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2.
Clin Immunol ; 230: 108812, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34329798

RESUMO

Autoimmune lymphoproliferative syndrome is a primary immunodeficiency caused by variants in FAS-mediated apoptosis related genes and is characterized by lymphadenopathy, splenomegaly and autoimmunity. A total of six different variants in CASP10 have been described as potential causative of disease, although two of them have recently been considered polymorphisms. The high allele frequency of these variants in healthy population in addition to the broad clinical spectrum of the disease difficult the interpretation of their pathogenicity. Here, we describe the clinical and analytical findings of three new patients carrying variants in CASP10 and summarize 12 more cases from the literature. Autoimmune cytopenias, adenopathies and increment of TCRαß+CD4-CD8- cells have been the most common findings, being possibly the FAS-mediated apoptosis pathway the pathogenic mechanism of this disease. The clinical impact and the consequences of CASP10 variants are not fully elucidated, therefore the description of new cases will contribute to solve this issue.


Assuntos
Síndrome Linfoproliferativa Autoimune/enzimologia , Síndrome Linfoproliferativa Autoimune/genética , Caspase 10/genética , Variação Genética , Adolescente , Adulto , Substituição de Aminoácidos , Apoptose/genética , Síndrome Linfoproliferativa Autoimune/diagnóstico , Feminino , Mutação da Fase de Leitura , Humanos , Masculino , Linhagem , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Deleção de Sequência
5.
Enferm Infecc Microbiol Clin (Engl Ed) ; 38(9): 438-443, 2020 Nov.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33161954

RESUMO

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Adulto , Transplante de Medula Óssea , Criança , Consenso , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Doenças da Imunodeficiência Primária/diagnóstico , Qualidade de Vida
6.
J Allergy Clin Immunol Pract ; 8(10): 3342-3347, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33161963

RESUMO

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Adulto , Transplante de Medula Óssea , Criança , Consenso , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Qualidade de Vida
7.
Artigo em Inglês | IBECS | ID: ibc-198629

RESUMO

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available


Las inmunodeficiencias primarias (IDP) son unas enfermedades raras, frecuentemente infradiagnosticadas y potencialmente fatales. Las manifestaciones clínicas de las IDP pueden ser muy graves y ocasionar secuelas que empeoran la calidad de vida de los pacientes. Tradicionalmente, el tratamiento de las IDP ha sido fundamentalmente de soporte, con excepción del trasplante de progenitores hematopoyéticos y, más recientemente, la terapia génica. El descubrimiento de nuevos mecanismos patogénicos, el desarrollo de nuevas moléculas y fármacos biológicos y los avances en el conocimiento de las bases moleculares de estas enfermedades han abierto oportunidades para el tratamiento de esta afección. El objetivo de este documento es revisar el conocimiento actual y aportar recomendaciones para el diagnóstico y el tratamiento clínico de los pacientes adultos y pediátricos con IDP basado en la evidencia científica disponible y teniendo en cuenta la actual práctica y los retos futuros. Se realizó una revisión sistemática, que justifica los niveles de evidencia para cada recomendación


Assuntos
Humanos , Criança , Adulto , Consenso , Guias de Prática Clínica como Assunto , Síndromes de Imunodeficiência/terapia , Síndromes de Imunodeficiência/diagnóstico , Imunoglobulinas/uso terapêutico
8.
Heliyon ; 6(9): e04914, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32995611

RESUMO

X-linked Agammaglobulinemia is a primary immunodeficiency caused by mutations in BTK, a tyrosine kinase essential for B lymphocytes differentiation. Patients usually have very low or absent B lymphocytes and are not able to develop humoral specific responses. Here we present a boy, diagnosed with XLA due to a mutation on the promoter region of the gene, whose phenotype is characterised by low percentage of B cells, hypogammaglobulinemia, oscillating neutropenia, antibodies responses to some antigens after vaccination and IgE-mediated allergy. Additional technology as flow cytometry was needed to demonstrate the pathological status of the variant. We focus on the idea that XLA should be suspected in males with B lymphopenia and hypogammaglobulinemia, even if they make humoral specific responses. We also highlight the importance of sequencing BTK's promoter region, as mutations on it can be disease-causing.

9.
Cell Rep ; 31(6): 107633, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32402279

RESUMO

Most monogenic disorders have a primary clinical presentation. Inherited ISG15 deficiency, however, has manifested with two distinct presentations to date: susceptibility to mycobacterial disease and intracranial calcifications from hypomorphic interferon-II (IFN-II) production and excessive IFN-I response, respectively. Accordingly, these patients were managed for their infectious and neurologic complications. Herein, we describe five new patients with six novel ISG15 mutations presenting with skin lesions who were managed for dermatologic disease. Cellularly, we denote striking specificity to the IFN-I response, which was previously assumed to be universal. In peripheral blood, myeloid cells display the most robust IFN-I signatures. In the affected skin, IFN-I signaling is observed in the keratinocytes of the epidermis, endothelia, and the monocytes and macrophages of the dermis. These findings define the specific cells causing circulating and dermatologic inflammation and expand the clinical spectrum of ISG15 deficiency to dermatologic presentations as a third phenotype co-dominant to the infectious and neurologic manifestations.


Assuntos
Citocinas/deficiência , Interferon Tipo I/imunologia , Pele/patologia , Ubiquitinas/deficiência , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Citocinas/genética , Citocinas/imunologia , Dermatite/genética , Dermatite/imunologia , Dermatite/patologia , Feminino , Células HEK293 , Humanos , Lactente , Masculino , Mutação , Células Mieloides/imunologia , Células Mieloides/patologia , Necrose , Linhagem , Ubiquitinas/genética , Ubiquitinas/imunologia
12.
J Allergy Clin Immunol ; 143(1): 359-368, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30273710

RESUMO

BACKGROUND: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. OBJECTIVE: We sought to investigate the incidence of gene mosaicism in patients with PIDs. METHODS: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. RESULTS: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. CONCLUSION: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.


Assuntos
Alelos , Frequência do Gene , Síndromes de Imunodeficiência/genética , Mosaicismo , Família , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes de Imunodeficiência/imunologia , Masculino
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