than those from natalizumab controls. Since SF2/ASF inhibits JCV, its early reduction might have a role in subsequent PML. We are aware of the limitations of the study, but the uniqueness of serial blood samples collected before and after PML onset in natalizumab-treated patients must be stressed. If confirmed in other patients, SF2/ASF evaluation could be a new and early biomarker of natalizumab-associated PML risk, allowing an 18–24-month interval before PML onset (presently ~ 5 months), in which clinicians could evaluate other risk factors and change therapy.