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Project Title
Deciphering the mechanisms of disease and therapeutic targets for proteasome maturation protein (pomp) related autoinflammation and immune dysregulation
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11181222
Principal Investigator
Start Date
2018

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First Report of Tocilizumab Use in a Cohort of Latin American Patients Hospitalized for Severe COVID-19 Pneumonia

2020 , VALENZUELA LETELIER, OMAR ANTONIO , IBAÑEZ, SEBASTIAN , M. Cecilia Poli , ROESSLER VERGARA, PATRICIA ANDREA , AYLWIN RAMIREZ, MABEL CRISTINA , Gigia Roizen , IRURETAGOYENA BRUCE, MIRENTXU INES , Vivianne Agar , Javiera Donoso , Margarita Fierro , José Montes

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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 , Bo Yuan , Richard A. Gibbs , Lindsay C. Burrage , James R. Lupski , Ivan K. Chinn , Tiphanie P. Vogel , Jordan S. Orange , M. Cecilia Poli

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 SLC7A7. 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.

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Refractory systemic juvenile idiopathic arthritis successfully treated with rapamycin

2021 , Sara Concha , Emma Rey-Jurado , M Cecilia Poli , Rodrigo Hoyos-Bachiloglu , Arturo Borzutzky

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Deep immunophenotyping reveals biomarkers of multisystemic inflammatory syndrome in children in a Latin American cohort

2022 , REY JURADO, EMMA , Yazmin Espinosa , Camila Astudillo , CORTES SALINAS, LINA JIMENA , HORMAZABAL CASTILLO, JUAN PATRICIO , Fernanda Cofré , Cecilia Piñera , Loreani P. Noguera , Ricardo González , Alexander Bataszew , MUÑOZ VENTURELLI, PAULA ANDREA , Dona Benadof , Patricia Álvarez , Valeria Acevedo , VIAL CLARO, PABLO AGUSTIN , VIAL COX, MARIA CECILIA , POLI HARLOWE, MARIA CECILIA BERTA

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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 , Valentina Jarur , Katja Hrovat Schaale , Pawat Laohamonthonkul , Klara Kong , Dale J. Calleja , Cassandra R. Harapas , Katherine R. Balka , Jacob Mitchell , Jacob T. Jackson , Niall D. Geoghegan , Fiona Moghaddas , Kelly L. Rogers , Katrin D. Mayer-Barber , Adriana A. De Jesus , Dominic De Nardo , Benjamin T. Kile , Anthony J. Sadler , M. Cecilia Poli , Elke Krüger , Raphaela Goldbach Mansky , Seth L. Masters

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.

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Prevalence of filaggrin loss‐of‐function variants in Chilean population with and without atopic dermatitis

2021 , Geovanna V. Cárdenas , Carolina Iturriaga , Caroll D. Hernández , Macarena Tejos‐Bravo , Guillermo Pérez‐Mateluna , Carolina Cabalin , Marcela Urzúa , Luis F. Venegas‐Salas , Juan P. Fraga , REBOLLEDO JARAMILLO, BORIS EDUARDO , Maria C. Poli , REPETTO LISBOA, MARIA GABRIELA , Paola Casanello , José A. Castro‐Rodríguez , Arturo Borzutzky

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Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19

2022 , Keith Sacco , Riccardo Castagnoli , Svetlana Vakkilainen , Can Liu , Ottavia M. Delmonte , Cihan Oguz , Ian M. Kaplan , Sara Alehashemi , Peter D. Burbelo , Farzana Bhuyan , Adriana A. de Jesus , Kerry Dobbs , Lindsey B. Rosen , Aristine Cheng , Elana Shaw , Mikko S. Vakkilainen , Francesca Pala , Justin Lack , Yu Zhang , Danielle L. Fink , Vasileios Oikonomou , Andrew L. Snow , Clifton L. Dalgard , Jinguo Chen , Brian A. Sellers , Gina A. Montealegre Sanchez , Karyl Barron , REY JURADO, EMMA , VIAL COX, MARIA CECILIA , POLI HARLOWE, MARIA CECILIA BERTA , Amelia Licari , Daniela Montagna , Gian Luigi Marseglia , Francesco Licciardi , Ugo Ramenghi , Valentina Discepolo , Andrea Lo Vecchio , Alfredo Guarino , Eli M. Eisenstein , Luisa Imberti , Alessandra Sottini , Andrea Biondi , Sayonara Mató , Dana Gerstbacher , Meng Truong , Michael A. Stack , Mary Magliocco , Marita Bosticardo , Tomoki Kawai , Jeffrey J. Danielson , Tyler Hulett , Manor Askenazi , Shaohui Hu , Jason Barnett , Xi Cheng , Krishnaveni Kaladi , Vasudev Kuram , Joseph Mackey , Neha M. Bansal , Andrew J. Martins , Boaz Palterer , Helen Matthews , Uma Mudunuri , Marshall Nambiar , Andrew J. Oler , Andre Rastegar , Smilee Samuel , Conrad Shyu , Varsha Waingankar , Sarah Weber , Sandhya Xirasagar , Yazmin Espinosa , Camila Astudillo , Cecilia Piñera , Ricardo González , Maria De Filippo , Martina Votto , Lorenza Montagna , Jeffrey I. Cohen , Helen C. Su , Douglas B. Kuhns , Michail S. Lionakis , Thomas M. Snyder , Steven M. Holland , Raphaela Goldbach-Mansky , John S. Tsang , Luigi D. Notarangelo

