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1.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809261

RESUMO

Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in Lpin2, which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a Lpin2 knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.


Assuntos
Anemia Diseritropoética Congênita/genética , Síndromes de Imunodeficiência/genética , Inflamação/genética , MAP Quinase Quinase Quinases/genética , Fatores de Transcrição NFATC/genética , Proteínas Nucleares/genética , Osteomielite/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Anemia Diseritropoética Congênita/metabolismo , Anemia Diseritropoética Congênita/patologia , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/genética , Humanos , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/genética , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Knockout , NF-kappa B/genética , Proteínas Nucleares/deficiência , Proteínas Nucleares/metabolismo , Osteoclastos/metabolismo , Osteogênese/genética , Osteomielite/metabolismo , Osteomielite/patologia , Ligante RANK/genética , Transdução de Sinais/genética , Fator de Transcrição RelA/genética
2.
J Int Med Res ; 49(4): 3000605211010644, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33900868

RESUMO

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive inherited disorder that is caused by the SMARCAL1 mutation. The phenotype can vary from mild to severe on the basis of the patient's age at onset. Herein, we report the case of a 14-year-old Chinese boy who presented with short stature, focal segmental glomerulosclerosis (FSGS), and facial dysmorphism. Genetic analysis revealed two compound heterozygous missense mutations, including a well-known mutation (c.1933C>T, p.R645C) and a novel mutation (c.2479G>A, p.V827M) in the SMARCAL1 gene, which were inherited from his parents. In silico analyses showed that the c.2479G>A (p.V827M) variant affects a highly conserved residue within the ATPase catalytic domain. Finally, we established the diagnosis of mild SIOD and treated the patient with diuretics and angiotensin receptor blockers. This report expands the mutational spectrum of SMARCAL1 and reinforces the importance of a detailed clinical evaluation, molecular detection, and appropriate genetic counseling.


Assuntos
Arteriosclerose , DNA Helicases , Síndromes de Imunodeficiência , Síndrome Nefrótica , Osteocondrodisplasias , Adolescente , DNA Helicases/genética , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Mutação , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Sequenciamento Completo do Exoma
3.
J Allergy Clin Immunol Pract ; 9(7): 2885-2893.e3, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33894394

RESUMO

BACKGROUND: Mutations in ITCH, which encodes an E3 ubiquitin-protein ligase, can result in systemic autoimmunity and immunodeficiency. The clinical phenotype and mechanism of disease have not been fully characterized, resulting in a paucity of therapeutic options for this potentially fatal disease. OBJECTIVE: We aimed to (1) expand the understanding about the phenotype of human ITCH deficiency (2) further characterize the associated immune dysregulation, and (3) report the first successful hematopoietic cell transplant (HCT) in a patient with ITCH deficiency. METHODS: Disease profiling was performed in a patient with multisystem immune dysregulation. Whole exome sequencing with trio analysis and functional validation of candidate disease variants were performed, including mRNA and protein expression. Analyses to further delineate the immunophenotype included quantitative evaluation of lymphoid and myeloid subsets with flow cytometry and mass cytometry. RESULTS: A patient with multisystem immune dysregulation presenting with growth failure, very-early-onset inflammatory bowel disease, arthritis, uveitis, psoriasis, and type 1 diabetes mellitus underwent whole exome sequencing, which identified novel compound heterozygous mutations in ITCH. Reduced expression of ITCH mRNA and absent ITCH protein were found. Abnormalities in both lymphoid and myeloid lineages were identified. The patient underwent HCT. He demonstrated excellent immune reconstitution and resolution of many manifestations of his systemic disease. CONCLUSIONS: Here we report ITCH deficiency with unique clinical features of colonic very-early-onset inflammatory bowel disease, arthritis, and uveitis in the setting of immune dysregulation and further characterize the underlying immune dysregulation. We demonstrate that HCT can be an effective, and potentially curative, therapy for ITCH deficiency.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Autoimunidade , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Imunofenotipagem , Masculino , Mutação , Ubiquitina-Proteína Ligases/genética
4.
J Mol Biol ; 433(9): 166910, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33676928

