title: CD4+ T cell-associated pathophysiology critically depends on CD18 gene dose effects in a murine model of psoriasis.
abstract: In a CD18 hypomorphic polygenic PL/J mouse model, the severe reduction of CD18 (beta(2) integrin) to 2-16% of wild-type levels leads to the development of a psoriasiform skin disease. In this study, we analyzed the influence of reduced CD18 gene expression on T cell function, and its contribution to the pathogenesis of this disease. Both CD4(+) and CD8(+) T cells were significantly increased in the skin of affected CD18 hypomorphic mice. But only depletion of CD4(+) T cells, and not the removal of CD8(+) T cells, resulted in a complete clearance of the psoriasiform dermatitis. This indicates a central role of CD4(+) T cells in the pathogenesis of this disorder, further supported by the detection of several Th1-like cytokines released predominantly by CD4(+) T cells. In contrast to the CD18 hypomorphic mice, CD18 null mutants of the same strain did not develop the psoriasiform dermatitis. This is in part due to a lack of T cell emigration from dermal blood vessels, as experimental allergic contact dermatitis could be induced in CD18 hypomorphic and wild-type mice, but not in CD18 null mutants. Hence, 2-16% of CD18 gene expression is obviously sufficient for T cell emigration driving the inflammatory phenotype in CD18 hypomorphic mice. Our data suggest that the pathogenic involvement of CD4(+) T cells depends on a gene dose effect with a reduced expression of the CD18 protein in PL/J mice. This murine inflammatory skin model may also have relevance for human polygenic inflammatory diseases.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kess
authors.forename: Thorsten
authors.initials: T
authors.lastname: Peters
authors.forename: Jan
authors.initials: J
authors.lastname: Zamek
authors.forename: Claudia
authors.initials: C
authors.lastname: Wickenhauser
authors.forename: Samir
authors.initials: S
authors.lastname: Tawadros
authors.forename: Karin
authors.initials: K
authors.lastname: Loser
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
authors.forename: Roswitha
authors.initials: R
authors.lastname: Nischt
authors.forename: Cord
authors.initials: C
authors.lastname: Sunderkötter
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D018821:CD18 Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D017449:Dermatitis, Allergic Contact / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D018628:Gene Dosage; D007274:Injections, Intraperitoneal; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D016207:Cytokines; D021122:Protein Subunits