Project Title
Functional genomics in autoinflammatory diseases
Partner Organisations
Internal ID
1221802
Principal Investigator
Type
basic research
Status
VIGENTE
Start Date
2021
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Now showing 1 - 6 of 6
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    Editorial: Immune response to gram-negative bacteria in the lungs
    (2024)
    Agnes Jara-Collao
    ;
    POLI HARLOWE, MARIA CECILIA BERTA  
    ;
    William Bain
    ;
    Hernán F. Peñaloza
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    TGFβ links EBV to multisystem inflammatory syndrome in children
    (Springer Science and Business Media LLC, 2025-03-12)
    Carl Christoph Goetzke
    ;
    Mona Massoud
    ;
    Stefan Frischbutter
    ;
    Gabriela Maria Guerra
    ;
    Marta Ferreira-Gomes
    <jats:title>Abstract</jats:title> <jats:p>In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock<jats:sup>1</jats:sup> termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion<jats:sup>2</jats:sup> and systemic hyperinflammation<jats:sup>3</jats:sup>. The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs. <jats:sup>4,5</jats:sup>). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein–Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation.</jats:p>
    Scopus© Citations 4  2
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    Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile
    (2024)
    POLI HARLOWE, MARIA CECILIA BERTA  
    ;
    Boris Rebolledo-Jaramillo  
    ;
    Víctor Faundes
    ;
    Catalina Lagos
    ;
    Joan Orellana
    <jats:title>Abstract</jats:title><jats:p>Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.</jats:p>
    Scopus© Citations 13  6
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    Scopus© Citations 16  8
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    Proteasome disorders and inborn errors of immunity
    (2023)
    M. Cecilia Poli
    <jats:title>Summary</jats:title><jats:p>Inborn errors of immunity (IEI) or primary immune deficiencies (PIDD) are caused by variants in genes encoding for molecules that are relevant to the innate or adaptive immune response. To date, defects in more than 450 different genes have been identified as causes of IEI, causing a constellation of heterogeneous clinical manifestations ranging from increased susceptibility to infection, to autoimmunity or autoinflammation. IEI that are mainly characterized by autoinflammation are broadly classified according to the inflammatory pathway that they predominantly perturb. Among autoinflammatory IEI are those characterized by the transcriptional upregulation of type I interferon genes and are referred to as interferonopathies. Within the spectrum of interferonopathies, genetic defects that affect the proteasome have been described to cause autoinflammatory disease and represent a growing area of investigation. This review is focused on describing the clinical, genetic, and molecular aspects of IEI associated with mutations that affect the proteasome and how the study of these diseases has contributed to delineate therapeutic interventions.</jats:p>
      2Scopus© Citations 5
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    Inborn errors of immunity: A field without frontiers
    (2023)
    Giorgia Bucciol
    ;
    Selket Delafontaine
    ;
    Isabelle Meyts
    ;
    POLI HARLOWE, MARIA CECILIA BERTA  
    <jats:title>Summary</jats:title><jats:p>The study of primary immunodeficiencies or inborn errors of immunity continues to drive our knowledge of the function of the human immune system. From the outset, the study of inborn errors has focused on unraveling genetic etiologies and molecular mechanisms. Aided by the continuous growth in genetic diagnostics, the field has moved from the study of an infection dominated phenotype to embrace and unravel diverse manifestations of autoinflammation, autoimmunity, malignancy, and severe allergy in all medical disciplines. It has now moved from the study of ultrarare presentations to producing meaningful impact in conditions as diverse as inflammatory bowel disease, neurological conditions, and hematology. Beyond offering immunogenetic diagnosis, the study of underlying inborn errors of immunity in these conditions points to targeted treatment which can be lifesaving.</jats:p>
    Scopus© Citations 7  1