RESUMO

The Smc5/6 complex facilitates chromosome replication and DNA break repair. Within this complex, a subcomplex composed of Nse1, Nse3 and Nse4 is thought to play multiple roles through DNA binding and regulating ATP-dependent activities of the complex. However, how the Nse1-Nse3-Nse4 subcomplex carries out these multiple functions remain unclear. To address this question, we determine the crystal structure of the Xenopus laevis Nse1-Nse3-Nse4 subcomplex at 1.7 Å resolution and examine how it interacts with DNA. Our structural analyses show that the Nse1-Nse3 dimer adopts a closed conformation and forms three interfaces with a segment of Nse4, forcing it into a Z-shaped conformation. The Nse1-Nse3-Nse4 structure provides an explanation for how the lung disease immunodeficiency and chromosome breakage syndrome-causing mutations could dislodge Nse4 from Nse1-Nse3. Our DNA binding and mutational analyses reveal that the N-terminal and the middle region of Nse4 contribute to DNA interaction and cell viability. Integrating our data with previous crosslink mass spectrometry data, we propose potential roles of the Nse1-Nse3-Nse4 complex in binding DNA within the Smc5/6 complex.


Assuntos
Proteínas Cromossômicas não Histona/química , Multimerização Proteica , Proteínas de Xenopus/química , Sequência de Aminoácidos , Animais , Proteínas Cromossômicas não Histona/metabolismo , Quebra Cromossômica , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Síndromes de Imunodeficiência/genética , Pneumopatias/genética , Modelos Moleculares , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Mutação , Células Procarióticas/química , Células Procarióticas/metabolismo , Conformação Proteica , Dobramento de Proteína , Proteínas de Xenopus/metabolismo , Xenopus laevis
5.
J Allergy Clin Immunol Pract ; 9(2): 613-625, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33551037

RESUMO

The field of immunology has a rich and diverse history, and the study of inborn errors of immunity (IEIs) represents both the "cake" and the "icing on top of the cake," as it has enabled significant advances in our understanding of the human immune system. This explosion of knowledge has been facilitated by a unique partnership, a triumvirate formed by the physician who gathers detailed immunological and clinical phenotypic information from, and shares results with, the patient; the laboratory scientist/immunologist who performs diagnostic testing, as well as advanced functional correlative studies; and the genomics scientist/genetic counselor, who conducts and interprets varied genetic analyses, all of which are essential for dissecting constitutional genetic disorders. Although the basic principles of clinical care have not changed in recent years, the practice of clinical immunology has changed to reflect the prodigious advances in diagnostics, genomics, and therapeutics. An "omic/tics"-centric approach to IEI reflects the tremendous strides made in the field in the new millennium with recognition of new disorders, characterization of the molecular underpinnings, and development and implementation of personalized treatment strategies. This review brings renewed attention to bear on the indispensable "trinity" of phenotypic, genomic, and immunological analyses in the diagnosis, management, and treatment of IEIs.


Assuntos
Síndromes de Imunodeficiência , Testes Diagnósticos de Rotina , Alimentos , Testes Genéticos , Humanos , Sistema Imunitário , Síndromes de Imunodeficiência/genética
6.
Adv Exp Med Biol ; 1289: 37-54, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32803731

RESUMO

Primary immunodeficiencies (PIDs) belong to a group of rare congenital diseases occurring all over the world that may be seen in both children and adults. In most cases, genetic predispositions are already known. As shown in this review, genetic abnormalities may be related to dysfunction of the immune system, which manifests itself as recurrent infections, increased risk of cancer, and autoimmune diseases. This article reviews the various forms of PIDs, including their characterization, management strategies, and complications. Novel aspects of the diagnostics and monitoring of PIDs are presented.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Adulto , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Criança , Predisposição Genética para Doença , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/genética , Neoplasias
7.
J Allergy Clin Immunol Pract ; 9(2): 792-802.e10, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33186766

