RESUMO
The autoimmune nature of the diabetogenic process and the major contribution of T lymphocytes stand now beyond any doubt. However, despite the identification of the three major type 1-diabetes-related autoantigens (insulin, GAD65 and phosphatase IA-2), the origin of this immune dysregulation still remains unknown. More and more evidence supports a thymic dysfunction in the establishment of central self-tolerance to the insulin family as a crucial factor in the development of the autoimmune response selective of pancreatic insulin-secreting islet beta cells. All the genes of the insulin family (INS, IGF1 and IGF2) are expressed in the thymus network. However, IGF-2 is the dominant member of this family first encountered by T cells in the thymus, and only IGFs control early T-cell differentiation. IGF2 transcription is defective in the thymus in one animal model of type 1 diabetes, the Bio-Breeding (BB) rat. The sequence B9-23, one dominant autoantigen of insulin, and the homologous sequence B11-25 derived from IGF-2 exibit the same affinity and fully compete for binding to DQ8, one class-II major histocompatibility complex (MHC-II) conferring major genetic susceptibility to type 1 diabetes. Compared to insulin B9-23, the presentation of IGF-2 B11-25 to peripheral mononuclear cells (PBMCs) isolated from type 1 diabetic DQ8+ adolescents elicits a regulatory/tolerogenic cytokine profile (*IL-10, *IL-10/IFN-g, *IL-4). Thus, administration of IGF-2 derived self-antigen(s) might constitute a novel form of vaccine/immunotherapy combining both an antagonism for the site of presentation of a susceptible MHC allele, as well as a downstream tolerogenic/regulatory immune response.
Assuntos
Doenças Autoimunes/fisiopatologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Timo/imunologia , Timo/patologia , Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Humanos , Tolerância ImunológicaRESUMO
Ontogenesis of oxytocin (OT) and vasopressin (VP) gene expression and function were investigated in murine thymus. OT and VP transcripts were detected in the thymus on embryonic days 13 and 15, respectively. Corresponding messenger RNAs were evidenced in thymic epithelial cells by in situ hybridization with a neurophysin probe. From all OT and VP receptors, only OTR was expressed by all T-cell subsets, while V1bR was found in double positive and single positive CD8 cells. In fetal thymic organ cultures, OTR antagonist d[D-Tyr(Et)2, Thr4]OVT increased early apoptosis of CD8 cells, while V1bR antagonist (Sanofi SSR149415) inhibited T-cell differentiation, and favored CD8 T-cell commitment.
Assuntos
Expressão Gênica , Ocitocina/metabolismo , Transdução de Sinais/fisiologia , Timo/metabolismo , Vasopressinas/metabolismo , Vasotocina/análogos & derivados , Análise de Variância , Animais , Animais Recém-Nascidos , Antagonistas dos Receptores de Hormônios Antidiuréticos , Southern Blotting/métodos , Encéfalo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Embrião de Mamíferos , Citometria de Fluxo/métodos , Hibridização In Situ/métodos , Indóis/farmacologia , Camundongos , Neurofisinas/genética , Técnicas de Cultura de Órgãos , Ocitocina/genética , Pirrolidinas/farmacologia , RNA Mensageiro/biossíntese , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/genética , Receptores de Vasopressinas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/metabolismo , Timo/citologia , Vasopressinas/genética , Vasotocina/farmacologiaRESUMO
Neurohypophysial oxytocin (OT) and vasopressin (VP) genes are transcribed in thymic epithelium, while immature T lymphocytes express functional neurohypophysial receptors. Neurohypophysial receptors belong to the G protein-linked seven-transmembrane receptor superfamily and are encoded by four distinct genes, OTR, V1R, V2R and V3R. The objective of this study was to identify the nature of neurohypophysial receptor in thymic T cell subsets purified by immunomagnetic selection, as well as in murine thymic lymphoma cell lines RL12-NP and BW5147. OTR is transcribed in all thymic T cell subsets and T cell lines, while V3R transcription is restricted to CD4+CD8+ and CD8+ thymic cells. Neither V1R nor V2R transcripts are detected in any kind of T cells. The OTR protein was identified by immunocytochemistry on thymocytes freshly isolated from C57BL/6 mice. In murine fetal thymic organ cultures, a specific OTR antagonist does not modify the percentage of T cell subsets, but increases late T cell apoptosis further evidencing the involvement of OT/OTR signaling in the control of T cell proliferation and survival. According to these data, OTR and V3R are differentially expressed during T cell ontogeny. Moreover, the restriction of OTR transcription to T cell lines derived from thymic lymphomas may be important in the context of T cell leukemia pathogenesis and treatment.
