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3.
Immunohorizons ; 4(3): 119-128, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144186

RESUMO

The RAG1 and RAG2 proteins are essential for the assembly of Ag receptor genes in the process known as VDJ recombination, allowing for an immense diversity of lymphocyte Ag receptors. Congruent with their importance, RAG1 and RAG2 have been a focus of intense study for decades. To date, RAG1 has been studied as a single isoform; however, our identification of a spontaneous nonsense mutation in the 5' region of the mouse Rag1 gene lead us to discover N-truncated RAG1 isoforms made from internal translation initiation. Mice homozygous for the RAG1 nonsense mutation only express N-truncated RAG1 isoforms and have defects in Ag receptor rearrangement similar to human Omenn syndrome patients with truncating 5' RAG1 frameshift mutations. We show that the N-truncated RAG1 isoforms are derived from internal translation initiation start sites. Given the seemingly inactivating Rag1 mutation, it is striking that homozygous mutant mice do not have the expected SCID. We propose that evolution has garnered RAG1 and other important genes with the ability to form truncated proteins via internal translation to minimize the deleterious effects of 5' nonsense mutations. This mechanism of internal translation initiation is particularly important to consider when interpreting nonsense or frameshift mutations in whole-genome sequencing, as such mutations may not lead to loss of protein.


Assuntos
Códon sem Sentido , Genes RAG-1 , Proteínas de Homeodomínio/genética , Animais , Modelos Animais de Doenças , Células HEK293 , Homozigoto , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Iniciação Traducional da Cadeia Peptídica/genética , Isoformas de Proteínas , Imunodeficiência Combinada Severa/genética , Transfecção , Recombinação V(D)J/genética
4.
Clin Immunol ; 213: 108366, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32092471

RESUMO

The nuclease Artemis is a enzyme for V(D)J recombination allowing for the creation of T and B lymphocytes as well as for the repair of radiation-induced DNA double strand breaks encoded by the DCLRE1C gene. Artemis-null mutations are a known cause of severe combined immunodeficiencies (SCIDs) with radiosensitivity. Hypomorphic mutations in Artemis have been reported to cause a "leaky SCID"" phenotype, typically with hypogammaglobulinemia. We present four patients, all harboring the same unique hypomorphic mutation in the DCLRE1C gene, an 8-base pair insertion (c.1299_1306dup, p.Cys436*) presenting with a relatively mild phenotype including pulmonary infectious EBV-related lymphoproliferative diseases, an autoimmune phenomenon. Non-typical findings of IgG hypergammaglobulinemia accompanied by IgA and IgE deficiency were recorded in all patients. The typical viral, fungal, and opportunistic infections were absent, and patients reached a relatively old age.


Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Hipergamaglobulinemia/genética , Imunoglobulina G , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Adolescente , Doenças Autoimunes/genética , Feminino , Humanos , Deficiência de IgA/genética , Imunoglobulina E/deficiência , Transtornos Linfoproliferativos/genética , Masculino , Mutação , Fenótipo , Imunodeficiência Combinada Severa/complicações
5.
Blood ; 135(9): 610-619, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31942628

RESUMO

Traditionally, primary immune deficiencies have been defined based on increased susceptibility to recurrent and/or severe infections. However, immune dysregulation, manifesting with autoimmunity or hyperinflammatory disease, has emerged as a common feature. This is especially true in patients affected by combined immune deficiency (CID), a group of disorders caused by genetic defects that impair, but do not completely abolish, T-cell function. Hypomorphic mutations in the recombination activating genes RAG1 and RAG2 represent the prototype of the broad spectrum of clinical and immunological phenotypes associated with CID. The study of patients with RAG deficiency and with other forms of CID has revealed distinct abnormalities in central and peripheral T- and B-cell tolerance as the key mechanisms involved in immune dysregulation. Understanding the pathophysiology of autoimmunity and hyperinflammation in these disorders may also permit more targeted therapeutic interventions.