RESUMO

BACKGROUND: Immune dysregulation is as important as susceptibility to infection in defining primary immunodeficiencies (PIDs). Because of the variability and nonspecificity of the symptoms of PIDs, diagnosis can be delayed-especially if a patient presents with immune dysregulation. Diagnosis is then based on certain combinations of symptoms and relies on the clinician's ability to recognize a pattern. So far there is no large report linking patterns of immune dysregulations to the underlying genetic defects. OBJECTIVE: To identify immune dysregulatory patterns associated with PIDs and to help clinicians to detect an underlying PID in certain patients with noninfectious inflammatory diseases. METHOD: A systematic literature review was performed. RESULTS: We included 186 articles that reported on n = 745 patients. The most common immune dysregulation category was "autoimmunity" (62%, n = 463), followed by "intestinal disease" (38%, n = 283) and "lymphoproliferation" (36%, n = 268). Most patients (67%) had 1 or more symptoms of immune dysregulation. Autoimmune hemolytic anemia, the most common autoimmune phenotype, was most frequently reported in patients with LPS responsive beige-like anchor protein deficiency (when combined with hypogammaglobulinemia or gastrointestinal symptoms), activation-induced cytidine deaminase deficiency (when combined with autoimmune hepatitis), or RAG1 deficiency (when it was the only symptom of immune dysregulation). Eczema, allergies, and asthma were reported in 34%, 4%, and 4% of the patients, respectively. CONCLUSION: Patterns of immune dysregulation may help the physician to recognize specific PIDs. This systematic review provides clinicians with an overview to better assess patients with immune dysregulation.


Assuntos
Doenças Autoimunes , Gastroenteropatias , Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Autoimunidade , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética
8.
Blood ; 137(4): 493-499, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-32905580

RESUMO

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.


Assuntos
Agamaglobulinemia/genética , Linfócitos B/patologia , Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Síndromes de Imunodeficiência/genética , Linfopenia/genética , Adulto , Animais , Linfócitos B/metabolismo , Criança , Pré-Escolar , Cromossomos Humanos Par 5/genética , Códon sem Sentido , Consanguinidade , Doença de Crohn/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Cardiopatias Congênitas/genética , Humanos , Infecções/etiologia , Mutação com Perda de Função , Masculino , Camundongos , Neutropenia/genética , Linhagem , Dissomia Uniparental , Sequenciamento Completo do Exoma
9.
Clin Immunol ; 222: 108638, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33276124

RESUMO

To assess how B cell phenotype analysis correlates with antigen responses in patients with class switch recombination defects (CSRD) we quantified memory B cells by flow-cytometry and immunized CSRD patients with the neoantigen bacteriophage phiX174 (phage). CSRD patients showed uniformly absent or markedly reduced switched memory B cells (IgM-IgD-CD27+). CD40L patients had reduced CD27+ memory B cells (both non-switched and switched). In NEMO patients, results varied depending on the IKKγ gene variant. Three of four AID patients had normal percentages of CD27+ memory B cells while CD27+IgM-IgD- switched memory B cells were markedly reduced in all AID patients. Antibody response to phage was remarkably decreased with lack of memory amplification and class-switching in immunized CD40L, UNG deficient, and NEMO patients. Distinct B-cell phenotype pattern correlated with abnormal antibody responses to a T-cell dependent neoantigen, representing a powerful tool to identify CSRD patients.


Assuntos
Linfócitos B/citologia , Bacteriófago phi X 174/imunologia , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Adolescente , Adulto , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Ligante de CD40/deficiência , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Proteínas I-kappa B/genética , Imunização , Imunoglobulina D/imunologia , Imunoglobulina M/imunologia , Síndromes de Imunodeficiência/patologia , Memória Imunológica/genética , Memória Imunológica/imunologia , Lactente , Masculino , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
10.
J Pediatr (Rio J) ; 97 Suppl 1: S3-S9, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33121930

RESUMO

OBJECTIVES: To rescue medical genetics concepts that are necessary to understand the advances in the genetic-molecular characterization of primary immunodeficiencies, to help in the understanding and adequate interpretation of their results. SOURCE OF DATA: Non-systematic literature review, searching for articles since 2000 on PubMed using the terms "genetic evaluation" OR "whole exome sequence" or "whole genome sequence" OR "next generation sequence" AND "immunologic deficiency syndromes" OR "Immune deficiency disease" OR "immune deficiency" NOT HIV. SUMMARY OF THE DATA: Knowledge of medical genetics is essential for the understanding of the principles of heredity and disease inheritance patterns, types of genetic variants, types of genetic sequencing and interpretation of their results. The clinical and immunophenotypic evaluation of each patient is essential for the correlation with the genetic variants observed in the genetic study of patients with primary immunodeficiencies. The discussion of the benefits and limitations of genetic tests should always guide the performance of genetic tests. CONCLUSIONS: There are many evident benefits of genetic analysis, such as the definitive diagnosis of the disease, family genetic counseling, and the possibility of a more adequate and accurate management. Cost, access and interpretation of genetic test results are limitations that need continuous improvement. The understanding of the benefits and limits of the several genetic assessment methodologies related to primary immunodeficiencies is essential to obtain more effective results from the sequencing.


