**2.2 Examples of inflammatory and autoimmune diseases and the ROS**

### *2.2.1 Systemic lupus erythematosus*

SLE is a complex autoimmune disease that affects at least 0.04% - 0.2% of every 100,000 people. The disease has a high prevalence in childbearing age women. This disease is marked by the increased presence of autoantibodies that target nuclear components and inflammation. This usually occurs in organs like the lungs, kidney, and joints. Although the exact cause of SLE remains not fully understood, a genetic predisposition that promotes the formation of lupus has been purported. Additionally, single nucleotide polymorphism in the Ncf2 gene that causes reduced ROS production is known to increase the likelihood of SLE occurrence. The promoting role of ROS deficiency in lupus-like phenotype has been demonstrated in mice where mutation of the Ncf1 shows high levels of anti-DNA, anti-histone, and anti-RNA antibodies with elevated deposits of Ig G and complement C3 in the glomeruli [43]. This contributes to the development of clinical signs of Arthritis, lung hemorrhage and enhanced glomerulonephritis. Increased risk of atherosclerosis is another feature of SLE. Atherosclerosis is developed due to endothelial dysfunction which is linked to a diminished bioavailability of nitric oxide and an increased generation of ROS. Studies in lupus-prone mice have shown increased activity of NADPH oxidase coupled with elevated systolic blood pressure and renal disease, a typical symptom of lupus [44]. ROS in SLE can play a double role depending on the stage of the disease. On one hand, it can be essential in the prevention of autoimmune diseases during the early stage, but it may exacerbate damage during the late stage of the disease.

#### *2.2.2 Type 1 diabetes (diabetes mellitus)*

Type 1 diabetes is a metabolic disease that results from the dysregulation of insulin due to the autoimmune destruction of β-cells in the pancreas. The disease emerges at an early age and is manifested as high levels of blood sugar.

#### *Reactive Oxygen Species in the Development and Resolution of Autoimmune and Inflammatory… DOI: http://dx.doi.org/10.5772/intechopen.99988*

The hyperglycemia-induced onset of diabetes has been linked to excessive oxidative stress damage. Mouse model-based experiments have demonstrated that ROS plays a key role in disease development of the disease [45]. For example, non-obese diabetic mice that produce is prone to type1 diabetes, contrary to their ROS deficient counterparts [46]. Reducing the ROS levels is known to help in transforming macrophages to M2 phenotype. Unlike M1, M2 is not a proinflammatory phenotype and does not cause diabetes mellitus. Cells taken from diabetic patients have been found to exhibit increased production of singlet oxygen molecules and a depletion of antioxidants or loss of antioxidant enzymes activity. Hyperglycemia coupled with oxidative stress can lead to macromolecule damage such as protein damage, DNA, and lipids. Islet β-cells are highly susceptible to this damage, which displaces the activation of signaling pathways [47].

#### *2.2.3 Rheumatoid arthritis*

Rheumatoid arthritis is an autoimmune and inflammatory disorder characterized by persistent joint inflammation, which can result in the production of autoantibodies, destruction of the bone and cartilage at the site of inflammation. Mutations in the genes that encode components involved in oxidative stress have been found to play a role in the progression of rheumatoid arthritis. By using murine-induced arthritis, pristine-induced arthritis (PIA), gene regions that are involved in the regulation of different phases of the disease and its severity have been identified using mouse models [48]. The loss of NOX2 function due to polymorphism of the *Ncf1* gene is associated with the manifestation of the arthritis phenotype. Recovery of NOX2 function shows protection against the development of the disease. Sever collageninduced arthritis with excessive cartilage destruction has also been found in mice with a mutated *Ncf1* gene [43]. Additionally, female mice with a mutated *Ncf1* gene develop spontaneous arthritis postpartum. Autoimmune responses that target cartilagederived molecules play a vital role in the development of arthritis. The recognition of type II collagen bound to MHC-II by T cells is important for disease initiation. However, this alone is not enough to break the immune tolerance. When the recognition of type II collagen by T cells is coupled with the dysregulation of NOX2, chronic collagen-induced arthritis is initiated [49]. Notably, tolerance break can still occur by modulation of T cell activation. Single nucleotide polymorphism in genes that encode for components of NADPH oxidase complex such as *Ncf4*, *Ncf2*, and *Rac2* and genes of antioxidants enzymes have been linked to arthritis incidence. Low copy numbers of the *Ncf1* gene are a common occurrence in patients with rheumatoid arthritis. Therefore, an increased copy number of the gene can lead to protection against the development of rheumatoid arthritis.

