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A 9-Centimorgan Interval of Chromosome 10 Controls the T Cell-Dependent Psoriasiform Skin Disease and Arthritis in a Murine Psoriasis Model¹

Honglin Wang^*, Daniel Kess^*, Anna-Karin B. Lindqvist, Thorsten Peters^*, Anca Sindrilaru^*, Meinhard Wlaschek^*, Robert Blakytny, Rikard Holmdahl and Karin Scharffetter-Kochanek^2,*

^* Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany; Medical Inflammation Research, University of Lund, Lund, Sweden; and Institute of Orthopaedic Research and Biomechanics, University of Ulm, Germany

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- producing macrophages were detected both in inflamed skin and joints in these congenic mice, with a complete resolution upon TNF- 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.

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¹ This work was supported by the German Research Foundation (DFG) within the SFB 497 "Signals and Signal Processing during Cellular Differentiation", and individual research grants from the German Research Foundation (DFG) (SCHA 411/12-1, -2), the Strategic Research Foundation, and the EU project LSHB CT-2006-018661 (AutoCure).

² Address correspondence and reprint requests to Dr. Karin Scharffetter-Kochanek, Department of Dermatology and Allergic Diseases, University of Ulm, Maienweg 12, D-89081 Ulm, Germany. E-mail: karin.scharffetter-kochanek{at}uniklinik-ulm.de

³ Abbreviations used in this paper: PsA, psoriatic arthritis; CD18^hypo, CD18 hypomorphic; cM, centimorgan; Mbp, megabase-pair; PASI, psoriasis area and severity index; PSD1, psoriasiform skin disease-associated locus 1; PSORS, psoriasis susceptibility; QTL, quantitative trait locus.