Assuntos
Exoma , Síndromes de Imunodeficiência , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética
11.
J Pediatr (Rio J) ; 97 Suppl 1: S17-S23, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33181112

RESUMO

OBJECTIVES: To provide an overview of drug treatment, transplantation, and gene therapy for patients with primary immunodeficiencies. SOURCE OF DATA: Non-systematic review of the literature in the English language carried out at PubMed. SYNTHESIS OF DATA: The treatment of patients with primary immunodeficiencies aims to control their disease, especially the treatment and prevention of infections through antibiotic prophylaxis and/or immunoglobulin replacement therapy. In several diseases, it is possible to use specific medications for the affected pathway with control of the condition, especially in autoimmune or autoinflammatory processes associated with inborn immunity errors. In some diseases, treatment can be curative through hematopoietic stem cell transplantation (HSCT); more recently, gene therapy has opened new horizons through new technologies. CONCLUSIONS: Immunoglobulin replacement therapy remains the main therapeutic tool. Precision medicine with specific drugs for altered immune pathways is already a reality for several immune defects. Advances in the management of HSCT and gene therapy have expanded the capacity for curative treatments in patients with primary immunodeficiencies.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Terapia Genética , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia
12.
J Allergy Clin Immunol Pract ; 9(2): 653-659, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33358993

RESUMO

There is a growing understanding of the clinical overlap between primary immune deficiency and autoimmunity. An atypical or treatment-refractory clinical presentation of autoimmunity may in fact signal an underlying congenital condition of primary immune dysregulation (an inborn error of immunity). Detailed profiling of the family history is critical in the diagnostic process and must not be limited to the occurrence of frequent or atypical infections, but additionally should include inquiries into chronic forms of autoimmunity, hyperinflammation, and malignancy. A genetic and a functional diagnostic approach are complementary and nonoverlapping methods of identifying and validating an inborn error of immunity. Extended immune phenotyping of both affected and unaffected family members may provide insight into disease mode of inheritance, penetrance, and secondary inherited or environmentally acquired modifiers. Clinical care of a family with an inborn error of immunity may require local and national expertise in addition to cross-disciplinary care from the disciplines of pediatrics and internal medicine. Physician communication across subspecialties as well as distinct medical institutes can facilitate the appropriate disclosure of genetic testing results toward their prompt incorporation into patient care. Targeted immunomodulation based directly on genetic and functional immune phenotyping has the potential to reduce unnecessary immunosuppression and provide more exacting therapeutic benefit to our patients.


Assuntos
Síndromes de Imunodeficiência , Neoplasias , Doenças da Imunodeficiência Primária , Autoimunidade , Criança , Humanos , Tolerância Imunológica , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia
13.
J Pediatr (Rio J) ; 97 Suppl 1: S75-S83, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33347837

RESUMO

OBJECTIVES: The aim of the report is to describe the main immunodeficiencies with syndromic characteristics according to the new classification of Inborn Errors of Immunity. DATA SOURCE: The data search was centered on the PubMed platform on review studies, meta-analyses, systematic reviews, case reports and a randomized study published in the last 10 years that allowed the characterization of the several immunological defects included in this group. DATA SYNTHESIS: Immunodeficiencies with syndromic characteristics include 65 immunological defects in 9 subgroups. The diversity of clinical manifestations is observed in each described disease and may appear early or later, with variable severity. Congenital thrombocytopenia, syndromes with DNA repair defect, immuno-osseous dysplasias, thymic defects, Hyper IgE Syndrome, anhidrotic ectodermal dysplasia with immunodeficiency and purine nucleoside phosphorylase deficiency were addressed. CONCLUSIONS: Immunological defects can present with very different characteristics; however, the occurrence of infectious processes, autoimmune disorders and progression to malignancy may suggest diagnostic research. In the case of diseases with gene mutations, family history is of utmost importance.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Erros Inatos do Metabolismo da Purina-Pirimidina , Humanos , Síndromes de Imunodeficiência/genética , Fenótipo , Purina-Núcleosídeo Fosforilase/genética
15.
Hematology Am Soc Hematol Educ Program ; 2020(1): 661-672, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33275711

