genetic susceptibility to PsO and PsA, the pathogenic role that these genes play in the development of PsA remains unclear. The canonical function of the class I HLA molecule is to present antigen to CD8+ T cells, but these cells are dispensable in the human HLA-B27-transgenic rat model of spondyloarthritis. The hypothesis of the unfolded protein response, which induces production of IL-23 in the endoplasmic reticulum, has been proposed to explain the indirect role of HLA-B27 in the pathogenesis of spondyloarthritis. As trauma and overload in enthesis have been associated with PsA onset, probably through stimulation of TLR and activation of the innate immune response, the case for an auto-inflammatory component of PsA has emerged.24
studies have demonstrated that synovial innate immune cells (CD163+ macrophages, neutrophils and mast cells) are relevant in PsA pathogenesis, as they were sensitive to change after effective therapy. Although human studies and clinical trials support the relevance of TNF-alpha and the IL-17/IL-23 axis in the pathophysiology of PsA, it remains unclear which cells are the source of IL-17 (isoforms A and F) and what is the relationship between TNF and IL-17/ IL-23 cytokines; these pathways are probably partially complementary, as suggested by the worse response of TNF-insufficient responders to ustekinumab.25
In contrast to the findings
of increased CD4+IL-17+ or CD8+ IL-17+ T cells in peripheral blood or synovial fluid in PsA, few CD3+IL-17+ T cells are detected in synovium, whereas the cells with the highest content of IL-17 belong to the innate immune system. The pathophysiological relationship between joint and skin manifestations in PsA is a relatively unexplored area of research. There is no convincing hypothesis that explains why only approximately 20–30% of PsO patients develop PsA. The pathophysiology of PsO is better-defined than that of PsA and the autoimmune component is clear, with an important role of presentation of known antigens to T cells by dendritic cells. Better responses in PsO than in PsA with IL-17 and IL-12/IL-23 inhibitors clearly support a greater role of these molecules in the pathophysiology of PsO than in PsA.26
Although, as expected, there is a clear overlap in the genetic susceptibility to PsO and PsA, an important missing genetic component remains to be identified and this, together with insights
on the role of the microbioma in the pathogenesis of PsO and PsA, may clarify the relationship between the different manifestations of psoriatic disease in the near future.27 l
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