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Title: Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management
Authors: López-Nevado, Marta
González-Granado, Luis I.
Ruiz-García, Raquel
Pleguezuelo, Daniel
Cabrera-Marante, Oscar
Salmón, Nerea
Blanco-Lobo, Pilar
Domínguez-Pinilla, Nerea
Rodríguez-Pena, Rebeca
Sebastián, Elena
Cruz-Rojo, Jaime
Olbrich, Peter
Ruiz-Contreras, Jesús
Paz-Artal, Estela
Neth, Olaf
Allende, Luis M.
metadata.dc.contributor.authoraffiliation: [López-Nevado,M; Pleguezuelo,D; Cabrera-Marante,O; Paz-Artal,E; Allende,LM] Immunology Department, University Hospital 12 de Octubre, Madrid, Spain. [López-Nevado,M; González-Granado,LI; Pleguezuelo,D; Cabrera-Marante,O; Salmón,N; Domínguez-Pinilla,N; Ruiz-Contreras,J; Paz-Artal,E; Allende,LM] Research Institute Hospital 12 Octubre (imas12), Madrid, Spain. [González-Granado,LI; Salmón,N; Ruiz-Contreras,J] Immunodeficiency Unit, Department of Pediatrics, University Hospital 12 de Octubre, Madrid, Spain. [Ruiz-García,R] Immunology Department, Centre Diagnòstic Biomèdic, Hospital Clínic, Barcelona, Spain. [Blanco-Lobo,P; Olbrich,P; Neth,O] Paediatric Infectious Diseases, Rheumatology and Immunology Unit, University Hospital Virgen del Rocío, Institute of Biomedicine, Biomedicine Institute (IBiS)/University of Seville/Superior Council of Scientific Investigations (CSIC), Seville, Spain. [Domínguez-Pinilla,N] Pediatric Hematology and Oncology Unit, Toledo Hospital Complex, Toledo, Spain and University Hospital 12 de Octubre, Madrid, Spain. [Rodríguez-Pena,R] Immunology Department, University Hospital La Paz, Madrid, Spain. [Sebastián,E] Hematology and Hemotherapy Unit, University Children’s Hospital Niño Jesús, Madrid, Spain. [Cruz-Rojo,J] Endocrine Unit, Department of Pediatrics, University Hospital 12 de Octubre, Madrid, Spain. [Ruiz-Contreras,J; Paz-Artal,E; Allende,LM] School of Medicine, Complutense University of Madrid, Madrid, Spain.
Keywords: ALPS;ALPS-like;Autoimmunity;Lymphoproliferation;Malignancy;Immune dysregulation;Síndrome linfoproliferativo autoinmune;Autoinmunidad
metadata.dc.subject.mesh: Medical Subject Headings::Diseases::Hemic and Lymphatic Diseases::Lymphatic Diseases::Lymphoproliferative Disorders::Autoimmune Lymphoproliferative Syndrome
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Early Diagnosis
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Antigens, Differentiation::Antigens, Differentiation, T-Lymphocyte::CTLA-4 Antigen
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Natural Killer Cell::Receptors, NK Cell Lectin-Like::NK Cell Lectin-Like Receptor Subfamily K
Medical Subject Headings::Phenomena and Processes::Immune System Phenomena::Immunity::Autoimmunity
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Monitoring, Physiologic
Issue Date: 10-Aug-2021
Publisher: Frontiers
Citation: López-Nevado M, González-Granado LI, Ruiz-García R, Pleguezuelo D, Cabrera-Marante O, Salmón N, et al. Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management. Front Immunol. 2021 Aug 10;12:671755.
Abstract: Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.
metadata.dc.identifier.doi: 10.3389/fimmu.2021.671755
ISSN: 1664-3224 (Online)
Appears in Collections:01- Artículos - Hospital Virgen del Rocío
01- Artículos - IBIS. Instituto de Biomedicina de Sevilla

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