**2.1. Rheumatoid factors**

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

degeneration of cartilage and consequent loss of function in RA patients [57]. Denaturation of CII also causes separation of α chains and loss of antigenic sites (epitopes) present in the molecule which are altered due to the disruption of its three dimensional structure [58]. Autoantibodies to both, native and denatured CII, have been reported in RA [59–62]. Varying levels of anti-CII antibodies were detected in the same patient at different times and also between patients, suggesting that these antibodies might be associated with specific events

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Increased anti-CII antibody levels may degrade CII molecules leading to acute inflammation which is mediated by anti-CII antibody containing surface-bound immune complexes (ICs) [60], which activates complement system activation and enhanced the production of proinflammatory cytokines (TNFα, IL-1β and IL-8) [63], which leads to the inflammation of the joints and hence cartilage damage. Antibodies have been detected against major CII epitopes at the site of inflammation, serum and synovial fluid samples from RA patients, supporting

CII is found to be arthritogenic in animals and an injection of native CII in adjuvant induces collagen-induced arthritis (CIA) characterized by antibodies to CII and inflammatory polyarthritis [64]. Variability in expression of arthritis is linked to the expression of particular class II major histocompatibility (MHC) alleles [65] and also depends on an intact immune system. For example, B cell deficient animals [66] or complement deficient ones [67] are protected. Moreover, monoclonal antibodies (mAb) to CII derived from mice with CIA can induce collagen antibody-induced arthritis (CAIA) in naïve mice. CAIA is a condition characterized by inflammation, formation of pannus and erosions of bone similar to that observed in RA [68]. This model disease does not require the help pf T cells and has proven to be an informative model to better understand how antibodies lead to development of arthritis. Not only is arthritis not MHC-restricted, but it can be induced in most strains of mice and represents a model of the effector arm of CIA. However, it depends on the specificity of the antibodies used. A triplet of arginine-glycine-hydrophobic acids, is a common amino acid motif, shared by these arthritogenic mAb, which recognize epitopes on CII. These map to surface-exposed regions on the collagen fibrils that are accessible for antibody binding [68]. These epitopes are conserved, and are also recognized by antibodies from rats [69–71] and from humans with RA [70, 72]. Amino acid arginine molecules are present on the surface of the major epitopes on the collagen fibrils can also become citrullinated [73] and mAb reactive with these citrullinated epitopes may be arthritogenic themselves, or induce more severe arthritis when injected with subclinical doses of anti-CII [74]. Antibodies to major CII epitopes could be useful as markers

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

the concept of an increased local immune response to CII in the joints [61].

for the biomonitoring of joint destruction in some patients.

**3. Role of cytokines in RA**

during arthritis development.
