**3. Rheumatoid arthritis**

RA is a systemic AD of the joints also known as inflammatory arthritis (IA), in which several additional organ systems are known to be involved, including the pulmonary, cardiovascular, ocular, and cutaneous systems. However, the presence of IA, defined as tenderness and swelling consistent with underlying synovitis is the hallmark for the clinical diagnosis of RA. It is characterized by persistent joint inflammation with accompanying bone and cartilage damage and the formation of autoantibodies [13] (**Figure 2**). Most of the RA patients have rheumatoid factor (RF,autoantibody against the Fc portion of IgG) and anti-citrullinated peptide antibodies (ACPA) [14–16]. The exact cause of RA

**Figure 2.**

*a. Rheumatoid arthritis. The oxidative stress and local inflammatory mediators manifest mainly in the joint resulting in pain and pain and inflammation which may lead to and joint damage and disability at a later stage (*reprinted and modified from *[13]). b. Oxidative stress and inflammation in rheumatoid arthritis (*reprinted and modified from *[13]).*

is still not completely understood, although there is a strong evidence of the genetic involvement in disease process. The class II major histocompatibility complex (MHC) molecules, HLA-DR1 and HLA-DR4 are regarded as the major genetic risk factors in the etiopathogensis of RA [17–19].

Several studies suggest that oxidative stress leads to defective redox signaling and damage to biomolecules in the pathogenesis of RA [12]. The mutations in genes that

encode inflammatory and enzymatic molecules involved in the oxidative burst are responsible for the development of RA. In arthritic inflammation, ROS acts as an inflammatory mediator and contributes to destruction of collagen tissues and the overproduction of ROS is associated with damage leading to cartilage degradation. The damaged chondrocytes, which are essential for the structure and function of cartilage, are stimulated to undergo apoptosis. Fewer chondrocytes are unable to self-repair the cartilage and therefore promote the breakdown of the extracellular matrix in joints. Furthermore, H2O2 leads to chondrocyte lipid peroxidation which is also linked to protein oxidation and degradation of cartilage matrix [20].

Additionally, the functional genetic analysis showed that the single nucleotide polymorphisms (SNPs) in the neutrophil cytosolic factor 1 (Ncf1) coding region is associated with genetic susceptibility to RA [21]. The patients with chronic granulomatous disease (CGD) also have amplified susceptibility to RA [21, 22]. Furthermore, a study of NOX2-deficient mice revealed that the absence of ROS averts resistance to autoimmune arthritis. A collagen-induced arthritis model produced by Ncf1 mutation in mice has more acute symptoms, higher anti-CII IgG levels, and stronger T helper type 1 (Th1) responses than wild-type mice. Interestingly, the study also found that T cells from Ncf1-mutated mice reacted more actively to antigen presenting cells (APCs) [23]. Mice with mutated collagen (MMC) have increased resistance to arthritis mediated by a mutated immunodominant epitope in collagen type II that binds to the MHC class II molecule. When these MMC mice are bred with NOX2 deficient mice, their immune tolerance to arthritis disappears, and they display increased autoimmune T cell and higher levels of anti-CII IgG levels [24]. Therefore, the pathophysiology of ROS in RA is an imbalance in homeostasis between pro- and antioxidative and pro and anti-inflammatory conditions, which may lead to the damage of connective tissues, multiple joints and other organs in the body.
