*4.2.3 Production of reactive oxygen species by neutrophils*

Recent evidence from animal models of RA emphasized the importance of neutrophils in the initiation and progression of AIA [70]. Progressive erosion of articular cartilage is a prominent feature of this disease. Not surprisingly, immunosuppressive approaches such as blockade of CD4+ lymphocytes effectively reduce the intensity of damage and the progression of AIA. The report of Santos et al. [71] convincingly demonstrates a requirement not only for CD4+ lymphocytes but also for neutrophils, the latter determined by the protective effects of neutrophil depletion. The sequence of events showed that CD4+ cells are necessary for the establishment of the immune response, which leads to the recruitment of neutrophils, with the involvement of cytokines (TNF-α, IL-1) and the IL-8 family of chemokines. The combination of products (oxidants, proteinases, and cytokines) from stimulated neutrophils, synovial macrophages, and lymphocytes is important to set the stage for acute and progressive polyarthritis [72]. We assessed ROS production in stimulated neutrophils of arthritic rats, and it was found to be increased, with a maximum on day 14 and 21 of AIA. Neutrophils in the whole blood of AIA animals reacted excessively to stimulation and produced 6–9 times more ROS [73]. We also demonstrated oxidative damage of tissues in AIA: ROS levels in the joint and the spleen were significantly elevated [74] (**Table 3**).
