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Th17 cells produce the pro-inflammatory cytokine IL-17A which has been found in increased concentrations in the peripheral blood plasma, serum and CD4+ T cells of adult SLE patients (70, 88, 121). IL-17 comprises of a group of six relatively recently identified cytokines: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. IL-17A and IL-17F are closely associated with each other sharing approximately 50% of gene sequence identity while IL-17B-to-D share 23-29% homology with IL-17A (122, 123). In addition the IL-17 family also comprises of five receptors: IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE. IL-17A and IL-17F, which both bind to the same receptors IL-17RA and IL-17RC, drive inflammation and autoimmunity and are produced by CD4+ and CD8+ T cells, Natural Killer cells and neutrophils (92, 94). IL-6 increases IL-17 production by memory T cells, suggesting that it parallels IL-12/Th1 in inducing Th17 differentiation, while IL-23 activates and upregulates IL-17 secreting potential in naive T cells committed to Th17 differentiation (92, 124). Current evidence indicates that IL-17A may factor in the immunopathogenesis of inflammatory clinical manifestations of SLE (70). However research on other members of the IL-17 family is scarce, especially in the context of SLE.

1.4.1 IL-17A

IL-17A is involved in the immune response against primarily bacterial and fungal pathogens such as Klebsiella pneumoniae and Candida albicans (35, 92). IL- 17A increases production of chemokines such as IL-8 and growth-regulated oncogene alpha and growth factors, granulocyte colony-stimulating factor (G-CSF) and GM-CSF, where these chemokines and growth factors recruit and develop neutrophils and monocytes (92, 125). This induces IL-6 and prostaglandin-E production, which encourages effector T cell infiltration and activation and enhances the immune response (92, 125). IL-17A also participates in the adaptive immune response by proliferating plasma cells and maintaining B cell survival (126). This increases autoantibody synthesis and proliferation as evidenced by increased anti-dsDNA and IgG production in lupus PBMCs compared in healthy controls (127). In addition it stimulates macrophages to produce IL-1β and TNF-α inflammatory cytokines which amplify tissue pro-inflammatory response (125). IL-6 is a

32 differentiation factor of Th17, hence increased induction by IL-17A would commit more naive T cells to the Th17 lineage (35). IL-17A has been shown to play a role in autoimmune conditions such as JIA, rheumatoid arthritis and psoriasis thus demonstrating that IL-17A and Th17 cells may act as pro-inflammatory agents in autoimmune disease (94, 128, 129). Adding to this, two recent double-blind, randomised placebo-controlled trials have reported significant improvements in psoriasis severity scores in patients treated with an anti-IL-17 monoclonal antibody or an anti-IL-17RA antibody, indicating the therapeutic value in tackling this pathway in autoimmune disease (130, 131). Previously, IL-17A has been found at significantly higher levels in the synovium and synovial fluid compared to the peripheral blood of patients with rheumatoid arthritis and JIA, indicating that IL-17A may be more localised to the site of inflammation (128, 132).

Adult SLE patients have been found to have increased numbers of IL-17A producing T cells and raised IL-17A, IL-17F and IL-23 plasma and serum levels in comparison to healthy controls (23, 82, 84, 88, 92, 110). In addition, these raised levels of IL-17A showed correlation with disease activity scores (91, 133). Increased IL-17A levels have also been found in the circulation and tissues of both murine models of lupus and adult lupus patients (70). Stimulation of CD4+ T cells with CD3/CD28 resulted in increased IL-17A in SLE adult patients compared to healthy controls while there were no differences between control and psoriatic patients, indicating that SLE CD4+ T cells expand more readily and skew toward IL-17A production (88, 109). Lupus patients have also been shown to have increased IL-17A expression in their kidneys and urine sediments, suggesting that IL-17A could play a role in target organ damage (121). Its strong presence at target organs may be causing an increased deposition of autoantibody-nucleosome immune complexes causing tissue inflammation (127). In addition, IL-17A has been found in a vast majority of skin tissue samples of patients with cutaneous and systemic lupus which correlated with IFN-α expression (134). Animal studies have shown that blocking IL- 17A reduces lupus manifestations, which may prove to be therapeutically useful for SLE patients (92).

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1.4.2 IL-17B

IL-17B and IL-17C have previously been found to stimulate the secretion of TNF-α and IL-1β from THP-1, a monocytic cell line (135). In a study reported by Yamaguchi et al, mRNA expression of IL-17A, IL-17B, IL-17C and IL-17F have been found to be elevated and associated with IL-6, IL-23 TNF-α and IL-1β production in the arthritic paws of murine arthritis models (136). Adding to this, flow cytometry found that CD4+ T cells from the arthritic paws significantly expressed IL-17A and IL- 17F, while IL-17B was only expressed in the chondrocytes of the inflamed joints of these mice (136). This suggests that CD4+ T cells may express members of the IL-17 family mainly at the site of inflammation. The study also reported that blocking IL- 17B, as well as IL-17A, suppressed the progression of arthritis in these mice, suggesting therapeutic potential (136).

1.4.3 IL-17C

In the study mentioned in section 1.4.2 by Yamaguchi et al, it was found that within mice with inflammatory arthritic paws, IL-17C was expressed not only by macrophages and dendritic cells but also by CD4+ cells (136). IL-17C has been shown to bind to an IL-17RA-IL-17RE heterodimer receptor cytokine to induce the expression of genes encoding chemokines such as IL-8 and pro-inflammatory cytokines such as TNF and IL-1β, bearing inflammatory similarities to IL-17A (135, 137, 138).

A recent study has shown that mRNA expression of IL-17C is increased in the central nervous system of mice with autoimmune encephalomyelitis (EAE) and that knocking out IL-17C in these mice showed reduced disease incidence and severity, as well as decreased expression of Th17 related cytokines IL-17A, IL-17F, IL-22 (139). In addition, increasing concentrations of IL-17C led to a significantly raised expression of IL-17A and IL-17F protein production in Th17 cells (139). However this study also found that IL-17C expression was increased in the localised inflamed central nervous system tissues as compared to the spleen, which led to the conclusion that Th17 cells may migrate to affected tissues where it is potentiated by IL-17C for local tissue inflammation. This is further supported by a study reporting

34 increased IL-17C expression in synovial fluid mononuclear cells (SFMCs) and PBMCs of patients with rheumatoid arthritis (140).

Figure 3: IL-17C binds to an IL-17RA-IL-17RE heterodimer (139).

IL-17C has been shown to bind to an IL-17RA-IL-17RE heterodimer receptor cytokine to induce the expression of chemokines and pro-inflammatory cytokines to potentiate the production of IL-17A. Image adapted from Haines et al 2011 (141).

1.4.4 IL-17RE

It has been found in previous studies that IL-17RE mRNA expression is upregulated in Th17 cells and not expressed in naive T cells, and that IL-6 and TGF-β cytokines regulate this expression while IL-1 and IL-23 promote it (139, 142). In addition Chang et al found that in the presence of IL-1β and IL-23, IL-17C binds to a IL-17RA - IL-17RE heterodimer to potentiate IL-17A cytokine production, and that increased IL-17RE signalling led to raised susceptibility to EAE in mice (see Figure 3) (139). Several other studies have also implicated IL-17RE as a crucial subunit of the heterodimer receptor through which IL-17C signals (137, 138).

Although the current evidence base is limited, the conclusions drawn from the aforementioned studies indicate IL-17 cytokine subsets may have a part to play in autoimmune pathology and would therefore be useful to explore in our subset of patients with juvenile-onset SLE.

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