**7.3. IL-21**

IL-21 is a member of the Type I cytokine superfamily of cytokine receptors. In this group, the common γ cytokine receptor complex is the functional component for receptor-mediated signal transduction of IL-2, IL-4, IL-7, IL-9 and IL-15 [151-153]. Although IL-21 has strong structural ho‐ mology to IL-15, IL-21 interacts with a unique receptor, termed, IL-21Rα, which pairs with the γcommon cytokine receptor chain (i.e. CD132) to form the active IL-21 receptor complex [154].

IL-21-mediated events affect the functions of NK cells, T-cells and B-cells. Although devel‐ opment of Treg cells from the Th17 lineage is generally considered to require IL-6 because IL-6 reciprocally controls Th17 and Treg cell development through its ability to inhibit TGF-βinduced FoxP3 and by inducing RORγ, in fact, IL-21 can also induce RORγ and Th17 devel‐ opment in the absence of IL-6. However, evidence also showed that the number of Th17 cells, the recruitment of Th17 cells to inflamed tissues and the development of autoimmune encephalitis and myocarditis did not differ between IL-21R and IL-21 deficient mice com‐ pared to their wild-type counterparts [155, 156]. More importantly, IL-6 was the more potent inducer of Th17 differentiation compared to IL-21 thus calling into question, whether IL-21 was even required for Th17 development.

Despite the emerging controversies regarding how important IL-21 is in T-cell development and immune responses, a therapeutic intervention designed to limit the responses of im‐ mune cells to IL-21 has long been considered for treating cancer and autoimmune diseases [157]. In addition, because the binding of IL-21R induces activation of several of the JAK iso‐ forms [153], it became apparent that it would be necessary to elucidate which cellular events were controlled by STAT proteins activated by phosphorylated JAKs in response to IL-21/ IL-21R. Attempting to address this point, Habib et al. [151] found that IL-21 induced prolif‐ eration of pro-B-lymphoid cells *in vitro* which was dependent on both γc and the γc-associ‐ ated JAK3 complex. However, a monoclonal antibody reactive only with γc was effective in limiting the proliferation of BaF3/IL21R α cells [151] indicating that neutralization of γc alone could cause inhibition of JAK activation by IL-21/IL-21R.

Implying a role for IL-21 in the development and progression of RA would also depend on finding an elevated level of IL-21 in human RA tissues and by demonstrating an involve‐ ment of IL-21 in the pathogenesis of CIA or inflammatory arthritis in other animal models. Thus the results of a study by Young et al. [158] were noteworthy in this regard for several reasons. First and foremost, treating DBA mice with CIA with an antibody to IL-21R (i.e. IL-21R.Fc) reduced the severity of arthritis. The reduction in hind paw swelling was accom‐ panied by lower levels of IL-6 in the hind paw but also in the sera of mice treated with IL-21R.Fc suggesting that one of the downstream events regulated by IL-21 was IL-6 gene expression. Of note, the level of INF-γ was increased in the hind paws of mice with CIA. Furthermore, the cultured cells from the lymph nodes of mice with CIA treated with IL-21R.Fc showed an increased level of IFN-γ *ex vivo*. These findings (i.e. reduced IFN-γ; in‐ creased IL-6) were mirrored *ex vivo* using Type II collagen-specific spleen cells from CIA mice treated with IL-21R.Fc. Most importantly from the perspective of potentially using an anti-IL-21R antibody as a therapeutic agent for RA was the finding that treating Lewis rats with adjuvant –induced arthritis therapeutically with IL-21R.Fc "reversed" the swelling in inflamed joints and tissues from these joints whilst the tissues showed improvement using a well-validated histological scoring system. More recently, Yuan et al. [159] showed that IL-21R mRNA was found in human RA synovial tissue samples. In addition, this group also confirmed the results of the Young et al. study [158] since they showed that an anti-IL-21R antibody ameliorated the severity of arthritis in CIA which was accompanied by reduced cytokine levels in cells derived from the anti-IL-21R antibody-treated mice. Interestingly, IL-21R-deficient K/BxN mice [160] failed to develop arthritis; a result which suggested that IL-21R played a critical role in the pathogenesis of K/BxN serum-induced arthritis.

There now are several lines of evidence that showed that the IL-21/IL-21R pathway plays a functional role in regulating inflammatory responses in autoimmune arthritis. In that re‐ gard, anti-IL-21 blockade should also be considered for future drug development for RA. However, what would also be crucial to improving our understanding of the role of IL-21 in RA would be to discover which pro-inflammatory cytokine levels are altered in response to the JAK/STAT activation by IL-21/IL21R. This could provide a novel paradigm for reducing pro-inflammatory cytokine levels in RA.
