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2.
Nature ; 619(7968): 193-200, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37344590

RESUMO

Lymphocytes of vertebrate adaptive immune systems acquired the capability to assemble, from split genes in the germline, billions of functional antigen receptors1-3. These receptors show specificity; unlike the broadly tuned receptors of the innate system, antibodies (Ig) expressed by B cells, for instance, can accurately distinguish between the two enantiomers of organic acids4, whereas T cell receptors (TCRs) reliably recognize single amino acid replacements in their peptide antigens5. In developing lymphocytes, antigen receptor genes are assembled from a comparatively small set of germline-encoded genetic elements in a process referred to as V(D)J recombination6,7. Potential self-reactivity of some antigen receptors arising from the quasi-random somatic diversification is suppressed by several robust control mechanisms8-12. For decades, scientists have puzzled over the evolutionary origin of somatically diversifying antigen receptors13-16. It has remained unclear how, at the inception of this mechanism, immunologically beneficial expanded receptor diversity was traded against the emerging risk of destructive self-recognition. Here we explore the hypothesis that in early vertebrates, sequence microhomologies marking the ends of recombining elements became the crucial targets of selection determining the outcome of non-homologous end joining-based repair of DNA double-strand breaks generated during RAG-mediated recombination. We find that, across the main clades of jawed vertebrates, TCRα repertoire diversity is best explained by species-specific extents of such sequence microhomologies. Thus, selection of germline sequence composition of rearranging elements emerges as a major factor determining the degree of diversity of somatically generated antigen receptors.


Assuntos
Evolução Molecular , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T , Receptores de Antígenos de Linfócitos T alfa-beta , Recombinação V(D)J , Animais , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Recombinação V(D)J/genética , Vertebrados/classificação , Vertebrados/genética , Reparo do DNA por Junção de Extremidades , Quebras de DNA de Cadeia Dupla , Genes RAG-1 , Especificidade da Espécie , Homologia de Sequência , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T/genética , Linfócitos/metabolismo
3.
Commun Biol ; 5(1): 1037, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36175547

RESUMO

Few human tumours present with a recurrent pathognomonic mutation in a transcription factor. Thymomas are an exception, with the majority of some subtypes exhibiting a distinct somatically acquired missense mutation in the general transcription factor GTF2I. Co-dominant expression of wild-type and mutated forms of Gtf2i in the mouse thymic epithelium is associated with aberrant thymic architecture and reduced thymopoietic activity. Phenotypic and molecular characterization of the mutant epithelium indicates that medullary differentiation is particularly affected as a result of impaired differentiation of bi-potent epithelial progenitors. The resulting gene expression signature is dominated by that of immature cortex-like thymic epithelial cells. TCR repertoire analysis of the cytopenic T cell compartment indicates efficient intrathymic selection; hence, despite marked homeostatic proliferation of T cell clones, autoimmunity is not observed. Thus, our transgenic mouse model recapitulates some aspects of the pathophysiology of a genetically defined type of human thymoma.


Assuntos
Timoma , Neoplasias do Timo , Fatores Genéricos de Transcrição , Fatores de Transcrição TFIII , Fatores de Transcrição TFII , Animais , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Receptores de Antígenos de Linfócitos T , Timoma/genética , Neoplasias do Timo/genética , Fatores de Transcrição , Fatores de Transcrição TFII/genética
4.
Commun Biol ; 4(1): 1201, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34671088

RESUMO

To capture the global gene network regulating the differentiation of immature T cells in an unbiased manner, large-scale forward genetic screens in zebrafish were conducted and combined with genetic interaction analysis. After ENU mutagenesis, genetic lesions associated with failure of T cell development were identified by meiotic recombination mapping, positional cloning, and whole genome sequencing. Recessive genetic variants in 33 genes were identified and confirmed as causative by additional experiments. The mutations affected T cell development but did not perturb the development of an unrelated cell type, growth hormone-expressing somatotrophs, providing an important measure of cell-type specificity of the genetic variants. The structure of the genetic network encompassing the identified components was established by a subsequent genetic interaction analysis, which identified many instances of positive (alleviating) and negative (synthetic) genetic interactions. Several examples of synthetic lethality were subsequently phenocopied using combinations of small molecule inhibitors. These drugs not only interfered with normal T cell development, but also elicited remission in a model of T cell acute lymphoblastic leukaemia. Our findings illustrate how genetic interaction data obtained in the context of entire organisms can be exploited for targeted interference with specific cell types and their malignant derivatives.


