**3. Role of cytokines in RA**

RA patients as yet. Additionally, the function of RF expressing B cells to take up immune complexes and present trapped antigens to T cells may allow these cells to bypass the need for specific T cell help and eventually lead to emergence of autoreactive T cells capable of

Some other names used to describe ACPA are anti-keratin, antiperinuclear factor antibodies, antifilaggrin antibodies, or anti-Sa [39]. ACPA have been associated with human pathology [40] as well as preclinical disease [16, 18, 41]. Latest ELISA assays, exhibited higher specificity (∼98%) and sensitivity between 40 and 76% (depending on disease stage) [42]. Recently proved that there is a potential association of ACPA with conditions like psoriatic arthritis [43], periodontitis [44], and osteoarthritis [45]. The key difference between ELISA assays was in the antigens used to detect ACPA. Thus, the diagnostic value of ACAP was established by demonstrating the significance of using appropriate citrullinated peptide [39, 46, 47]. Consequentially, a highly sensitive noncommercial ELISA, based on protein targets identified as reactive with ACPA in synovial tissue such as alpha and beta fibrinogen was therefore developed [48]. The positivity of ACPA for one or both to these two citrullinated peptides

Citrullinated peptides are generated in response to a posttranslational modification mediated by peptidyl-arginine deiminase (PAD) enzymes. Multiple antibody isotypes including IgG, IgA, and IgM directed against these citrullinated peptides are detected in RA [50]. Citrullinated proteins are present in the synovial fluid of inflamed RA joints, exhibiting that ACPA could bind to these antigens in the joint and possibly increase local inflammation [51]. A protein that is commonly targeted by ACPA is Vimentin. In collagen-induced arthritis, mouse models passive transfer of ACPA cannot cause synovitis, although it can worsen preexistent synovitis [52]. Therefore, it is suggested that multiple events are necessary for the development of RA. ACPA causes inflammation via binding to Fc receptors or complement activation. Autoantibodies are usually glycoproteins that means both Fc and Fab region of the antibody bind to the carbohydrate chains, which is essential for immune effector functions. Compared to IgG antibodies, the Fc region of ACPA has a lower level of galactosylation and sialylation against recall antigens [53]. The decreased sialylation of IgG in immune complexes can drive osteoclastogenesis, both *in vitro* and *in vivo*, through altered FcγR signaling. Moreover, it has been found that RA patients with low levels of ACPA-IgG Fc sialylation displayed lower bone volumes and trabecula numbers [54]. Thus, disease pathophysiology could be influenced by the specific Fc glycan signature

Type II collagen (CII) are abundantly present in joint cartilage [55]. Native CII protein consists of a triple-helix structure containing three identical α chains. The collagen fibrils contribute to cartilage integrity by resisting stretching forces caused by hydrophilic proteoglycan molecules in extracellular matrix of articular cartilage, [56]. The degradation of CII leads to the

triggering RF synthesis in the absence of an external antigen [38].

**2.2. Anti-citrullinated proteins antibodies (ACPA) in RA**

covered all reactivity in RA sera [49].

104 Autoantibodies and Cytokines

**2.3. Autoantibodies against type II collagen**

of ACPA.

The network of cytokine in the RA disease is very complex system, with a numerous of cytokines showing pleiotropic actions and many different targets. This network can be divided in two groups, the pro-inflammatory and anti-inflammatory cytokines. Controlling the balance between these two groups is considered as an important therapeutic goal. This chapter provide an important role of TNF-α in the pathogenesis of RA, leading to the first clinical trials of a biological therapeutic in this disease. Other than TNF-α we address other cytokines such as IL-1, IL-6 and IL-23 that might play a role in the disease, together with selected cytokines that bind a receptor containing the common γ-chain (γc) [75].

leads to intracellular signal transduction and regulation of gene expression and hence cellular responses [91]. The extent of response of IL-1β in the rheumatoid joint depends on a few factors such as (1) IL-1β and IL-1Rα have similar affinity for IL-1RI on synoviocytes, chondrocytes and other cells and hence, the relative concentrations of IL-1β and IL-1Rα are important in determining the level of cell activation and biological responses, (2) a greater number of IL-1RII reduces the amount of IL-1β and IL-1Rα, that is available for binding to IL-1RI. Similarly, soluble IL-1 receptors found in synovial fluid and in the circulation also decrease the amount of these cytokines available to interact with IL-1RI. The response of IL-1β, as well as to other proinflammatory cytokines, is regulated by various anti-inflammatory and immunomodulatory cytokines, including IL-4, IL-10, IL-11, IL-13 and transforming growth

Autoantibodies and Cytokines in Pathogenesis of Rheumatoid Arthritis

http://dx.doi.org/10.5772/intechopen.82265

107

IL1 causes inflammatory cells to move into the joints and the synovium in RA patients. An unspecified antigenic trigger is thought to activate the production of IL1 in joints by macrophages (lymphocytes, monocytes and transformed fibroblasts) [54, 93]. These cells secrete proteases and proteoglycans as cellular signals, that may result in pannus formation, which accumulates in the joints. Destructive enzymes can enter and destroy cartilage and ultimately degrade and erode bone. Importantly, specifically blocking IL1 is a targeted, rational treat-

Evidence from experimental studies in animal models of arthritis and from an x randomized controlled trials in patients with RA indicates that IL-1 plays an important role in RA pathogenesis, and that IL-1 inhibition with anakinra is effective in slowing further radiographic progression of the disease and hence models significantly reduces bone erosions and cartilage degradation [14]. It is important to elucidate that, whether slowing radiographic progression with these biological therapies will significantly improve long-term

IL-6 is an essential and multifunctional proinflammatory cytokine of the immune system and could be a key mediator for the development of many chronic inflammatory or autoimmune

It is well established that increased levels of autoantibodies are the characteristics of autoimmune RA and hence decreased levels of antibody producing B cells are might have a therapeutic efficacy demonstrates the impact of B-cell activity on synovial inflammation and joint damage. IL-6 stimulates B cells to differentiate into plasma cells to produce immunoglobulins [97]. IL-6 induces B-cell differentiation [98] and it has been established that B-cells induced

Neutrophils can be directly activated by IL-6 through membrane-bound receptor IL-6R, which in turn help inflammation and joint destruction through the secretion of proteolytic enzymes and reactive oxygen intermediates [100]. An *in vitro* study with fibroblasts from patients with RA showed the role of IL-6 in actively encourage the recruitment of neutrophil by activated fibroblasts. Although untreated fibroblasts were able to recruit neutrophils, it was found that

the recruitment was inhibited in the presence of anti-IL-6 antibody [101].

ment against the destructive functions of IL1 in RA [54, 94].

factor-β [91, 92].

outcomes in RA.

**3.3. Interleukin-6**

diseases including RA [95, 96].

antibody production [99].
