Deciphering the mechanisms of disease and therapeutic targets for proteasome maturation protein (pomp) related autoinflammation and immune dysregulation

Project Title

Partner Organisations

Facultad de Medicina Clínica Alemana Universidad del Desarrollo

Internal ID

11181222

Principal Investigator

POLI HARLOWE, MARIA CECILIA BERTA

Start Date

2018

Publications

Now showing 1 - 10 of 14

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HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease
(2020)
Sarah A. Cook
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William A. Comrie
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POLI HARLOWE, MARIA CECILIA BERTA
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Morgan Similuk
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Andrew J. Oler
<jats:title>An inherited disorder makes WAVEs</jats:title> <jats:p> 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 <jats:italic>et al.</jats:italic> 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. </jats:p> <jats:p> <jats:italic>Science</jats:italic> , this issue p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6500" page="202" related-article-type="in-this-issue" vol="369" xlink:href="10.1126/science.aay5663">202</jats:related-article> </jats:p>
10Scopus© Citations 94
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Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome
(2019)
Alejandra Aird
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Macarena Lagos
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Alexander Vargas-Hernández
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Jennifer E. Posey
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Zeynep Coban-Akdemir
4Scopus© Citations 27
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Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19
(2022)
Carmelo Carmona-Rivera
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Yu Zhang
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Kerry Dobbs
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Tovah E. Markowitz
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Clifton L. Dalgard
13Scopus© Citations 30
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Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)
(2019)
Frédéric Ebstein
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María Cecilia Poli Harlowe
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Maja Studencka-Turski
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Elke Krüger
11Scopus© Citations 71
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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
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Mabel A. Ladino
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Katherine Aránguiz
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Gonzalo P. Mendez
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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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Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19
(2022)
Keith Sacco
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Riccardo Castagnoli
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Svetlana Vakkilainen
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Can Liu
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Ottavia M. Delmonte
Scopus© Citations 204 11
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HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related autoinflammatory disease
(2021)
Caridad Martinez
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Frédéric Ebstein
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Sarah K. Nicholas
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Marietta De Guzman
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Lisa R. Forbes
8Scopus© Citations 21
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Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C
(2022)
Peter D. Burbelo
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Riccardo Castagnoli
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Chisato Shimizu
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Ottavia M. Delmonte
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Kerry Dobbs
<jats:p>The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring <jats:italic>in vivo</jats:italic> decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring &gt;100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.</jats:p>
Scopus© Citations 25 1
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Deep immunophenotyping reveals biomarkers of multisystemic inflammatory syndrome in children in a Latin American cohort
(2022)
REY JURADO, EMMA
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Yazmin Espinosa
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Camila Astudillo
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CORTES SALINAS, LINA JIMENA
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HORMAZABAL CASTILLO, JUAN PATRICIO
Scopus© Citations 16 8
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Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency
(2021)
Francesco Saettini
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POLI HARLOWE, MARIA CECILIA BERTA
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Jaime Vengoechea
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Sonia Bonanomi
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Julio C. Orellana
<jats:title>Abstract</jats:title> <jats:p>Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1−/− animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.</jats:p>
Scopus© Citations 28 2

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