**1.2 Inflammation**

Inflammation is a none-specific immune response of cells or tissues to a stimulus such as a pathogen, cell damage, or toxicity that plays an important role in host defense. This response involves the signaling molecules, immune cells and blood vessels. The process is marked by the proliferation of inflammatory cells like monocytes, neutrophils, and lymphocytes. These cells release various molecules such as ROS, pro-inflammatory cytokines and various enzymes that have the ability to induce oxidative stress in the target tissues [3]. Therefore, inflammation and oxidative stress can co-occur, and one process can induce the other and vice versa.

Inflammatory responses can be complex as they involve multiple interactions of many cells and mediators. There are four major patterns of inflammatory response that are also common mechanisms of diseases. These patterns depend on the type of hypersensitivity. Two or more types of hypersensitivity can occur at once in a patient.


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


Inflammation is triggered to eliminate harmful agents so as to minimize the effects of the injuries. However, minimal inflammation (acute inflammation) usually does not inhibit these effects and prolonged inflammation (chronic inflammation) is associated with multiple diseases and conditions [3]. Acute inflammation is known to be part of the innate immune response as it is the initial response to a stimulus. In this phase of inflammation, platelets and granulocytic cells like basophils, eosinophils and mast cells are activated. These cells migrate from the blood vessels to the site of injury and release molecules that initiate, stimulate and attenuate inflammation for a short period [8]. For this to occur, the blood vessel becomes more permeable, consequently leading to the escape of proteins, outflow of fluids known as exudate and migration of other blood cells from the vessels to the site of inflammation, causing a swelling known as edema on the site. Neutrophils are the primary cells during this phase and they tend to engulf the foreign materials and organisms together with other debris. As neutrophils are short-lived cells, they are replaced by monocytes that differentiate into macrophages [8]. The acute phase usually resolves after hours or days, or even within a week. The persistent presence of monocytic cells due to ongoing and longterm response to stimuli leads to the development of chronic inflammation.

During chronic inflammation, there is a continuous accumulation of macrophages and lymphocytes at the site of inflammation due a persistent stimulus from the immune system [9]. The prolonged inflammatory response that might last for a week, months and in some cases a lifetime, will eventually lead to tissue injury. This can be induced by viral or certain bacterial infection and in some individuals,



*Summary of types of hypersensitivity.*

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

genetic polymorphism of inflammation mediators and cell receptors can also induce and favor extensive chronic inflammation [10]. In addition to the accumulation of macrophages, chronic inflammation is also marked by the proliferation of fibroblasts and small blood vessels. In rare cases when the inflammatory response encounters an agent that is difficult to eliminate, the response proceeds to granulomatous inflammation.

Granulomatous inflammation is a specific type of chronic inflammation that is marked by the presence of crystalline materials embedded into the tissues. Macrophages are the predominant effectors and they are recruited by T cells. Th1 cells have been reported to be the major mediators of granulomatous inflammation reactions [11]. Following the activation of Th1 cells by the antigens presented on MHC-II on the macrophages, Th1 secretes IFN-γ and other cytokines. These molecules then transform macrophages into activated tissue macrophages. Although the activated macrophages have increased capacity to eliminate foreign pathogens, they have a tendency to fuse and form multinucleated giant cells which forms concentric nodules that are known as granulomas [12]. Central necrosis can develop in these granulomas. This phenomenon has have been observed in infections caused by *M. tuberculosis* and other pathogens [13]. Such a phenomenon has also been reported in some autoimmune diseases.

Although inflammation is an essential process to the host defense, it can easily induce excessive tissue damage, resulting in acute or chronic tissue damage, organ or system dysfunction with fatal outcomes. Studies have shown increasing evidence of the involvement of chronic inflammation in autoimmune diseases, including but not limited to rheumatoid arthritis (RA), inflammatory bowel disease (IBD) systemic lupus erythematosus (SLE), gout, and diabetes [14]. This happens when inflammatory activity causes the production of autoimmune molecules and reactive species that sensitizes the immune system to a non-pathogenic component of the body.

#### **1.3 Autoimmune diseases**

Autoimmune diseases are chronic conditions that result from the loss of immune tolerance to self-antigens, causing the immune system to attack the organisms' healthy cells, tissues, and/or organs. Autoreactive T cells and autoantibodies are identified as the major attackers of self-antigen [15]. The differentiation and activation of these key attackers are still not fully elaborated. These disorders can be classified into two major groups, organ-specific autoimmune diseases and multiple organs or systemic autoimmune diseases. Different types of autoimmune diseases have been found to share common phenotypic features, from clinical signs and symptoms to genetic factors and pathophysiology mechanisms [16–18]. However, it is likely that some inducing factors may differ as different autoimmune diseases target different cells, organs and systems. Additionally, environmental factors also play a role in the onset of these diseases.

Factors that are common in different autoimmune diseases include but is not limited to the following features.

1.Pathology: The phenotypic manifestation of autoimmune varies, depending on the affected or target cell or system. However, the major pathogenic role is contributed by the phagocytic T cells and B cells. Other predominant cells include macrophages, neutrophils, and CD8+ T cells. Other cells that also contribute to the pathogenesis of autoimmune diseases are T helper cells, especially Th1, Th9 and Th17 [19]. The array of complex biological functions displayed by these cells such as cytokine production, antigen presentation, exosome release, the release of neutrophil extracellular traps (NETs), ROS, Arginase 1 and programmed death-ligand 1 have been implicated in the induction of autoreactive T cells and B cells as well as tissue damage and inflammation [20]. Abnormalities in the function of cells that participate in the classic immune response such as higher expression of IL-6, interferon-α, APRIL and BAFF can cause the dysregulation of adaptive immune cells [21]. These cells then go on to cause cell death either directly or indirectly by releasing cytokines, ROS, RNS and prostaglandins. Interestingly, specialized pro-inflammatory neutrophils with enhanced NETs and inflammatory cytokine production capacity have been found in the peripheral blood of patients suffering from different autoimmune diseases [15]. These cells have a low density due to altered buoyancy properties.

Peripheral tissues contain activated regulatory T cells that control inflammation and autoimmunity responses by eliminating malfunctioning neutrophils, lymphocytes and macrophages. Cells such as CD25+ and CD4+ T cells can secrete anti-inflammatory cytokines that can reduce Th1, Th9 and Th17 activity, thereby preventing autoimmune disease development [22]. However, their function can be inhibited by environmental agents such as pathogenic toxins or smoking.
