A 9-centimorgan interval of chromosome 10 controls the T cell-dependent psoriasiform skin disease and arthritis in a murine psoriasis model
| Autor: | Rikard Holmdahl, Thorsten Peters, Meinhard Wlaschek, Daniel Kess, Anca Sindrilaru, Robert Blakytny, Anna-Karin B. Lindqvist, Honglin Wang, Karin Scharffetter-Kochanek |
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| Rok vydání: | 2008 |
| Předmět: |
CD4-Positive T-Lymphocytes
T cell Immunology Congenic Arthritis Pathogenesis Centimorgan Mice Mice Congenic Psoriasis medicine Immunology and Allergy Animals Humans Genetic Predisposition to Disease Allele Psoriasiform Dermatitis Alleles integumentary system business.industry Chromosomes Human Pair 10 Tumor Necrosis Factor-alpha medicine.disease Disease Models Animal medicine.anatomical_structure CD18 Antigens business |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 180(8) |
| ISSN: | 0022-1767 |
| Popis: | Psoriasis is a complex genetic disease of unresolved pathogenesis with both heritable and environmental factors contributing to onset and severity. In addition to a disfiguring skin inflammation, approximately 10–40% of psoriasis patients suffer from destructive joint involvement. Previously, we reported that the CD18 hypomorphic PL/J mouse carrying a mutation resulting in reduced expression of the common chain of β2 integrins (CD11/CD18) spontaneously develops a skin disease that closely resembles human psoriasis. In contrast, the same mutation on C57BL/6J background did not demonstrate this phenotype. By a genome-wide linkage analysis, two major loci were identified as contributing to the development of psoriasiform dermatitis under the condition of low CD18 expression. Using a congenic approach, we now demonstrate that the introduction of a 9-centimorgan fragment of chromosome 10 derived from the PL/J strain into the disease-resistant CD18 hypomorphic C57BL/6J was promoting the development of psoriasiform skin disease and notably also arthritis. We therefore designated this locus psoriasiform skin disease-associated locus 1 (PSD1). High numbers of CD4+ T cells and TNF-α producing macrophages were detected both in inflamed skin and joints in these congenic mice, with a complete resolution upon TNF-α inhibitor therapy or depletion of CD4+ T cells. For the first time, we have identified a distinct genetic element that contributes to the T cell-dependent development of both psoriasiform skin disease and associated arthritis. This congenic model will be suitable to further investigations of genetic and molecular pathways that cause psoriasiform dermatitis and arthritis, and it may also be relevant for other autoimmune diseases. |
| Databáze: | OpenAIRE |
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