Assuntos
Imunodeficiência Combinada Severa/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/imunologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Proteínas Nucleares/deficiência , Proteínas Nucleares/imunologia , Imunodeficiência Combinada Severa/genética
6.
Ann Dermatol Venereol ; 147(2): 131-134, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-31973905

RESUMO

BACKGROUND: Severe combined immunodeficiency (SCID) is a the most severe form of primary immunodeficiency and is highly heterogeneous. We report an atypical form of SCID revealed by exfoliative erythroderma. PATIENTS AND METHODS: A 3-month-old boy, born to consanguineous parents, was admitted to the dermatology department with exfoliative erythroderma associated with eczematous patches and alopecia of the scalp, eyelashes, and eyebrows, but with no lymphadenopathy or hepatosplenomegaly. He displayed chronic diarrhea and recurrent infection since birth. A complete blood count showed marked leukocytosis with eosinophilia and lymphocytosis. These clinical and biological findings improved partly with topical steroids. The patient no longer had erythroderma and showed regrowth of hair, eyelashes and eyebrows. The subsequent CBC showed less marked eosinophilia with mild lymphopenia and no leukocytosis. Immunoglobulin levels were undetectable. Primary immunodeficiency was discussed. Immunological investigations concluded on a diagnosis of T-B-NK+ SCID. Mutation analysis revealed a homozygous c.1338C>G (pCys446Trp) mutation in the RAG2 gene. Hematopoietic stem cell transplantation is planned in the near future. CONCLUSION: This case illustrates atypical T-B-NK+ SCID revealed by severe exfoliative erythroderma in a 3-month-old boy with RAG2 gene mutation. Neonatal erythroderma must be considered a warning sign of primary immunodeficiency requiring immediate immunological phenotyping as well as genetic testing for a definitive diagnosis.


Assuntos
Dermatite Esfoliativa/etiologia , Imunodeficiência Combinada Severa/complicações , Alopecia/etiologia , Alopecia/patologia , Doença Crônica , Consanguinidade , Proteínas de Ligação a DNA/genética , Dermatite Esfoliativa/patologia , Diarreia/etiologia , Eczema/etiologia , Eczema/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Proteínas Nucleares/genética , Fotografação , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia
8.
Iran J Immunol ; 16(4): 334-338, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31885011

RESUMO

Severe Combined Immunodeficiency (SCID), characterized by a profound decrease in both the number and function of T cells, is related to more than 20 different mutations. Recombination-activating gene (RAG) 1 and 2 seem to be two of the most common forms presenting with various manifestations, including typical SCID, Omenn syndrome (OS), atypical SCID (AS), or delayed onset combined immunodeficiency with granulomas. One interesting manifestation in RAG mutation is the change in the immunophenotype over time, even after hematopoietic stem cell transplantation (HSCT). As bone marrow transplantation (BMT) is the only curative treatment of SCID, it is necessary to differentiate between SCID and OS due to the different conditioning regimens (CR). We present a novel case of atypical SCID (SCID manifestations with more than 300 CD3+T cells) caused by RAG 2 gene mutation whose immunophenotype changed to atypical Omenn syndrome (all Omenn syndrome manifestations except rash, eosinophilia, and elevated IgE) over time. Differentiation of leaky SCID, SCID and Omenn syndrome in RAG mutation genes and overlap manifestations is important in treatment plan and prognosis.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Aloenxertos , Complexo CD3/genética , Complexo CD3/imunologia , Proteínas de Ligação a DNA/imunologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Proteínas Nucleares/imunologia , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Linfócitos T/imunologia , Linfócitos T/patologia
9.
J Immunol Res ; 2019: 5902391, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781678

RESUMO

Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency (PID), characterized by fatal opportunistic infections. The ADA gene encodes adenosine deaminase, an enzyme that catalyzes the irreversible deamination of adenosine and deoxyadenosine in the catabolic pathway of purine. Mutations of the ADA gene have been identified in patients with severe combined immunodeficiency. In this study, we performed a bioinformatics analysis of the human ADA gene to identify potentially harmful nonsynonymous SNPs and their effect on protein structure and stability. Using eleven prediction tools, we identified 15 nsSNPs (H15D, H15P, H17Q, H17Y, D19N, T26I, G140E, C153F, A183D, G216R, H258Y, C262Y, S291L, S291W, and K34OE) as harmful. The results of ConSurf's analysis revealed that all these nsSNPs are localised in the highly conserved positions and affect the structure of the native proteins. In addition, our computational analysis showed that the H15D, G140E, G216R, and S291L mutations identified as being associated with severe combined immunodeficiency affect protein structure. Similarly, the results of the analyses of Rmsd, Rmsf, and Rg showed that all these factors influence protein stability, flexibility, and compaction with different levels of impact. This study is the first comprehensive computational analysis of nsSNPs of the ADA gene. However, functional analyses are needed to elucidate the biological mechanisms of these polymorphisms in severe combined immunodeficiency.


