Metabolischer Einfluss eines mitochondrialen Genpolymorphismus im mt-Cytb Gen auf die Pathogenese der Psoriasis
Immunologie
Zusammenfassung der Projektergebnisse
Psoriasis, a prototype of inflammatory skin diseases, has a high prevalence worldwide, has a severe impact on quality of life, and overall results in an increased risk of mortality. Yet, the effectiveness and safety of currently available therapies for psoriasis would benefit from further improvement. Efforts to identify novel pathways in psoriasis pathogenesis will further improve the understanding of the disease etiology and form the basis for innovative treatments that could modulate psoriasis therapy outcomes. Psoriasis is thought to be caused by both genetics and environmental factors. Many genetic studies have been conducted, and several candidate genes have been proposed: e.g., HLA locus and various immune system-related genes. In contrast, very few studies focusing on the risk association of mitochondrial DNA (mtDNA) variants have been performed in psoriasis. One association study in the UK suggests a potential link between mtDNA variants in the mitochondrial complex III gene (Cytochrome b gene) and the pathogenesis of psoriasis. Therefore, we hypothesized that the variants in the mitochondrial genome in the mitochondrial complex III contribute to the pathogenesis of psoriasis. Our data showed a very mild impact of the mtDNA-encoded complex III gene variant on psoriasis and immune cell phenotypes (cellular function and mitochondrial functions). The initial investigations in this project did not yield sufficiently strong phenotypical effects. However, we expanded our investigation and explored the effects of respiratory chain deficiency in keratinocytes. When a nuclear genome encoded complex III gene was deleted in basal keratinocytes of adult mice, mice exhibited spontaneous, severe skin lesions, which mimic the clinical presentation of psoriasis. The current findings build on the proposed mechanisms of this project and suggest that a genetic deficiency in complex III of the respiratory chain results in spontaneous, psoriasis-like skin inflammation and would constitute a novel model to study the disease in mice. We plan to continue the characterization of these spontaneously developing skin lesions.
