Pathomechanisms underlying the psoriasiform skin disease in CD18 hypomorphic PL/J mice
LizenzStandard (Fassung vom 03.05.2003)
Macrophage infiltration is a hallmark of psoriasis. In the psoriasiform skin disease, activated macrophages were significantly increased in lesional skin as well as in inflamed skin draining lymph nodes (DLNs) of affected CD18hypo mice and were identified to be an important source of TNF-alpha. In vivo both depletion of macrophages and neutralization of TNF-alpha resulted in a significant reduction of the psoriasiform dermatitis. The injection of combination of recombinant JE/MCP-1 and recombinant TNF-alpha elicited skin lesion in healthy PL/J CD18hypo mice. To shed light on the mechanisms that mediate Treg cells suppression of autoimmunity, the functions of Treg and Tresp cells were examined in CD18hypo mice. Low expression of CD18 is responsible for the disruption of cell-cell contacts between dendritic cells and CD4+CD25+ Treg cells. This disruption of cell-cell contacts results in an impaired suppressor function of CD4+CD25+ Treg cells on pathogenic responder T cells. Reduced expression of TGF-beta1 on CD4+CD25+ Treg cells of CD18 hypomorphic mice was found to be causal for their impaired suppressor function. Psoriasis appears to result from a combination of genetic and environmental factors. In this thesis, modifier genes which contribute to the development of psoriasiform skin disease were isolated from the susceptible PL/J CD18hypo mice, and were transferred into the resistant C57BL/6J CD18hypo mice using a speed congenic approach. Five congenic strains for PL/J alleles were constructed, two congenic stains carrying the PL/J CD18hypo fragment from D10Mit126 to D10Mit194 on chromosome 10 developed the psoriasiform skin disease with identical characterizations of psoriasiform skin disease in PL/J background. In contrast, the other congenic strains with the absence of this fragment were collectively referred to as controls and did not develop any cutaneous phenotype.
Erstellung / Fertigstellung
Normierte SchlagwörterAutoimmunity [MeSH]