Assuntos
Redes Reguladoras de Genes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Mutações Sintéticas Letais , Linfócitos T/metabolismo , Animais , Modelos Animais de Doenças , Epistasia Genética , Fenótipo , Peixe-Zebra
5.
Sci Adv ; 7(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33523858

RESUMO

The rules underlying the structure of antigen receptor repertoires are not yet fully defined, despite their enormous importance for the understanding of adaptive immunity. With current technology, the large antigen receptor repertoires of mice and humans cannot be comprehensively studied. To circumvent the problems associated with incomplete sampling, we have studied the immunogenetic features of one of the smallest known vertebrates, the cyprinid fish Paedocypris sp. "Singkep" ("minifish"). Despite its small size, minifish has the key genetic facilities characterizing the principal vertebrate lymphocyte lineages. As described for mammals, the frequency distributions of immunoglobulin and T cell receptor clonotypes exhibit the features of fractal systems, demonstrating that self-similarity is a fundamental property of antigen receptor repertoires of vertebrates, irrespective of body size. Hence, minifish achieve immunocompetence via a few thousand lymphocytes organized in robust scale-free networks, thereby ensuring immune reactivity even when cells are lost or clone sizes fluctuate during immune responses.


Assuntos
Receptores de Antígenos de Linfócitos T , Vertebrados , Imunidade Adaptativa , Animais , Peixes , Mamíferos , Receptores de Antígenos de Linfócitos T/genética
6.
EBioMedicine ; 59: 102961, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32841837

RESUMO

BACKGOUND: The potential of a single progenitor cell to establish and maintain long-term protective T-cell immunity in humans is unknown. For genetic disorders disabling T-cell immunity, somatic reversion was shown to support limited T-cell development attenuating the clinical phenotype. However, the cases reported so far deteriorated over time leaving unanswered the important question of long-term activity of revertant precursors and the robustness of the resulting T-cell system. METHODS: We applied TCRß-CDR3 sequencing and mass cytometry on serial samples of a now 18 year-old SCIDX1 patient with somatic reversion to analyse the longitudinal diversification and stability of a T-cell system emerging from somatic gene rescue. FINDINGS: We detected close to 105 individual CDR3ß sequences in the patient. Blood samples of equal size contained about 10-fold fewer unique CDR3ß sequences compared to healthy donors, indicating a surprisingly broad repertoire. Despite dramatic expansions and contractions of individual clonotypes representing up to 30% of the repertoire, stable diversity indices revealed that these transient clonal distortions did not cause long-term repertoire imbalance. Phenotypically, the T-cell system did not show evidence for progressive exhaustion. Combined with immunoglobulin substitution, the limited T-cell system in this patient supported an unremarkable clinical course over 18 years. INTERPRETATION: Genetic correction in the appropriate cell type, in our patient most likely in a T-cell biased self-renewing hematopoietic progenitor, can yield a diverse T-cell system that provides long-term repertoire stability, does not show evidence for progressive exhaustion and is capable of providing protective and regulated T-cell immunity for at least two decades. FUNDING: DFG EH 145/9-1, DFG SCHW 432/4-1 and the German Research Foundation under Germany's Excellence Strategy-EXC-2189-Project ID: 390939984.


Assuntos
Diferenciação Celular/genética , Linfopoese/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adolescente , Biomarcadores , Estudos de Casos e Controles , Criança , Evolução Clonal/genética , Feminino , Citometria de Fluxo , Testes Genéticos , Humanos , Imunofenotipagem , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Subpopulações de Linfócitos T/citologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia
7.
Sci Immunol ; 5(45)2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32169953

RESUMO

The antibodies of jawless vertebrates consist of leucine-rich repeat arrays encoded by somatically assembled VLRB genes. It is unknown how the incomplete germline VLRB loci are converted into functional antibody genes during B lymphocyte development in lampreys. In Lampetra planeri larvae lacking the cytidine deaminase CDA2 gene, VLRB assembly fails, whereas the T lineage-associated VLRA and VLRC antigen receptor gene assemblies occur normally. Thus, CDA2 acts in a B cell lineage-specific fashion to support the somatic diversification of VLRB antibody genes. CDA2 is closely related to activation-induced cytidine deaminase (AID), which is essential for the elaboration of immunoglobulin gene repertoires in jawed vertebrates. Our results thus identify a convergent mechanism of antigen receptor gene assembly and diversification that independently evolved in the two sister branches of vertebrates.


