**2. Pathogenic foreign bodies, ROS, inflammation and autoimmunity**

Production of ROS in phagocytic cells during the oxidative burst is essential to the elimination of pathogens during an immune response. However, it is also connected with the promotion of inflammation and tissue damage. Interestingly, recent studies have demonstrated that phagocyte derived ROS plays a role in the regulation of inflammation as well as providing protection against autoimmunity. This is mainly because chronic inflammation in multiple pathologic conditions has been associated with ROS deficiency.

The activation of the oxidative burst is highly marked by increased uptake of oxygen in the neutrophils. The consumed oxygen is primarily converted to singlet-oxygen molecules. This leads to an increase of the membrane-permeable hydrogen peroxide due to elevated dismutation activity within the phagocytes. This initiates the generation of various radical and non-radical ROS molecules via the activity of myeloperoxidase. In the events of oxidative burst, the NADPH oxidase complexes serve as one of the major generators of ROS but the localization and timing of the products depend on the stimulus [35]. Despite the localization and efficiency of ROS production, a high concentration of the molecules has been reported to cause the inactivation of proteins and enzymes via the adduct formation due to lipid peroxidation products [36]. Among the enzymes that are inactivated by this mechanism is NOX2, a potent producer of superoxide molecules. To counter this inhibition, phagocytic cells recruit cytochrome-b558 from the lysosomal pool via the soluble NSF attachment receptor 23 (SNARE) [37]. This enables the continuous production of ROS even after the inactivation of NOX2. This mechanism ensures the efficient eradication of pathogens and has been reported to potentially play a vital role in the regulation of autoimmunity [38]. The failure to move the NOX2 to the endosomes due to decreased Ncf4 expression in phagocytic cells can cause autoimmune responses but without the elimination of pathogenic molecules. Notably, increased activity of NOX2 is known to cause the destruction of membranes because of lipid peroxidation and this results in the leakage of the endosome contents such as antigens [39]. This process allows the presentation as well as cross-presentation of antigens to MHC-I. ROS production is therefore essential for the eradication of intracellular pathogens [39, 40].

Some evidence of the role of ROS in the maturation of dendritic cells and the increased expression of MHC-II molecules has been proposed, however, this is met with conflicting research results that NOX2-ROS production does not play a role in the maturation, differentiation and production of cytokines. This is despite its

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

important role in the elimination of intracellular foreign stimuli. Nevertheless, ROS enables regulated presentation of antigen by MHC-II via the oxidation of cathepsin cysteinyl thiols which prevents excessive protein degradation in early phagosomes. Intracellular foreign pathogen infections such as bacterial and fungal infections have been reported to be persistent in conditions where NOX2 activity is lacking [41]. NOX2 is also involved in backup mechanisms of pathogen capturing such as the formation of neutrophil extracellular traps (NETs) [42]. NETs are mainly composed of chromatin coated in antimicrobial peptides and proteases. During NETs formation, ROS are required for the release of elastase while myeloperoxidase participates in the formation of azurophilic neutrophils granules that facilitate histone degradation in the nucleus [42].

#### **2.1 ROS in inflammatory and autoimmune development**

Oxidative damage caused by ROS can generate deleterious byproducts consisting mainly of proteins and lipids that are modified into peroxides. These molecules play important roles in the pathogenesis of several diseases. These molecules have also been implicated in the pathophysiology of cell death and tissue damage. Some of these have the ability to cause immunogenic reactions by inducing pathogenic antibody release in diseases such as systemic lupus erythematous, alcoholic liver disease, diabetes mellitus, inflammation, degenerative diseases, and rheumatoid arthritis. Aldehydic by-products that form adducts with proteins make up two-thirds of molecules that have been implicated in these conditions.

Stress-induced by ROS or any other factor compromises the antioxidant activity within a cell can lead leading to an imbalance in the pro-oxidant/antioxidant balance. The prevalence of this phenomenon has been shown to increase lipid peroxidation. Lipid peroxidation is the degeneration of polyunsaturated fatty acids by free radical activity. The process involves three steps: initiation, propagation and termination. In the first step, a reactive radical extracts a hydrogen molecule from the methylene group. This leaves an unpaired electron on the carbon that combines with molecular oxygen in the propagation phase which then forms reactive peroxyl radicals that react with other lipids thereby forming hydroperoxides. Notably, peroxyl can produce fatty acid radicals and this can cause a chain reaction that causes lipid peroxide toxicity. Lipid peroxidation can also be induced by incidences of exacerbated conjugated dienes, 4-hydroxyl-2-nonenal modified proteins, malondialdehyde modified proteins and 4-hydroxynonenal among other molecules. Products of lipid peroxidation such as 4-hydroxy-2-alkenals can form the an adduct with the amino groups of proteins, leading to ROS induced protein modification. Modified proteins that gain the function of an aldehyde are highly immunogenic. ROS-induced lipid peroxidation and protein modification are likely to co-occur, and the two processes can mutually induce each other. Some products of these processes can avidly react with antioxidants including glutathione and cofactors of ketoglutarate dehydrogenase causing further damage to the antioxidant response.

Lipid peroxides are not bystanders when it comes to the destruction of cellular membranes, cell-matrix and the accelerators in the development of conditions such as atherosclerosis in arthritis especially rheumatoid arthritis. The destruction of the cell membrane can cause the leakage of cellular content, thereby inducing an inflammatory response as the phagocytic cells attempt to clean the debris. The process of debris clearance can percussively cause tissue damage. During this process two sets of macrophages are activated, the first set is M1 which is classically activated, and the second set is M2, which is alternatively activated. M1 is known for excessive production of toxic production which M2 tries to resolve by producing molecules like EVG and VEGF. The difference in function is made vivid by the distinction in the cytokine profile of the two sets. M1 releases excessive proinflammatory cytokines IL1, IL6 and ROS which ultimately causes cell death by activating death receptors and/or caspases. M2 on the other hand releases anti-inflammatory cytokines like IL-4 and IL-10. In situations that lead to excessive tissue injury, there is little to no anti-inflammatory response as compared to proinflammatory. Aside from this, oxidation of lowdensity lipoproteins can cause the upregulation of chemokines, adhesion molecules and glycan end-products, thereby inducing an increased inflammatory response. Inflammation in the presence of oxidative stress is known to result in the nonenzymatic degradation of proteins through glycoxidation. Glycoxidation of immunoglobins produces modified immunoglobins which can induce a systemic inflammatory response. Neo-epitopes created by protein modifications can be recognized by toll-like receptor-4, advanced glycan end-product receptors, and scavenger receptors as invasive and can induce pathogen-associated molecular patterns in the immune system that will ultimately lead to autoimmunity. Additionally, there is a correlation between ROS-altered biomolecules and the severity score of autoimmune and inflammatory diseases.
