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

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    Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature
    (2021)
    Josefina Longeri Contreras
    ;
    Mabel A. Ladino
    ;
    Katherine Aránguiz
    ;
    Gonzalo P. Mendez
    ;
    Zeynep Coban-Akdemir
    <jats:p>Lysinuric protein intolerance (LPI) is an inborn error of metabolism caused by defective transport of cationic amino acids in epithelial cells of intestines, kidneys and other tissues as well as non-epithelial cells including macrophages. LPI is caused by biallelic, pathogenic variants in <jats:italic>SLC7A7</jats:italic>. The clinical phenotype of LPI includes failure to thrive and multi-system disease including hematologic, neurologic, pulmonary and renal manifestations. Individual presentations are extremely variable, often leading to misdiagnosis or delayed diagnosis. Here we describe a patient that clinically presented with immune dysregulation in the setting of early-onset systemic lupus erythematosus (SLE), including renal involvement, in whom an LPI diagnosis was suspected post-mortem based on exome sequencing analysis. A review of the literature was performed to provide an overview of the clinical spectrum and immune mechanisms involved in this disease. The precise mechanism by which ineffective amino acid transport triggers systemic inflammatory features is not yet understood. However, LPI should be considered in the differential diagnosis of early-onset SLE, particularly in the absence of response to immunosuppressive therapy.</jats:p>
      5Scopus© Citations 18
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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
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      12  1Scopus© Citations 5