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

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 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.

Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis

“…Several investigations in experimental animal models already indicate a central role of CD18 integrins in SpA-like disease [14-16,37]. We previously demonstrated alterations in the sCD18 complexes in the blood and synovial fluid of patients with arthritis and the ability of sCD18 to inhibit leukocyte binding to ICAM-1.…”

“…The mouse PL/J strain carries the CD18 hypomorphic mutation, which reduces the expression of CD18 to 2% to 16% of wild-type levels [13]. These mice develop a skin disease that closely resembles human psoriasis together with a condition very similar to psoriatic arthritis dominated by enthesitis [14], and the inflammatory response critically involves macrophages and T helper 17 (Th17) cells [15,16]. Tumor necrosis factor-alpha (TNFα) induces endothelial expression of ICAM-1 as well as activation of integrins for ligand binding [17].…”

The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology

“…Next to SNPs for genes involved in IL-23 signaling, loci including A20 and ABIN-1 (also known as TNFAIP3-interacting protein 1 or TNIP1) showed strong association with psoriasis [55]. Interestingly, in the mouse PL/J strain, carrying a CD18 hypomorphic mutation which gives rise to a skin disease resembling human psoriasis, a region of mouse chromosome 10 encompassing A20 was identified as contributing to the psoriasiform skin disease [56]. Notably, the same region of the mouse genome has been associated with atherosclerosis [57], a most prevalent co-morbidity of psoriasis [58].…”

Reduced CD18 Levels Drive Regulatory T Cell Conversion into Th17 Cells in the CD18hypo PL/J Mouse Model of Psoriasis

“…CD18 represents the common b-chain of four different heterodimeric integrins expressed on distinct hematopoietic cell subsets, namely CD18/ CD11a, CD18/CD11b, CD18/CD11c, and CD18/CD11d, that as leukocyte adhesion molecules regulate cell-cell contacts through interaction with .20 known ligands, such as ligands of the ICAM family (19,20). Homozygous CD18 hypo PL/J mice spontaneously develop a T cell-mediated psoriasiform skin disease at 12-14 wk of age that closely resembles human psoriasis histologically, clinically, and in its polygenic base (16,21). Evidence indicating that reduced CD18 expression may also causally be involved in the development of psoriasis in humans comes from the clinical observation that some patients suffering from leukocyte adhesion deficiency syndrome 1, even with moderately reduced CD18 expression levels, develop a psoriasiform skin disease (22).…”