Effect of interferon alpha on MHC class II gene expression in ex vivo human islet tissue.
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 (IFNalpha) 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 IFNalpha-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 B-lymphoblastoid cell lines. Third, there is allele-specific regulation of the HLA-DQA1 gene by IFNalpha 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.
Harris
Paul E
PE
Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, Naples, Italy.
Malanga
Donatella
D
Liu
Zhuoro
Z
Hardy
Mark A
MA
Souza
Fabiola
F
Del Pozzo
Giovanna
G
Winchester
Robert J
RJ
Maffei
Antonella
A
D000483:Alleles; D005786:Gene Expression Regulation / Q000187:drug effects*; D005802:Genes, MHC Class II / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059805:HLA-DR alpha-Chains; D006801:Humans; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics
D006683:HLA-DQ Antigens; C051568:HLA-DQ1 antigen; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D016898:Interferon-alpha; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D015534:Trans-Activators