Assuntos
Adenosina Desaminase/química , Adenosina Desaminase/genética , Modelos Moleculares , Polimorfismo de Nucleotídeo Único , Imunodeficiência Combinada Severa/genética , Sequência de Aminoácidos , Sequência de Bases , Sequência Conservada , Dano ao DNA , Humanos , Simulação de Dinâmica Molecular , Mutação , Conformação Proteica , Estabilidade Proteica , Relação Estrutura-Atividade
11.
Mol Biol Rep ; 46(6): 6571-6575, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31520268

RESUMO

The recombination activating genes, including RAG1 and RAG2, are essential for V(D)J somatic recombination in lymphocytes. Leaky severe combined immunodeficiency disorder (SCID) is characterized by normal or intermediate T cells and normal to absent B cells associated with partial T cell and B cell dysfunction. We present a newly found RAG1 deficiency in a 21-year-old boy with leaky SCID. Immunoglobulin levels, flow cytometry, and whole exome sequencing (WES) were evaluated. Flow cytometric analysis revealed a decreased number of CD3+, CD4+, and CD8+ T cells, and B cells whereas NK cell counts were normal. Immunoglobulin levels were also decreased. The WES revealed a newly found homozygous mutation of RAG1 gene (NM_000448: exon 2: c.C2275T). Atypical features, including leukopenia, candidiasis, and low lymphocyte counts in patients with late-onset combined immunodeficiency disorders (CID) such as leaky SCID due to RAG1 deficiency may result in misdiagnosis and inadequate therapy instead of adopting the curative hematopoietic stem cell transplantation in these patients.


Assuntos
Proteínas de Homeodomínio/genética , Mutação , Imunodeficiência Combinada Severa/genética , Linfócitos B/metabolismo , Homozigoto , Humanos , Mutação com Perda de Função , Contagem de Linfócitos , Masculino , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem
12.
J Dermatol ; 46(11): 1019-1023, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31456262

RESUMO

Prominent dermal infiltration by Langerhans cells (LC) is a rare finding in patients with Omenn syndrome (OS). Here, we report the case study of a 7-month-old boy with OS and with prominent dermal infiltration by LC, which is a rare histological manifestation of the skin. Striking erythroderma appeared in the patient 2 weeks after birth. We also noted alopecia, lymphadenopathy, hepatosplenomegaly, eosinophilia and an elevated serum immunoglobulin E level with hypogammaglobulinemia. Peripheral blood flow cytometry showed the Tlow NK+ B+ immunophenotype and genetic analysis, a novel mutation in the IL2RG gene (c.337_339delTCT, p.Ser113del). The final diagnosis was that of OS. He responded well to an allograft umbilical cord blood transplantation that was performed when the patient was 8 months of age. We speculate that the LC accumulated in the dermis will eventually migrate to the regional lymph node, then stimulate autoreactive T cells by overpresenting antigens, thus causing OS-specific skin symptoms.


Assuntos
Derme/patologia , Subunidade gama Comum de Receptores de Interleucina/genética , Células de Langerhans/patologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Biópsia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Derme/imunologia , Humanos , Lactente , Masculino , Mutação , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/cirurgia
13.
Pediatr Dermatol ; 36(5): 672-676, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31309596

RESUMO

Bacille Calmette-Guérin (BCG), a live attenuated vaccine prepared using Mycobacterium bovis, can prevent tuberculosis in children and is routinely administered to infants in China and many other countries. A serious complication following vaccination is disseminated BCG infection. The risk is greatly increased in patients with severe combined immunodeficiency disease (SCID), a syndrome characterized by deficiency of both humoral and cellular immunity. We report a case of disseminated BCG infection in an infant with SCID caused by two novel janus kinase 3 (JAK3) gene mutations.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Vacina BCG/efeitos adversos , Janus Quinase 3/genética , Mutação/genética , Imunodeficiência Combinada Severa/complicações , Tuberculose/etiologia , Feminino , Humanos , Lactente , Mycobacterium bovis , Imunodeficiência Combinada Severa/genética
14.
BMJ Case Rep ; 12(5)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151968

