Journal
GENES AND IMMUNITY
Volume 8, Issue 6, Pages 445-455Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gene.6364409
Keywords
systemic lupus erythematosus; type I interferon; interferon signature; polymorphism; interferon regulatory factor 5; genetics
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It was more than 20 years ago that patients with systemic lupus erythematosus ( SLE) were first reported to display elevated serum levels of type I interferon ( IFN). Since then, extensive studies revealed a crucial role for type I IFN in SLE pathogenesis. The current model proposes that small increase of type I IFN production by plasmacytoid dendritic cells ( pDCs) is sufficient to induce unabated activation of immature peripheral DCs. IFN-matured DCs select and activate autoreactive T cells and B cells, rather than deleting them, resulting in peripheral tolerance breakdown, a characteristic feature of SLE. Furthermore, immune complexes provide an amplification loop to pDCs for further IFN production. In the past 5 years, high-throughput technologies such as expression profiling and single-nucleotide polymorphism ( SNP) typing established the role of altered type I IFN system in SLE, and a detailed picture of its molecular mechanisms is beginning to emerge. In this review, we discuss two major lines of genetics studies on type I IFN pathway related to human SLE: ( 1) expression profiling of IFN-responsive genes and ( 2) disease-associated SNPs of IFN-related genes, especially IRF5 ( IFN-regulatory factor 5). Lastly, we discuss how such genetic alterations in type I IFN pathway fit in the current model of SLE pathogenesis.
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