**2. Pathogenesis of rheumatoid arthritis**

RA is a chronic, progressive, inflammatory autoimmune disease associated with articular, extra-articular, and systemic effects. It has been reported that RA affects multiple comorbidities [4]. Mortality rates are more than twice as high in patients with RA as in the general population (Wolfe et al. [5]). Although the exact cause of RA remains unknown [5, 6], several findings suggest a genetic basis for disease development. More than 80% of patients carry the epitope of the HLA-DRB1\*04 cluster [7], and patients expressing two HLA-DRB1\*04 alleles are at elevated risk for major organ involvement and surgery related to joint destruction [8]. Environmental factors, such as smoking and infection, may also influence the development, rate of progression, and severity of RA [9, 10]. In addition to joint symptoms, many patients experience extra-articular or systemic manifestations or both. Extraarticular manifestations include rheumatoid nodules, vasculitis, pericarditis, uveitis, and rheumatoid lung [11]. Systemic manifestations include often anemia, cardiovascular disease, osteoporosis, fatigue, and depression [12, 13]. The earliest event in RA pathogenesis is the activation of the innate immune response that includes the activation of dendritic cells by exogenous material and autologous antigens. Antigen-presenting cells, including dendritic cells, macrophages, and activated B cells, present arthritis-associated antigens to T cells. T-cell activation and B-cell activation result in increased production of cytokines and chemokines. In addition to antigen presentation, macrophages are involved in osteoclastogenesis and are a major source of cytokines, including TNF-α, IL-1, and IL-6 [6, 7]. Within the synovial membrane, there is a great increase in activated fibroblast-like synoviocytes, which also produce inflammatory cytokines, prostaglandins, and matrix metalloproteinases (MMPs). Synoviocytes contribute to the destruction of cartilage and bone by secreting MMPs into the synovial fluid (SF) and by direct invasion into these tissues [7]. Pro-inflammatory cytokines are involved in the pathogenesis of RA [2, 14]. TNF-α and IL-6 play dominant roles in the pathobiology of RA; however, IL-1, vascular endothelial growth factor (VEGF), and IL-17 have also a significant impact on the disease process. These cytokines activate genes associated with inflammatory responses, including additional cytokines and MMPs involved in tissue degradation [6]. Th-17 lymphocytes have a critical role in synovitis in RA patients [15]. TNF-α, IL-6, and IL-1 are key mediators of cell migration and inflammation in RA [7]. IL-6 acts directly on neutrophils through membrane IL-6 receptors that contribute to inflammation and joint destruction by secreting proteolytic enzymes and reactive oxygen intermediates [12]. Furthermore, an in vitro study with fibroblasts from patients with RA demonstrated the role of IL-6 in promoting neutrophil recruitment by activated fibroblasts [16]. The principal

*Impact of Oxidative Stress on Inflammation in Rheumatoid and Adjuvant Arthritis: Damage… DOI: http://dx.doi.org/10.5772/intechopen.89480*

cause of bone erosion is the pannus that is found at the interface with the cartilage and bone. Angiogenesis is a key process in the formation and maintenance of pannus because invasion of cartilage and bone requires increased blood supply. In patients with RA, many pro-angiogenic factors are expressed in synovium, among them, VEGF plays the central role in new blood vessel development [17]. Cartilage degradation in RA occurs when TNF-α, IL-1, and IL-6 activate synoviocytes, resulting in the secretion of MMPs into the SF [6, 7]. Cytokines also activate chondrocytes (**Figure 1**), leading to the direct release of additional MMPs into the cartilage [7]. ROS have been produced mainly during oxidative phosphorylation and by activated phagocytic cells during oxidative burst. It has been known that ROS can function as a second messenger to activate nuclear factor kappa-B (NF-κB) which orchestrates the expression of a spectrum of genes involved in the inflammatory response. Several cytokines, including TNF-α and IL-1β, are known initiators of NF-κB activation cascade [18] and are under its transcriptional control.

