Identification of Susceptibility Loci for Skin Disease in a Murine Psoriasis Model

Abstract

Psoriasis is a frequently occurring inflammatory skin disease characterized by thickened erythematous skin that is covered with silvery scales. It is a complex genetic disease with both heritable and environmental factors contributing to onset and severity. The CD18 hypomorphic PL/J mouse reveals reduced expression of the common chain of β2 integrins (CD11/CD18) and spontaneously develops a skin disease that closely resembles human psoriasis. In contrast, CD18 hypomorphic C57BL/6J mice do not demonstrate this phenotype. In this study, we have performed a genome-wide scan to identify loci involved in psoriasiform dermatitis under the condition of low CD18 expression. Backcross analysis of a segregating cross between susceptible CD18 hypomorphic PL/J mice and the resistant CD18 hypomorphic C57BL/6J strain was performed. A genome-wide linkage analysis of 94 phenotypically extreme mice of the backcross was undertaken. Thereafter, a complementary analysis of the regions of interest from the genome-wide screen was done using higher marker density and further mice. We found two loci on chromosome 10 that were significantly linked to the disease and interacted in an additive fashion in its development. In addition, a locus on chromosome 6 that promoted earlier onset of the disease was identified in the most severely affected mice. For the first time, we have identified genetic regions associated with psoriasis in a mouse model resembling human psoriasis. The identification of gene regions associated with psoriasis in this mouse model might contribute to the understanding of genetic causes of psoriasis in patients and pathological mechanisms involved in development of disease.

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

“…On day 7 after transfer or as indicated, recipient mice were analyzed for IL-17 production in CFSE labeled Tregs (n $ 3 per mouse line and per time point expression levels and the enhanced conversion of Tregs into Th17 cells enhancing the psoriasiform phenotype in CD18 hypo PL/J mice. Although a complete block of CD11a/CD18 (LFA-1), previously also used therapeutically by anti-psoriatic drugs such as the Ab efalizumab (34), primarily affects migration of autoreactive lymphocytes into the skin and may lead to symptoms of immunodeficiency comparable to human leukocyte adhesion deficiency as a consequence of decreased T cell activation, suboptimal CD18 function, and impaired interaction with its ICAM ligands on DCs-that is, mimicked in the CD18 hypo PL/J mouse model and potentially also occurs in psoriasis patients as a consequence of altered ICAM and or CD18 expression (17,35)results in the Treg dysfunction described in this study and in autoimmunity such as psoriasiform skin disease in mice. Notably, apart from sporadic cases of progressive multifocal leukoencephalopathy, severe relapses of pustular psoriasis were reported in patients treated with efazilumab (34), possibly indicating that under nonsaturating efazilumab conditions, activated Teffs rush into the skin, whereas Tregs may be still suppressed or may not have functionally recovered from efazilumab treatment yet.…”

Reduction of CD18 Promotes Expansion of Inflammatory γδ T Cells Collaborating with CD4+ T Cells in Chronic Murine Psoriasiform Dermatitis

“…Notably, reduced or altered expression of CD18 itself or of the b 2 integrin ligands ICAM-1 and -2, located in proximity to PSORS6 on 19p13 and PSORS2 on 17q25, respectively, may also affect susceptibility to psoriasis in humans, underlining the clinical relevance of the CD18 hypo PL/J psoriasis model (33)(34)(35)(36)(37)(38)(39). A critical role of CD4 + T cells in psoriasiform dermatitis of CD18 hypo PL/J mice was previously confirmed by resolution of skin disease after treatment anti-CD4 Abs (31).…”

“…hypo PL/J model has proved to be particularly useful because its skin pathology closely resembles human psoriasis histologically, clinically, and in its polygenic base as previously described (30)(31)(32)(33). Notably, reduced or altered expression of CD18 itself or of the b 2 integrin ligands ICAM-1 and -2, located in proximity to PSORS6 on 19p13 and PSORS2 on 17q25, respectively, may also affect susceptibility to psoriasis in humans, underlining the clinical relevance of the CD18 hypo PL/J psoriasis model (33)(34)(35)(36)(37)(38)(39).…”

“…To further evaluate the function of gd T cells in psoriasiform skin disease, in this investigation we used the CD18 hypomorphic PL/J mouse model (26)(27)(28)(29)(30)(31)(32)(33), an established model of psoriasis on the PL/J background with reduction of CD18/b 2 integrin (Itgb2) levels to 2-16% of wild-type levels due to a hypomorphic CD18 allele (CD18 hypo PL/J mouse), which offers the possibility to analyze T cell subsets in lesional skin and lymph nodes at different disease stages. Compared to IL-23-or IMQ-induced transient skin inflammation mediated selectively via the IL-23-or type I IFN-arm of the inflammatory cascade, leading to a transient psoriasiform disease, the CD18 hypo PL/J psoriasis model is likely more physiological to study non-drug-induced psoriasis for a number of reasons: CD18 hypo PL/J mice commonly develop a spontaneous, chronic, T cell-mediated psoriasiform skin disease around weeks 12-14 after birth due to reduced CD18 expression on a number of immune cell types relevant to human psoriasis (26,27).…”

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

“…Performing a genome-wide linkage analysis, we identified two quantitative trait loci (QTL) on chromosome 10 with significant linkage to the development of psoriasiform skin disease and one QTL on chromosome 6 with linkage to its early onset (34). To further investigate whether loci on chromosome 10 (PSD1, or psoriasiform skin disease-associated locus 1) and/or chromosome 6 are causal for the development of psoriasiform skin disease, we have developed speed congenic strains by means of microsatelliteassisted selection (35).…”