**1. Introduction**

Autoimmunity arises as a result of failure of immune self-tolerance. The condition may involve both T and B cells however it has been found that in most autoimmune diseases, T cells play a pivotal role in both dysregulation and autoimmune aggression, but autoantibodies are also widely produced by B cells. Such autoantibodies play a key pathogenic role in diseases such as autoimmune hemocytopenias, Grave's disease, rheumatoid arthritis, type 1

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

diabetes and systemic lupus erythemathosus (SLE). Similarly, autoantibodies are also found in other diseases, where although they may play a minor pathogenic role, but can be used as valuable diagnostic markers [1–7].

**2. Autoantibodies in RA**

**2.1. Rheumatoid factors**

Several studies have been demonstrated that levels of disease-related biomarkers (such as RF and antibodies to citrullinated protein antigen, as well as secretory phospholipase A2, C-reactive protein (CRP), glycated HSA, and multiple cytokines/chemokines) may be elevated

Autoantibodies and Cytokines in Pathogenesis of Rheumatoid Arthritis

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These findings suggest that there is a substantial "preclinical" period of RA, during which detectable immunologic and inflammatory changes are occurring that are related to disease development. These increased levels of RA related autoantibodies in preclinical RA may be highly specific for early RA detection [18, 19]. There is a great hope that these autoantibodies may be used to predict which currently asymptomatic individuals are at sufficiently high risk

The RA is associated with systemic autoimmunity as evidenced by the presence of serum and synovial fluid autoantibodies. The first autoantibody to be described in RA was the rheumatoid factor (RF) by Waaler in 1940 [25], and it was later found to be directed to the Fc region of IgG. It is well characterized, although its exact origin still remains unclear. Typically, RF is of IgM isotype, but IgG and IgA may also occur. IgM RFs are the major RF species in RA and are detected in 60–80% of RA patients [26]. In the past, RF levels were determined by classical agglutination reactions; however, sensitivities and specificities depended on the type of test (e.g., latex fixation test, or Waaler-Rose test using sheep erythrocytes). RF levels were also determined by nephelometry [27]. RF has been observed in many other autoimmune diseases, such as, in systemic lupus erythematosus, mixed connective tissue disease and primary Sjogren syndrome, as well as in non-autoimmune conditions, such as in chronic infections and old age [26]. RF specificity to RA is increased at high titers (e.g., IgM RF > 50 IU/ml) and with IgA isotypes [26, 28, 29]. High titer RF and IgA isotypes are also associated with radiologic erosion, extra-articular manifestations and thus, poorer outcomes [26, 28, 30, 31]. The association between high titer RF status and a poor prognosis indicates that RF may have a role in the pathogenesis of RA. The functions of RFs under normal physiological conditions were observed as (i) enhancement of immune complex clearance by increasing its avidity and size, (ii) aiding B cells in uptake of immune complex through efficient antigen presentation to T cells, and (iii) facilitation of complement fixation by binding to IgG containing immune complexes [32–34]. RFs with high affinity and high-titer in synovial fluid of RA patients are considered to exert pathogenic functions and to enhance inflammation and antigen trapping in joints. However, no clear evidence yet suggests that RFs are involved in the initial events triggering the disease process of RA. In fact, it is understood that they may themselves be triggered by RA. Somatic mutations accumulates in RA and the presence of isotype switching indicate that RF production is T-cell driven, although T cells infiltrate RA synovium [35] and contain autoreactive clones [36], which were polyclonal and lack specificity for any particular autoantigen [36, 37]. T-cell clones reactive with autologous IgG were not detected in

prior to the onset of symptomatic rheumatoid arthritis [16–24].

for future RA that they may be targeted with preventive therapies.

Furthermore, in addition to T cells and autoantibodies, cytokines also play a pivotal role in development of the autoimmune response. Proinflammatory cytokines have significant involvement in autoimmune associated damage. This chapter aims to discuss the involvement of autoantibodies and cytokines in the pathogenesis of RA.

Immune system has the capacity to mount an immune response against virtually all foreign molecules as well as self. However, several mechanisms exist within the human system that prevent or subdue the response to self-antigens. The immune system has developed a series of checks and balances that enable it to distinguish dangerous signals from harmless ones and allow it to respond to foreign or non-self-antigens. When these mechanisms undergo a breakdown or are overridden, a response directed against self-antigen can occur, resulting in autoimmune reactions and/or autoimmune diseases [8].

RA is a complex chronic disease, primarily affects the lining of the synovial joints and can cause progressive disability, premature death, and socioeconomic burdens. The clinical manifestations of symmetrical joint involvement include arthralgia, swelling, redness, and even limiting the range of motion [9].

Autoantibodies have been associated with human pathologies for a long time, particularly with autoimmune diseases. RA is more frequent in females as compared to males [10]. Organ specific autoimmune diseases involve single or multiple autoantigens. In RA, presence of various autoantibodies such as RF and ACPA, and anti-cartilage type II antibodies in serum and synovial fluid have long been associated with RA severity [11].

The pathological hallmarks of synovitis in rheumatoid arthritis include the proliferation of resident synovial fibroblasts, new blood vessel formation and the recruitment of a wide range of leukocytes including B and T lymphocytes, monocytes/macrophages and mast cells; in turn this leads to synovial hypertrophy and the invasion of cartilage and bone by activated inflammatory tissue. Cytokines are fundamental orchestrators of the development and maintenance of this lesion [12]. RA disorder is a multifactorial disorder other than autoantibodies there are many other important factors involved such as proinflammatory cytokines such as TNF-α, IL-6 and IL-1 are key mediators of cell migration and inflammation in RA [13]. Cartilage degradation in RA occurs when TNF-α, IL-1 and IL-6 activate synoviocytes, resulting in the secretion of matrix metalloproteinases (MMPs), cathepsins and mast cell proteinases into the synovial fluid [14, 15]. Cytokines also activate chondrocytes, leading to the direct release of additional MMPs into the cartilage [14, 15].

Although the availability of advanced drugs and treatment regimes, however the complete remission of the disease is still not achieved. This chapter shed light on the complex network of the autoantibodies and proinflammatory cytokines as immune responses in the RA disease pathogenesis and the development of bio-therapeutics used in RA disorder.
