[18, 19] The joints of patients with RA are characterized by an infiltration of immune cells into the synovium, leading to chronic inflammation, pannus formation and subsequent irreversible joint and cartilage damage.[20] The RA synovium

comprises largely of macrophages (30–40%), T cells (30%) and synovial fibroblasts and also of B cells, dendritic cells, other immune cells and synovial cells, such as endothelium.[20, 21] Recognition of Th17 cells led to breaking the dichotomy of the Th1/Th2 axis in the immunopathogenesis of RA. Th17 cells produce cytokines, including IL-17, IL-6, IL-21, IL-22 and TNF-α, with pro-inflammatory effects, which appear to have a role in immunopathogenesis of RA. Regarding the wide range of production of cytokines and chemokines by Th17 cells, it is expected that Th17 cells could be a potent pathogenic factor CX-4945 chemical structure in disease immunopathophysiology.[22] Regarding the role of autoreactive T cells (Th1 and Th17 cells) in pathophysiology of RA, it might be assumed that the regulatory T cells (Tregs) will be able to control the initiation and

progression of disease. Recently, the frequency, function and properties of various subsets of Tregs, including natural Tregs (nTregs), IL-10 producing type 1 Tregs (Tr1 cells), TGF-β producing Th3 cells, CD8+ Tregs, and also defects in Tregs function or their reduced numbers, have been investigated in several human autoimmune diseases, including RA and juvenile TSA HDAC in vitro idiopathic arthritis.[23, 24] Rheumatoid arthritis is a chronic inflammatory disease, and synovial angiogenesis is considered to be a notable stage in its pathogenesis.[25] However, the molecular mechanisms that promote angiogenesis in RA have not been clearly identified.[26] Angiogenesis has been suggested to be a pivotal mechanism involved PAK5 both in inflammation/immune activation and in joint damage. During RA, angiogenesis contributes to disease progression at multiple

levels, including synovial growth, leukocyte recruitment and tissue remodeling.[27] During RA, the most important role of vascularization is an increased capacity to sustain the metabolic and nutritional requirements for synovium hyperproliferation.[28] However, it has been found that neoangiogenesis by itself is not entirely sufficient to mitigate the intra-articular hypoxia associated with RA.[29] Indeed, the result of synovial hyperplasia and augmented proliferation of the synovial cells is increased distance from the nearest blood vessels and also increase demand for nutrients and oxygen. The effects of hypoxia and hypoperfusion, quickly imposes an additional demand on the vasculature, further promoting hypoxia.