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Enthesitis and the IL-17 Pathway. Entheses or insertion sites are locations where tendons and ligaments attach to bone. These attachment sites hold the muscles and skeleton together and they are numerous. Enthesitis, which refers to the inflammation of these insertion sites, is thought to be the primary event in psoriatic arthritis. Imaging suggests that enthesitis is an early inflammatory event in psoriatic nail disease, with nail disease often preceding psoriatic arthritis. Dactylitis, another key feature of psoriatic arthritis, is also linked to tendon pulley enthesitis. Looking closely at a healthy enthesis we see that the Achilles tendon insertion is associated with a adjacent fibrocartilage, bursal cavity, associated fat pad and synovium. This collection of tissues is defined as the enthesis organ. A key component of it is the synovio‐entheseal complex: the integration between the insertion sites and the adjacent synovium. The enthesis is a site of repeated biomechanical stress, causing microdamage that needs to be repaired. Because of this, it has resident immune cells that are involved in this process. These include type 3 innate lymphoid cells and gamma-delta T-cells that may respond quickly to stress and tissue damage by producing various inflammatory cytokines. Also, myeloid cell production of the IL‐23 cytokine and other mechanisms drive gamma‐delta T‐cells, the intermediate cells between the innate and adaptive immune response. Collectively these cells are capable of producing proinflammatory or tissue repair cytokines that likely regulate normal enthesis biology. The Role of IL‐17A in Inflammation. IL‐23 activates resident T‐cells within the enthesis to release inflammatory mediators including IL‐17A, IL‐22, GM‐CSF, and TNF‐α further driving the inflammatory response. Subsequent activation of the adaptive immune system including CD8 T cells amplifies the production of these cytokines which promotes chronic enthesitis. IL‐17A in particular has been identified as a key modulator of entheseal inflammation as well as a potent stimulator of osteoclastogenesis, through the induction of RANK ligand, contributing to enthesis, bone erosion and cartilage damage. Overactivity of IL‐17A appears to contribute to the chronic inflammation that occurs in patients with psoriatic arthritis. Levels of IL‐17A also correlate with disease activity and active synovitis. IL‐17A Inhibition. Inhibition of IL‐17A may block the release of proinflammatory cytokines, disrupting the inflammatory cascade and the inflammatory response. Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds with IL‐17A and inhibits its interaction with the IL‐17 receptor. Ixekizumab thus inhibits the release of proinflammatory cytokines and chemokines.

Video Details

Duration: 4 minutes and 26 seconds
Language: English
License: Dotsub - Standard License
Genre: None
Views: 17
Posted by: gabriella61 on Oct 1, 2019


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