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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 model

Wang, Honglin; Kess, Daniel; Lindqvist, Anna-Karin LU ; Peters, Thorsten; Sindrilaru, Anca; Wlaschek, Meinhard; Blakytny, Robert; Holmdahl, Rikard LU and Scharffetter-Kochanek, Karin (2008) In Journal of Immunology 180(8). p.5520-5529
Abstract
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 beta(2) 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... (More)
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 beta(2) 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-alpha producing macrophages were detected both in inflamed skin and joints in these congenic mice, with a complete resolution upon TNF-alpha 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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
180
issue
8
pages
5520 - 5529
publisher
American Association of Immunologists
external identifiers
  • wos:000257506900042
  • scopus:45949098797
ISSN
1550-6606
language
English
LU publication?
yes
id
430190f2-2588-451a-977b-88fe3c43a598 (old id 1254673)
alternative location
http://www.jimmunol.org/cgi/content/abstract/180/8/5520
date added to LUP
2008-10-29 15:47:12
date last changed
2017-01-01 06:16:54
@article{430190f2-2588-451a-977b-88fe3c43a598,
  abstract     = {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 beta(2) 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-alpha producing macrophages were detected both in inflamed skin and joints in these congenic mice, with a complete resolution upon TNF-alpha 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.},
  author       = {Wang, Honglin and Kess, Daniel and Lindqvist, Anna-Karin and Peters, Thorsten and Sindrilaru, Anca and Wlaschek, Meinhard and Blakytny, Robert and Holmdahl, Rikard and Scharffetter-Kochanek, Karin},
  issn         = {1550-6606},
  language     = {eng},
  number       = {8},
  pages        = {5520--5529},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {A 9-centimorgan interval of chromosome 10 controls the T cell-dependent psoriasiform skin disease and arthritis in a murine psoriasis model},
  volume       = {180},
  year         = {2008},
}