The protective role of ROS in rheumatoid arthritis seems to oppose its destructive role in joint inflammation. During arthritic inflammation, reactive species can exacerbate inflammation while contributing to tissue damage via collagen degradation. Overproduction of ROS is also known to cause cartilage degradation in osteoarthritis. This is achieved by inducing apoptosis in the chondrocytes, cells that are essential for the formation and function of the cartilage [50]. The prevalence of ROS coupled with inflammation causes the disruption of tissue homeostasis and depletion of antioxidants. Hydrogen peroxide and hydroxyl species react with membrane lipids, causing lipid peroxidation and promoting cartilage degeneration while inhibiting self-repair [51]. Cartilage degeneration is achieved by affecting the structures of the structural proteins found on the joint, such as collagen and proteoglycan, causing

the chondrocytes to enter the stage of senescence or cell death, which can eventually lead to subchondral sclerosis and meniscal and ligament damage. ROS and inflammatory cells are contained in the synovial fluid in the joint. Their intense activity not only causes the thinning of the proteoglycan layer and collagen fiber but can also cause functional impotence to the DNA mismatch repair system. This activates the NF-kB and the overproduction of metalloproteinase and DNA adducts such as 8-oxohydroxy-7,8-dihydro-2′-deoxyguanosine there by contributing to DNA damage and cell arrest. With reduced antioxidant activity, arthritis progression is favored.

### *2.2.4 Chronic granulomatous disease*

Chronic granulomatous disease (CGD) also known as Bridges-Good or Quie syndrome is a rare inheritable immunodeficiency disorder that affects phagocytes such as neutrophils, monocytes and macrophages. These phagocytes lose their capability to form reactive oxygen compounds such as superoxides, and their capability to eliminate invasive pathogens will therefore, become greatly reduced. CGD is characterized by recurrent bacterial or fungal infection and other dysregulated inflammatory responses, leading to the formation of granulomatous and development of other inflammatory disorders such as colitis. Clinical manifestation of CGD includes pneumonia, adenitis, subcutaneous and hepatic cellulitis, lymphadenitis, osteomyelitis, and sepsis. Clinical studies have also shown the involvement of the genitourinary system and gastrointestinal tract in granulomas [52]. CGD is caused by a reduction in ROS production due to defective activity of the NADPH complex's NOX2. The defect is a result of mutations in the NOX2 catalytic subunit gene gp91phox. About 70% of all reported CGD cases are found in males and they are X-linked. Mutations in the Ncf1 and Ncf2 which are recessive autosomal inherited account for a large number of cases [53]. These mutations can cause reduced ROS production and disable the ability to form NETs, leading to reduced efficiency in pathogen elimination. Interestingly, CGD patients have reduced long term memory immunity. A reduced long term memory in CGD patients and mice may can be due to the relation between the number of neutrophils, NOX2 normal activity and percentage of memory B cells. ROS is known to directly influence the process of memory B cells, and hence a loss of function of NOX2 will reduce this process. Contrary to a reduced number of memory B cells, Cd19+ B cells and immature Ig, the D + CD27- B cells availability increases in patients [54]. ROS also plays a role in the activation and proliferation of B cells. According to *in vitro* studies, the neutralization of ROS in B cells is associated with the attenuation of B cell receptor signaling. CGD patients with Ncf1 mutation have increased expression of type 1 IFNs, which is comparable to 1 IFNs in SLE patients. Type 1 IFNs are known to cause autoimmune disease by inducing the differentiation of dendritic cells capable of presenting organisms own materials to the phagocytic immune cells [55]. This puts CGD patients at a high risk of developing SLE and other autoimmune diseases, including juvenile idiopathic arthritis, antiphospholipid syndrome, and IgG nephropathy.
