Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing beta-cells of the islets of Langerhans. One still open question is where naive islet-reactive T cells encounter antigens and become stimulated. In this report we have re-examined the expression of MHC class II (MHCII) genes in human islets to further explore the possibility that non-professional antigen presenting cells (APCs) within islets contribute to autoimmunity. Since development of T1D has been linked to viral infections, we also studied ex-vivo MHCII expression in response to interferon-alpha (IFN alpha) in islet tissue and in different APCs. The findings are: first, MHCII genes expression in human islets is linked with the expression of the class II transactivator isoform transcribed from the promoter IV, similar to that described in non-professional APCs. Second, there is IFN alpha-mediated lineage-specific regulation of MHCII genes expression, seen as a decrease in the accumulation of MHCII transcripts in pancreatic islets opposite to an increase in dendritic cells and beta-lymphoblastoid cell lines. Third, there is allele-specific regulation of the HLA-DQA1 gene by IFN alpha in islet tissue. These findings may begin to explain the molecular events that create favorable conditions for organ-specific autoimmunity and explain the incomplete penetrance of T1D susceptibility alleles. (c) 2006 Elsevier B.V. All rights reserved.
Effect of interferon alpha on MHC class II gene expression in ex vivo human islet tissue
Del Pozzo Giovanna;Maffei Antonella
2006
Abstract
Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing beta-cells of the islets of Langerhans. One still open question is where naive islet-reactive T cells encounter antigens and become stimulated. In this report we have re-examined the expression of MHC class II (MHCII) genes in human islets to further explore the possibility that non-professional antigen presenting cells (APCs) within islets contribute to autoimmunity. Since development of T1D has been linked to viral infections, we also studied ex-vivo MHCII expression in response to interferon-alpha (IFN alpha) in islet tissue and in different APCs. The findings are: first, MHCII genes expression in human islets is linked with the expression of the class II transactivator isoform transcribed from the promoter IV, similar to that described in non-professional APCs. Second, there is IFN alpha-mediated lineage-specific regulation of MHCII genes expression, seen as a decrease in the accumulation of MHCII transcripts in pancreatic islets opposite to an increase in dendritic cells and beta-lymphoblastoid cell lines. Third, there is allele-specific regulation of the HLA-DQA1 gene by IFN alpha in islet tissue. These findings may begin to explain the molecular events that create favorable conditions for organ-specific autoimmunity and explain the incomplete penetrance of T1D susceptibility alleles. (c) 2006 Elsevier B.V. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
