RESUMO
Promiscuous expression of tissue-specific self-antigens in the thymus imposes T cell tolerance and protects from autoimmune diseases, as shown in animal studies. Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon. Medullary thymic epithelial cells overexpress a highly diverse set of genes (>400) including many tissue-specific antigens, disease-associated autoantigens, and cancer-germline genes. Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes. These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.
Assuntos
Expressão Gênica , Timo/imunologia , Animais , Autoantígenos/genética , Autoimunidade/genética , Sequência de Bases , Cromossomos Humanos/genética , Sequência Conservada , Primers do DNA/genética , Células Epiteliais/imunologia , Feminino , Humanos , Lactente , Masculino , Camundongos , Família Multigênica , RNA/genética , Tolerância a Antígenos Próprios/genética , Especificidade da Espécie , Linfócitos T/imunologia , Timo/citologiaRESUMO
Intrathymic expression of peripheral auto-antigens, termed promiscuous gene expression, extends the scope of central T-cell tolerance to peripheral organs and proves essential for the induction and maintenance of self-tolerance. The purification of antigen-presenting cells has been instrumental in identifying promiscuous gene expression as an inherent property of medullary epithelial cells. The pool of promiscuously expressed genes might encompass up to 10% of the whole genome. The remarkable diversity of this gene pool implies a complex mode of regulation, which cannot be solely explained by the action of a single factor, such as the transcriptional autoimmune regulator AIRE. Co-localization of promiscuously expressed genes in clusters also suggests epigenetic mechanisms (e.g. DNA methylation) to account for this unorthodox gene expression pattern. The identification of the molecular components controlling the expression of tissue-restricted genes in the thymus promises to add valuable new insights into the complex genetic regulation underlying most autoimmune diseases.