Assuntos
Anticorpos Monoclonais/genética , Citidina Desaminase/genética , Lampreias/genética , Receptores de Antígenos/genética , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Citidina Desaminase/imunologia , Citidina Desaminase/metabolismo , Lampreias/imunologia , Lampreias/metabolismo , Receptores de Antígenos/imunologia , Receptores de Antígenos/metabolismo
8.
Medicina (B Aires) ; 76(2): 65-70, 2016.
Artigo em Espanhol | MEDLINE | ID: mdl-27135842

RESUMO

X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels and clinically by extracellular bacterial infections which mainly compromise the respiratory tract as well as recurrent diarrheas. The mainstay of treatment is gammaglobulin replacement therapy, which allows most patients to reach adulthood with high quality of life. We analyzed the clinical features of 14 patients over 18 years of age with XLA diagnosis that received treatment in our unit from the year 2003, the date the first patient was derived, until 2015. The average age at which patients were referred was 20.4 years old; age at the last consult was 25.5. The average follow-up time was 59.8 months. Previously to being diagnosed all patients had suffered infections, most frequently respiratory. After diagnosis all were started on intravenous gammaglobulin replacement treatment and in spite of infections being reduced in severity and frequency, there were cases of severe disease with long term sequelae. At the beginning of our follow-up 35.7% presented impaired respiratory function with only one case being severe. In no cases during this period did the respiratory function worsen, nor were there severe clinical complications. Three patients were switched to subcutaneous immunoglobulin treatment with good tolerance. The number of XLA cases is increasing, as most reach the second decade of life without serious complications and remain free of severe infectious disease and further impairment of their respiratory functions with the treatment.


Assuntos
Agamaglobulinemia/complicações , Agamaglobulinemia/tratamento farmacológico , Progressão da Doença , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Imunoglobulinas Intravenosas/administração & dosagem , gama-Globulinas/administração & dosagem , Administração Cutânea , Administração Intravenosa , Adulto , Seguimentos , Humanos , Masculino , Qualidade de Vida , Infecções Respiratórias/etiologia , Estudos Retrospectivos , Adulto Jovem
9.
Medicina (B.Aires) ; 76(2): 65-70, abr. 2016. tab
Artigo em Espanhol | LILACS | ID: biblio-841544

RESUMO

La agammaglobulinemia ligada al cromosoma X (XLA) se caracteriza por la ausencia o reducción significativa de linfocitos B, niveles bajos o indetectables de inmunoglobulinas y, clínicamente, por infecciones principalmente respiratorias por bacterias capsuladas extracelulares y diarrea recurrente. El tratamiento de reemplazo con gammaglobulina ha permitido a la mayor parte de los enfermos llegar a adultos con una buena calidad de vida. Analizamos las características clínicas de 14 pacientes mayores de 18 años con diagnóstico de XLA asistidos en nuestra Unidad desde 2003, fecha en que fue derivado el primer paciente, hasta 2015. La edad promedio en el momento de la derivación fue de 20.4 años, en el momento de la última consulta de 25.5. El tiempo promedio de seguimiento fue de 59.8 meses. Previo al diagnóstico todos habían presentado infecciones, las más frecuentes fueron las respiratorias. Posteriormente al diagnóstico todos iniciaron tratamiento de reemplazo con gammaglobulina endovenosa, y a pesar de que las infecciones disminuyeron en frecuencia y gravedad, en este período se presentaron enfermedades con secuelas graves. Al comenzar el seguimiento en nuestra Unidad, 35.7% presentaban deterioro de la función respiratoria, solo grave en un paciente. Durante el seguimiento ninguno presentó deterioro de la función respiratoria ni complicaciones clínicas importantes. Tres pasaron a gammaglobulina subcutánea con buena tolerancia. El número de adultos con XLA es cada vez mayor, la mayoría llegan a la segunda década de la vida sin complicaciones graves y bajo tratamiento se mantienen libres de enfermedades infecciosas graves y de progresión de sus secuelas pulmonares.


X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels and clinically by extracellular bacterial infections which mainly compromise the respiratory tract as well as recurrent diarrheas. The mainstay of treatment is gammaglobulin replacement therapy, which allows most patients to reach adulthood with high quality of life. We analyzed the clinical features of 14 patients over 18 years of age with XLA diagnosis that received treatment in our unit from the year 2003, the date the first patient was derived, until 2015. The average age at which patients were referred was 20.4 years old; age at the last consult was 25.5. The average follow-up time was 59.8 months. Previously to being diagnosed all patients had suffered infections, most frequently respiratory. After diagnosis all were started on intravenous gammaglobulin replacement treatment and in spite of infections being reduced in severity and frequency, there were cases of severe disease with long term sequelae. At the beginning of our follow-up 35.7% presented impaired respiratory function with only one case being severe. In no cases during this period did the respiratory function worsen, nor were there severe clinical complications. Three patients were switched to subcutaneous immunoglobulin treatment with good tolerance. The number of XLA cases is increasing, as most reach the second decade of life without serious complications and remain free of severe infectious disease and further impairment of their respiratory functions with the treatment.


Assuntos
Humanos , Masculino , Adulto , Adulto Jovem , Imunoglobulinas Intravenosas/administração & dosagem , Progressão da Doença , Agamaglobulinemia/complicações , Agamaglobulinemia/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Qualidade de Vida , Infecções Respiratórias/etiologia , Administração Cutânea , gama-Globulinas/administração & dosagem , Estudos Retrospectivos , Seguimentos , Administração Intravenosa
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