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| Status |
Public on Mar 01, 2017 |
| Title |
Immunostimulatory endogenous nucleic acids drive the lesional inflammation in cutaneous lupus erythematosus |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Cutaneous lupus erythematosus (CLE) is a photosensitive autoimmune disease characterized by a strong type-I-interferon (IFN) associated inflammation. Keratinocytes are known to determine the interface-dermatitis-pattern in CLE by production of proinflammatory cytokines in the lower epidermis. These cytokines drive a cytotoxic anti-epithelial immune response resulting in keratinocytic cell death and release of endogenous nucleic acids (eNA). We hypothesized that these eNA (RNA- and DNA-motifs) have the capacity to activate innate immune pathways in keratinocytes via pathogen-recognition-receptors (PRR).
Gene expression analyses revealed an excessive activation of innate immune response pathways with strong expression of IFN-regulated cytokines in CLE skin lesions. Cultured keratinocytes produce large amounts of these cytokines in response to stimulation of PRR with eNA. UV-stimulation enhances the immunogenicity of eNA and induces CLE-like skin lesions in knockout mice lacking the cytosolic DNase TREX1.
Our results provide evidence for a pathogenetic role of endogenous nucleic acids in CLE. They are released within the cytotoxic inflammation along the dermo-epidermal junction and have the capacity to drive the LE-typical inflammation. UV-irradiation supports this inflammation by generation of highly immunostimulatory DNA motifs (8-OHG).
These findings explain the photosensitivity of lupus patients and identify pathways of the innate immune system as targets for future therapies.
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| Overall design |
Lesional skin biopsies were taken from patients with active, untreated lupus skin disease (Chronic discoid lupus erythematosus = CDLE, n=6; subacute cutaneous lupus erythematosus = SCLE, n=5). Healthy control (HC) specimens were obtained from healthy skin of 5 patients undergoing plastic surgery. In every case, two 4mm punch biopsies were taken. One was flash-frozen in liquid nitrogen and afterwards processed for mRNA isolation and gene expression analyses. The second biopsy was fixed in 5% formalin solution overnight, and was proceeded for histological investigation.
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| Contributor(s) |
Scholitissek B, Wenzel J |
| Citation(s) |
28351661 |
| Submission date |
Feb 28, 2017 |
| Last update date |
Mar 27, 2018 |
| Contact name |
Joerg Wenzel |
| E-mail(s) |
joerg.wenzel@ukb.uni-bonn.de
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| Organization name |
University of Bonn
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| Department |
Dermatology
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| Street address |
Sigmund Freud Str 25
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| City |
Bonn |
| ZIP/Postal code |
53121 |
| Country |
Germany |
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| Platforms (1) |
| GPL16699 |
Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Feature Number version) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA377232 |
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