RESUMO

The identification of genetic disorders associated with dysregulated immunity has upended the notion that germline pathogenic variants in immune genes universally result in susceptibility to infection. Immune dysregulation (autoimmunity, autoinflammation, lymphoproliferation, and malignancy) and immunodeficiency (susceptibility to infection) represent 2 sides of the same coin and are not mutually exclusive. Also, although autoimmunity implies dysregulation within the adaptive immune system and autoinflammation indicates disordered innate immunity, these lines may be blurred, depending on the genetic defect and diversity in clinical and immunological phenotypes. Patients with immune dysregulatory disorders may present to a variety of clinical specialties, depending on the dominant clinical features. Therefore, awareness of these disorders, which may manifest at any age, is essential to avoid a protracted diagnostic evaluation and associated complications. Availability of and access to expanded immunological testing has altered the diagnostic landscape for immunological diseases. Nonetheless, there are constraints in using these resources due to a lack of awareness, challenges in systematic and logical evaluation, interpretation of results, and using results to justify additional advanced testing, when needed. The ability to molecularly characterize immune defects and develop "bespoke" therapy and management mandates a new paradigm for diagnostic evaluation of these patients. The immunological tests run the gamut from triage to confirmation and can be used for both diagnosis and refinement of treatment or management strategies. However, the complexity of testing and interpretation of results often necessitates dialogue between laboratory immunologists and specialty physicians to ensure timely and appropriate use of testing and delivery of care.


Assuntos
Doenças Autoimunes , Doenças Genéticas Inatas , Síndromes de Imunodeficiência , Adulto , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia
16.
Allergol. immunopatol ; 48(6): 686-693, nov.-dic. 2020. graf, tab
Artigo em Inglês | IBECS | ID: ibc-199259

RESUMO

BACKGROUND: Activated Phospho-Inositide 3 (PI3) Kinases Delta syndrome (APDS) can underlie primary immune deficiency. The prevalence and phenotypic characterization of these patients are not well described in Egypt. OBJECTIVES: To describe patients with APDS in hospitalized children with recurrent respiratory tract infections with suspected primary immune deficiency. METHODS: 79 patients were included in the study. E1021K and E525K mutations of PI3K δ chain gene were screened by Sanger sequencing technique. RESULTS: one patient was heterozygous to E1021K mutation; a female child was diagnosed clinically as Combined Immune Deficiency with CD4 and B lymphopenia and markedly deficient IgG and increased IgM. The E525K mutation was not detected in our cohort. CONCLUSIONS: Screening for APDS in patients with recurrent respiratory tract infections with undefined antibody deficiency or combined immune deficiency with or without bronchiectasis is required. These patients need great attention to benefit from the available treatment. Further studies on the Egyptian population are recommended to increase the knowledge about the prevalence and phenotypic characterization of this disease in Egypt


No disponible


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Síndromes de Imunodeficiência/epidemiologia , Infecções Respiratórias/epidemiologia , Estudos Transversais , Classe I de Fosfatidilinositol 3-Quinases , Infecções Respiratórias/genética , Síndromes de Imunodeficiência/genética , Estatísticas não Paramétricas , Citometria de Fluxo , Distribuição por Sexo , Egito/epidemiologia , Prevalência , Criança Hospitalizada/estatística & dados numéricos
17.
Am J Hum Genet ; 107(6): 1029-1043, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33202260

RESUMO

Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a "cloning-free" saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Variação Genética , Guanilato Ciclase/genética , Síndromes de Imunodeficiência/genética , Adenina/análogos & derivados , Adenina/farmacologia , Proteína 10 de Linfoma CCL de Células B/genética , Linfócitos B/citologia , Linhagem Celular , Diploide , Éxons , Genes Dominantes , Humanos , Células Jurkat , Linfoma/genética , Subunidade p50 de NF-kappa B/genética , Piperidinas/farmacologia , Polimorfismo de Nucleotídeo Único , Doenças da Imunodeficiência Primária/genética , Sensibilidade e Especificidade
19.
Mol Immunol ; 128: 79-88, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33096415

