1. Department of Immunology, and,
2. Department of Melanoma Medical Oncology, M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA
3. Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8002, USA
4. Genentech., 1 DNA Way, South San Francisco, California 94080, USA
5. Department of Dermatology, Heinrich-Heine-University, Düsseldorf 40225, Germany
6. St John's Institute of Dermatology, King's College London School of Medicine, London SE1 9RT, UK
7. Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, University of Kiel, Kiel 24105, Germany

Correspondence to: Michel Gilliet^1,2 Correspondence and requests for materials should be addressed to M.G. (Email: mgilliet@mdanderson.org).

Abstract

Plasmacytoid dendritic cells (pDCs) sense viral and microbial DNA through endosomal Toll-like receptors to produce type 1 interferons. pDCs do not normally respond to self-DNA, but this restriction seems to break down in human autoimmune disease by an as yet poorly understood mechanism. Here we identify the antimicrobial peptide LL37 (also known as CAMP) as the key factor that mediates pDC activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger Toll-like receptor 9. Thus, our data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.

1. Department of Immunology, and,
2. Department of Melanoma Medical Oncology, M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA
3. Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8002, USA
4. Genentech., 1 DNA Way, South San Francisco, California 94080, USA
5. Department of Dermatology, Heinrich-Heine-University, Düsseldorf 40225, Germany
6. St John's Institute of Dermatology, King's College London School of Medicine, London SE1 9RT, UK
7. Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, University of Kiel, Kiel 24105, Germany

Correspondence to: Michel Gilliet^1,2 Correspondence and requests for materials should be addressed to M.G. (Email: mgilliet@mdanderson.org).

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