#### **Figure 1.**

the knowledge on human and animal models will allow to create a comprehensive

Rheumatoid arthritis occurs due to the continuous deterioration of cells and tissues that ultimately affects major organs. Both oxidative stress (OS) and inflammation are considered major role players in the pathogenesis of RA [2]. Even if there is a lot of evidence from animal models of RA and human RA, about that OS plays an important role in tissue damage and also promotes cardiovascular diseases in patients with RA [3]; until now, a therapeutic strategy to reduce OS in RA has not yet been established. Thus, understanding how the OS is influencing the develop-

In this chapter, we will discuss the importance of OS in the pathogenesis of

RA is a chronic, progressive, inflammatory autoimmune disease associated with articular, extra-articular, and systemic effects. It has been reported that RA affects multiple comorbidities [4]. Mortality rates are more than twice as high in patients with RA as in the general population (Wolfe et al. [5]). Although the exact cause of RA remains unknown [5, 6], several findings suggest a genetic basis for disease development. More than 80% of patients carry the epitope of the HLA-DRB1\*04 cluster [7], and patients expressing two HLA-DRB1\*04 alleles are at elevated risk for major organ involvement and surgery related to joint destruction [8]. Environmental factors, such as smoking and infection, may also influence the development, rate of progression, and severity of RA [9, 10]. In addition to joint symptoms, many patients experience extra-articular or systemic manifestations or both. Extraarticular manifestations include rheumatoid nodules, vasculitis, pericarditis, uveitis, and rheumatoid lung [11]. Systemic manifestations include often anemia, cardiovascular disease, osteoporosis, fatigue, and depression [12, 13]. The earliest event in RA pathogenesis is the activation of the innate immune response that includes the activation of dendritic cells by exogenous material and autologous antigens. Antigen-presenting cells, including dendritic cells, macrophages, and activated B cells, present arthritis-associated antigens to T cells. T-cell activation and B-cell activation result in increased production of cytokines and chemokines. In addition to antigen presentation, macrophages are involved in osteoclastogenesis and are a major source of cytokines, including TNF-α, IL-1, and IL-6 [6, 7]. Within

the synovial membrane, there is a great increase in activated fibroblast-like synoviocytes, which also produce inflammatory cytokines, prostaglandins, and matrix metalloproteinases (MMPs). Synoviocytes contribute to the destruction of cartilage and bone by secreting MMPs into the synovial fluid (SF) and by direct invasion into these tissues [7]. Pro-inflammatory cytokines are involved in the pathogenesis of RA [2, 14]. TNF-α and IL-6 play dominant roles in the pathobiology of RA; however, IL-1, vascular endothelial growth factor (VEGF), and IL-17 have also a significant impact on the disease process. These cytokines activate genes associated with inflammatory responses, including additional cytokines and MMPs involved in tissue degradation [6]. Th-17 lymphocytes have a critical role in synovitis in RA patients [15]. TNF-α, IL-6, and IL-1 are key mediators of cell migration and inflammation in RA [7]. IL-6 acts directly on neutrophils through membrane IL-6 receptors that contribute to inflammation and joint destruction by secreting proteolytic enzymes and reactive oxygen intermediates [12]. Furthermore, an in vitro study with fibroblasts from patients with RA demonstrated the role of IL-6 in promoting neutrophil recruitment by activated fibroblasts [16]. The principal

human RA and its experimental model, rat adjuvant arthritis (AIA).

"pathogenesis map" to the subset of disease they mimic [1].

*Animal Models in Medicine and Biology*

ment of animal and human RA is of great importance.

**2. Pathogenesis of rheumatoid arthritis**

**196**

*Pathogenesis of cartilage and bone damage in rheumatoid arthritis. MHC, major histocompatibility complex; TCR,T-cell receptor; TACI, transmembrane activator and CAML interactor; BLyS, B-lymphocyte stimulator; RANK, receptor activator of nuclear factor κ B; RANKL, receptor activator of nuclear factor κ B ligand; TNF, tumor necrosis factor; INF, interferon; IL, interleukin; CR, complement receptor; RF, rheumatoid factor.*

TNF-α participates positively in the phosphorylation of kinase kappa inhibitor, allowing NF-κB dimers (p50 and p65 portions) to migrate to the nucleus and then bind to promoters of pro-inflammatory genes [19] and stimulate the NADPH oxidase activation. Increased cytokine production driven by NF-κB can enhance expression of vascular adhesion molecules that attract leucocytes into the joint as well as MMPs.