RESUMO

Heterozygous gain-of-function (GOF) mutations in the interferon-driven transcription factor STAT1 (signal transducer and activator of transcription 1) cause chronic mucocutaneous candidiasis (CMC). In this study, we characterized the molecular basis of a CMC-associated missense mutation by introducing a threonine-to-alanine exchange in the STAT1 DNA-binding domain at position 387. This substitution had previously been described in a CMC patient with suppurative eyelid infection and cutaneous abscesses, which are both unusual symptoms in this immunodeficiency. The STAT1-T387A mutant generated was compared to the wild-type protein and, in addition, to the missense mutant in the neighbouring position 386. Our results showed that the T387A mutant displayed distinct properties different from the wild-type molecule, namely elevated levels of tyrosine phosphorylation in conjunction with increased DNA-binding activity, hyperactive transcriptional regulation, and prolonged nuclear accumulation. The elevated tyrosine phosphorylation of the T387A mutant did not result in an increased mRNA production above the level of the wild-type molecule for all transcripts tested, indicating that the transcriptional activity of this mutant is largely gene-dependent. Nonetheless, these data demonstrate that the pathogenic T387A mutation associated with an atypical CMC symptomatology is biochemically similar to other well-characterized GOF mutants, while the H386A mutant was indistinguishable from the wild-type molecule. Our findings are in line with the assumption that the phenotype of this dominant STAT1 GOF mutation probably results from a disturbed shift in the equilibrium between the parallel and antiparallel dimer conformation, which is required for physiological gene activation.


Assuntos
Regulação da Expressão Gênica/genética , Mutação de Sentido Incorreto/genética , Fator de Transcrição STAT1/genética , Transdução de Sinais/genética , Transcrição Genética/genética , Ativação Transcricional/genética , Transcriptoma/genética , Candidíase Mucocutânea Crônica/genética , Linhagem Celular Tumoral , Citocinas/genética , Mutação com Ganho de Função/genética , Células HeLa , Heterozigoto , Humanos , Síndromes de Imunodeficiência/genética , Fenótipo , Domínios Proteicos/genética
20.
Front Immunol ; 11: 2020, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849667

RESUMO

Background: Live viral vaccines are generally contraindicated in patients with combined immunodeficiency including cartilage-hair hypoplasia (CHH); however, they may be tolerated in milder syndromes. We evaluated the safety and efficacy of live viral vaccines in patients with CHH. Methods: We analyzed hospital and immunization records of 104 patients with CHH and measured serum antibodies to measles, mumps, rubella, and varicella zoster virus (VZV) in all patients who agreed to blood sampling (n = 50). We conducted a clinical trial (ClinicalTrials.gov identifier: NCT02383797) of live VZV vaccine on five subjects with CHH who lacked varicella history, had no clinical symptoms of immunodeficiency, and were seronegative for VZV; humoral and cellular immunologic responses were assessed post-immunization. Results: A large proportion of patients have been immunized with live viral vaccines, including measles-mumps-rubella (MMR) (n = 40, 38%) and VZV (n = 10, 10%) vaccines, with no serious adverse events. Of the 50 patients tested for antibodies, previous immunization has been documented with MMR (n = 22), rubella (n = 2) and measles (n = 1) vaccines. Patients with CHH demonstrated seropositivity rates of 96%/75%/91% to measles, mumps and rubella, respectively, measured at a medium of 24 years post-immunization. Clinical trial participants developed humoral and cellular responses to VZV vaccine. One trial participant developed post-immunization rash and knee swelling, both resolved without treatment. Conclusion: No serious adverse events have been recorded after immunization with live viral vaccines in Finnish patients with CHH. Patients generate humoral and cellular immune response to live viral vaccines. Immunization with live vaccines may be considered in selected CHH patients with no or clinically mild immunodeficiency.


Assuntos
Cabelo/anormalidades , Herpesvirus Humano 3/imunologia , Doença de Hirschsprung/imunologia , Síndromes de Imunodeficiência/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Osteocondrodisplasias/congênito , Doenças da Imunodeficiência Primária/imunologia , Vacinas Virais/imunologia , Anticorpos Antivirais/sangue , Células Cultivadas , Estudos de Coortes , ELISPOT , Cabelo/imunologia , Doença de Hirschsprung/genética , Humanos , Imunidade Celular , Imunidade Humoral , Síndromes de Imunodeficiência/genética , Interferon gama/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/imunologia , Doenças da Imunodeficiência Primária/genética , RNA Longo não Codificante/genética , Vacinação
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