RESUMO
Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Processamento Alternativo , Ciclo Celular , Linhagem Celular , Análise Mutacional de DNA , Estudos de Associação Genética/métodos , Genótipo , Humanos , Mutação , FenótipoRESUMO
Regulatory T cells (Treg) are involved in the maintenance of peripheral tolerance and in the prevention of autoimmune diseases. They are also essential to the regulation of immune responses observed in allergy, transplantation, cancers and infectious diseases. Most of Treg, called natural, differentiate in the thymus and are defined by their expression of CD4, CD25 and the transcription factor FOXP3. However, another population of Treg induced in the periphery has been recently characterized and appears to play an important role as well. In this review, we will discuss certain aspects of Treg, concerning notably their characterization, their role in normal and disease states, their mechanisms of action. Finally, we will discuss the significance of induced Treg.
Assuntos
Linfócitos T CD4-Positivos/fisiologia , Linfócitos T Reguladores/fisiologia , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Tolerância Imunológica/imunologia , Modelos Biológicos , Neoplasias/etiologia , Neoplasias/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Self tolerance is dependent on regulatory T cells (Treg) which suppress effector T cells, avoiding autoimmunity. Functional and quantitative deficits of Treg have been reported in autoimmune diseases. A new therapeutic approach consisting in Treg adoptive transfer has proved to be efficient and safe in murine models. Two populations seem to be available for a clinical application: CD4(+)CD25(+)Foxp3(+) natural Treg derived from the thymus and induced regulatory T cells. First clinical trials have been applied to patients with autoimmune diseases. Classical treatments of autoimmune diseases are usually non-curative and require long-term administration. Treg cellular therapy may have a long-term effect and offers an alternative attractive approach.