RESUMO

Severe combined immunodeficiency (SCID) is an extremely rare disease caused by a disruption in the forkhead box N1 (FOXN1) gene, with an incidence of <1 per 1 000 000 live births. We report a boy aged 4 months who presented with a history of fever for 3 weeks and enlarged lymph nodes. The fever was associated with dry cough and runny nose. On physical examination, we noted oral thrush, generalised lymphadenopathy, nail dystrophy and alopecia. Flow cytometry of lymph node biopsy showed high-grade B-cell lymphoma. In addition, Epstein-Barr virus (EBV) infection was documented by PCR. The diagnosis of SCID was made by genetic testing, which revealed a homozygous variant of the FOXN1 gene. The variant was confirmed with Sanger sequencing. Management of EBV infection and lymphoma was initiated; unfortunately, the patient passed away on day 45 of hospitalisation.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Fatores de Transcrição Forkhead/deficiência , Linfoma de Células B/complicações , Imunodeficiência Combinada Severa/complicações , Diagnóstico Diferencial , Infecções por Vírus Epstein-Barr/diagnóstico , Evolução Fatal , Fatores de Transcrição Forkhead/genética , Herpesvirus Humano 4 , Humanos , Lactente , Masculino , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética
15.
Vet J ; 248: 71-73, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31113566

RESUMO

The highly selective breeding of Arabian horses results in inbreeding depression and genetic disorders, thereby causing significant economic loss. The Polish population of Arabians has a great impact on many breeding programmes. The aim of the current study was to monitor genetic variants involved in the most common genetic disorders of this breed. A total of 808 elite Arabian horses were screened for cerebellar abiotrophy (CA), severe combined immunodeficiency (SCID) and lavender foal syndrome (LFS) genetic disorders by Sanger sequencing and allelic discrimination methods. The investigated population was clear of LFS. The unfavourable SCID allele was detected in three heterozygous horses (q = 0.00185). Regarding CA, the minor allele frequency was q = 0.04029. This is the first report of SCID carriers in Poland. This investigation demonstrates the value of genetic testing to support breeding decisions and to facilitate genetic disease monitoring.


Assuntos
Doenças Cerebelares/veterinária , Testes Genéticos/veterinária , Doenças dos Cavalos/genética , Amaurose Congênita de Leber/veterinária , Imunodeficiência Combinada Severa/veterinária , Animais , Doenças Cerebelares/genética , Feminino , Predisposição Genética para Doença , Doenças dos Cavalos/imunologia , Cavalos , Amaurose Congênita de Leber/genética , Masculino , Linhagem , Polônia , Imunodeficiência Combinada Severa/genética , Síndrome
16.
Clin Immunol ; 205: 1-5, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071452

RESUMO

Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections. The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86. Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels. Whole exome sequencing (WES) identified a novel heterozygous mutation in RAC2(c.275A > C, p.N92 T). Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP. Cell lines transfected with RAC2 [N92 T] displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA. Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease.


Assuntos
Imunodeficiência Combinada Severa/genética , Proteínas rac de Ligação ao GTP/genética , Infecções por Adenovirus Humanos , Linfócitos B , Transtornos da Insuficiência da Medula Óssea , Criança , Evolução Fatal , Feminino , Transplante de Células-Tronco Hematopoéticas , Heterozigoto , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Memória Imunológica , Linfopenia , Mutação , Recidiva , Linfócitos T , Viroses
19.
Nat Rev Drug Discov ; 18(6): 447-462, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30858502

RESUMO

Pioneering gene therapy trials have shown that the genetic engineering of haematopoietic stem and progenitor cells can be an alternative to allogeneic transplantation in the treatment of primary immunodeficiencies. Early trials also highlighted the risk of insertional mutagenesis and oncogene transactivation associated with the first generation of gammaretroviral vectors. These events prompted the development of safer, self-inactivating lentiviral or gammaretroviral vectors. These lentiviral vectors have been successfully used to treat over 200 patients with 10 different haematological disorders (including primary immunodeficiencies, haemoglobinopathies and metabolic disorders) and for the generation of chimeric antigen receptor-T cells for cancer therapy. However, several challenges, such as effective reconstitution during inflammation, remain if gene therapy is to be extended to more complex diseases in which haematopoietic stem and progenitor cells can be altered by the disease environment. We discuss the progress made and future challenges for gene therapy and contrast gene therapy with gene-editing strategies.


Assuntos
Anemia Falciforme/terapia , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Imunodeficiência Combinada Severa/terapia , Talassemia beta/terapia , Anemia Falciforme/genética , Animais , Engenharia Genética , Humanos , Imunodeficiência Combinada Severa/genética , Talassemia beta/genética
20.
Rheumatol Int ; 39(5): 911-919, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30783801

RESUMO

Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle-Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.


Assuntos
Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Adolescente , Adulto , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/genética , Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Feminino , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/genética , Pessoa de Meia-Idade , Proteínas de Transporte de Nucleosídeos/genética , Osteomielite/diagnóstico , Osteomielite/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Pirina/genética , Análise de Sequência de DNA , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Adulto Jovem
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