A compass that points to lupus: genetic studies on type I interferon pathway.
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.
Kyogoku
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C
Department of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA.
Tsuchiya
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N
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D020641:Polymorphism, Single Nucleotide; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D051193:Toll-Like Receptors