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A compass that points to lupus: genetic studies on type I interferon pathway

Genes & Immunity volume 8, pages 445–455 (2007)Cite this article

Abstract

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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Acknowledgements

We are greatly indebted to Dr Robert R Graham (Harvard University, Massachusetts Institute of Technology) and Dr Timothy W Behrens (Genentech Inc.) for collaboration, supervision and inspiration. We also thank Dr Emily C Baechler-Gillespie (University of Minnesota), Aya Kawasaki and Koki Hikami (University of Tsukuba) for collaboration and helpful comments.

This work was supported by Grant-in-Aid for Scientific Research on Priority Areas ‘Applied Genomics’ from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Grants from the Ministry of Health, Labour and Welfare of Japan, Japan Society for the Promotion of Science (JSPS), Takeda Science Foundation, and Japan Rheumatism Foundation.

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  1. Department of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA

    C Kyogoku

  2. Division of Molecular Pharmacology and Pharmacogenomics, Kobe University Graduate School of Medicine, Kobe, Japan

    C Kyogoku

  3. Doctoral Program in Social and Environmental Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

    N Tsuchiya

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Kyogoku, C., Tsuchiya, N. A compass that points to lupus: genetic studies on type I interferon pathway. Genes Immun 8, 445–455 (2007). https://doi.org/10.1038/sj.gene.6364409

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