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Author: search.filters.author.M. Cecilia PoliSubject: search.filters.subject.human

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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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    Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency
    (2023)
    Tom Le Voyer
    ;
    Audrey V. Parent
    ;
    Xian Liu
    ;
    Axel Cederholm
    ;
    Adrian Gervais
    <jats:title>Abstract</jats:title><jats:p>Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)<jats:sup>1,2</jats:sup>, conferring a predisposition to life-threatening COVID-19 pneumonia<jats:sup>3</jats:sup>. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52<jats:sup>LOF</jats:sup>/IκBδ<jats:sup>GOF</jats:sup>). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for <jats:italic>NFKB2</jats:italic> variants causing haploinsufficiency of p100 and p52 (hereafter, p52<jats:sup>LOF</jats:sup>/IκBδ<jats:sup>LOF</jats:sup>) or gain-of-function of p52 (hereafter, p52<jats:sup>GOF</jats:sup>/IκBδ<jats:sup>LOF</jats:sup>). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.</jats:p>
      3Scopus© Citations 90
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    HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related autoinflammatory disease
    (2021)
    Caridad Martinez
    ;
    Frédéric Ebstein
    ;
    Sarah K. Nicholas
    ;
    Marietta De Guzman
    ;
    Lisa R. Forbes
      8Scopus© Citations 21
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      8Scopus© Citations 185
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    Coronavirus disease 2019 in patients with inborn errors of immunity: An international study
    (2021)
    Isabelle Meyts
    ;
    Giorgia Bucciol
    ;
    Isabella Quinti
    ;
    Bénédicte Neven
    ;
    Alain Fischer
    Scopus© Citations 309  3
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    Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia
    (2022)
    Matilde I. Conte
    ;
    M. Cecilia Poli
    ;
    Angelo Taglialatela
    ;
    Giuseppe Leuzzi
    ;
    Ivan K. Chinn
      9Scopus© Citations 13
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    Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders
    (2022)
    Lisa R. Forbes
    ;
    Olive S. Eckstein
    ;
    Nitya Gulati
    ;
    Erin C. Peckham-Gregory
    ;
    Nmazuo W. Ozuah
      14Scopus© Citations 15
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    Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24
    (2022)
    Sophia Davidson
    ;
    Chien-Hsiung Yu
    ;
    Annemarie Steiner
    ;
    Frédéric Ebstein
    ;
    Paul J. Baker
    <jats:p>Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor–induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum–associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.</jats:p>
    Scopus© Citations 55  3