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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 , Ottavia M. Delmonte , Marita Bosticardo , Riccardo Castagnoli , Robert Krance , Luigi D. Notarangelo , Elke Krüger , Jordan S. Orange , M. Cecilia Poli

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HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease

2020 , Sarah A. Cook , William A. Comrie , POLI HARLOWE, MARIA CECILIA BERTA , Morgan Similuk , Andrew J. Oler , Aiman J. Faruqi , Douglas B. Kuhns , Sheng Yang , Alexander Vargas-Hernández , Alexandre F. Carisey , Benjamin Fournier , D. Eric Anderson , Susan Price , Margery Smelkinson , Wadih Abou Chahla , Lisa R. Forbes , Emily M. Mace , Tram N. Cao , Zeynep H. Coban-Akdemir , Shalini N. Jhangiani , Donna M. Muzny , Richard A. Gibbs , James R. Lupski , Jordan S. Orange , Geoffrey D. E. Cuvelier , Moza Al Hassani , Nawal Al Kaabi , Zain Al Yafei , Soma Jyonouchi , Nikita Raje , Jason W. Caldwell , Yanping Huang , Janis K. Burkhardt , Sylvain Latour , Baoyu Chen , Gehad ElGhazali , V. Koneti Rao , Ivan K. Chinn , Michael J. Lenardo

An inherited disorder makes WAVEs The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook et al. studied five patients from four unrelated families who harbor missense variants of the gene encoding the WRC component HEM1. These patients presented with recurrent infections and poor antibody responses, along with enhanced allergic and autoimmune disorders. HEM1 was found to be required for the regulation of cortical actin and granule release in T cells and also interacted with a key metabolic signaling complex contributing to the disease phenotype. By linking these interactions to immune function, this work suggests potential targets for future immunotherapies. Science , this issue p. 202

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Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

2022 , Carmelo Carmona-Rivera , Yu Zhang , Kerry Dobbs , Tovah E. Markowitz , Clifton L. Dalgard , Andrew J. Oler , Dillon R. Claybaugh , Deborah Draper , Meng Truong , Ottavia M. Delmonte , Francesco Licciardi , Ugo Ramenghi , Nicoletta Crescenzio , Luisa Imberti , Alessandra Sottini , Virginia Quaresima , Chiara Fiorini , Valentina Discepolo , Andrea Lo Vecchio , Alfredo Guarino , Luca Pierri , Andrea Catzola , Andrea Biondi , Paolo Bonfanti , POLI HARLOWE, MARIA CECILIA BERTA , Yasmin Espinosa , Camila Astudillo , REY JURADO, EMMA , VIAL COX, MARIA CECILIA , Javiera de la Cruz , Ricardo Gonzalez , Cecilia Pinera , Jacqueline W. Mays , Ashley Ng , Andrew Platt , Beth Drolet , John Moon , Edward W. Cowen , Heather Kenney , Sarah E. Weber , Riccardo Castagnoli , Mary Magliocco , Michael A. Stack , Gina Montealegre , Karyl Barron , Danielle L. Fink , Douglas B. Kuhns , Stephen M. Hewitt , Lisa M. Arkin , Daniel S. Chertow , Helen C. Su , Luigi D. Notarangelo , Mariana J. Kaplan

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