Evaluation of the influence of the innate and adaptive immune response in the pathogenesis of post-traumatic osteoarthritis based on an in-depth analysis of the cellular inflammation pattern and its molecular driving factors

Abstract

Post-traumatic osteoarthritis (ptOA) remains a common and debilitating musculoskeletal disease affecting a large population of patients. While initially it was believed that ptOA was purely caused by wear and tear of the cartilage recently the role of an aberrant immune response was postulated as a contributing factor and furthermore pro-inflammatory immune cells subsets of the innate and adaptive immune system implicated as key players in the aetiology of ptOA. Therefore, this thesis investigates the role of the immune system during onset and development of ptOA, and finally test if immunomodulation could be used to prevent ptOA from developing after joint injury. New laboratory techniques were developed specifically for these studies and validated prior to their implementation. Hereafter, a set of subsequent studies was conducted that characterized the immune response immediately after joint injury, during progression of ptOA and finally at the stage of established ptOA. In addition, immunomodulation of the IL12/23 pathway, immunomodulation of the CD40 axis, as well as depletion of the pro-inflammatory subsets of monocytes (Ly6Chigh monocytes) and its effect on ptOA development was investigated. The key findings of this thesis are: What you injure (ACL vs meniscus) rather than how you injure it (surgery vs non-surgical) determines the temporal pattern and systemic involvement of the immune response and the structural ptOA progression and severity. The IL12/23 pathway plays an important role in orchestrating the immune response following joint injury and during development of ptOA while promoting a production of IL17 producing Th17. Depletion of Ly6Chigh monocytes leads to a persistent anti-inflammatory response both in blood originated macrophages as well as STRM. Finally, anti-CD40L treatment results in an anti-inflammatory polarization of not only migrating macrophages but also STRM while histologically a reduction of joint pathology was achieved.