Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium and cartilage degradation and bone destruction. The initial pathological changes take place in the synovium where there is massive infiltration of inflammatory cells. An increased number of IL-17-producing cells are present in RA synovium and IL-17 in synovial fluid in high levels. The level of IL-17 is correlated with the level of IL-23 [1, 2, 3].

Gene transfer of IL-17A into the joint of collagen-induced arthritis (CIA) promoted arthritis and reproduced the key features of RA, such as massive inflammation, cartilage degradation, and bone erosion [4]. Properties of IL-17A are involved in many aspects of RA pathogenesis including activation of endothelial cells; stimulation of epithelial cells, macrophages, dendritic cells, and fibroblast-like synoviocytes to other inflammatory cytokines; activation of macrophages and dendritic cells to produce matrix metalloproteinases causing cartilage degradation; and stimulation of chondrocytes to produce nitric oxide and stimulation of expression RANKL by osteoblasts causing bone erosion [5]. The pathogenic role of IL-17 is confirmed by therapeutic effect of blocking IL-17 activity in arthritis models [6, 7].

Several lines of evidence support a critical role of the IL-23–IL-17 pathway in ankylosing spondylitis (AS). First, the loss of function of IL-23R R381Q gene mutation is associated with protection from AS because of impaired IL-17A production [8]. Conversely, IL-23R variants and other AS-associated genes with known effects on the IL-23 pathway are also identified to be strongly associated with AS [9]. Misfolded human leukocyte antigen (HLA)-B27 can generate endoplasmic reticulum stress that orchestrates the unfolded protein response leading to IL-23 production. Macrophages from AS produce increased levels of IL-23. The number of Th17 cells in AS peripheral blood is increased. Monocyte-derived dendritic cells (DC) from AS patients produce increased levels of IL-23 [10]. IL-23 is also overexpressed in AS spinal facet joints [11].

Spondyloarthritis in animal models of HLA-B27 transgenic rats is associated with CD4⁺ Th17 cells activation. Ankylosing enthesitis in (BXSBxNZB) F1 mice is associated in IL-17 production by T cells. IL-23 overexpression induces a spondyloarthritis-like disease in B10.RIII mice via RORγt⁺ CD3⁺ CD4⁻CD8⁻ T cells that produce IL-17 and IL-22 [12].

Psoriatic arthritis (PsA) is a chronic inflammatory and destructive arthritis associated with psoriasis (PsO). Evidence of IL-17/Th17 pathway association with PsO and PsA is from genetic studies on the presence of IL-17 in disease tissue and animal models. For instance, PsA is associated with single nucleotide polymorphisms (SNPs) in the genes encoding IL-23R and IL-23 [13, 14] and in the gene encoding Act1 (TRAF3IP2), the adaptor molecule of IL-17R [15]. These data suggest that the IL-23-mediated IL-17 axis has a central role in the pathogenesis of PsO and PsA. This notion is further supported by elevated expression of IL-23 and IL-23R and IL-17A and IL-17R in psoriatic skin and synovial fluid from patients with PsA [16–19]. In animal models, both IL-23 and IL-17A are shown to induce psoriasis-like skin inflammation. For instance, intradermal injection of IL-23, but not IL-12, induces epidermal hyperplasia with parakeratosis [20]. IL-23-induced psoriasis is IL-17A-dependent [21]. Imiquimod-induced psoriasis-like inflammation of skin exhibits increased expression of IL-23, IL-17A, and IL-17F. Furthermore, IL-17RA deficiency completely abolished the inflammation [22]. In humans with psoriasis, IL-17RA is highly expressed in both lesional and non-lesional skin keratinocytes. In lesional but not non-lesional skin, IL-17A is also overexpressed [23]. It has been shown that IL-17A stimulates keratinocyte expression of CCL20, CXCL1, CXCL2, CXCL3, CXCL5, and CXCL8 (IL-8), which induces recruitment of inflammatory cells including neutrophils into the site of inflammation [24]. CCL20 may directly recruit CCR6+ inflammatory cells including Th17 cells, thereby establishing a positive feedback loop for maintenance of skin inflammation [24].

Experimental autoimmune encephalomyelitis (EAE) is a mouse model of human multiple sclerosis (MS). EAE is commonly used to investigate into the pathogenesis of MS. The essential role of the IL-23 and IL-17/Th17 pathway in the pathogenesis of EAE has been clearly demonstrated in many studies [25, 26] (see above). Elevated levels of IL-23 in blood and cerebral spinal fluid (CSF) have been demonstrated in patients with MS [27, 28]. The elevated level of IL-23 is downregulated in patients treated with interferon-β, which correlates with clinical improvement suggesting the pathogenic role of IL-23. IL-17A levels are elevated in the blood and central nervous system (CNS) of MS patients, especially during relapse [29–31], and CNS Th17 cells are associated with active disease [32]. It was also shown that human Th17 cells are able to kill neurons and promote CNS inflammation [33].

Crohn’s disease is a chronic inflammatory bowel disease, which is also associated with extraintestinal manifestations such as peripheral arthritis and/or axial spondylitis. Genomic data have implicated the IL-23 and IL-17/Th17 pathway in /-17 axis in inflammatory bowel disease in general and Crohn’s disease in particular. SNPs in Il23r as well as in genes involved in IL-23 and IL-17 regulation have been reported in Crohn’s disease [34]. IL-17A-producing CD4⁺ Th17 cells are increased in both peripheral blood and lamina propria of Crohn’s disease [35]. However, conflicting results have been observed in Crohn’s disease when IL-23 is blocked or IL-17A and IL-17RA are blocked (see Chap. 5), that is, blockade of IL-23 is beneficial, while blocking IL-17 signaling either provides no benefit or is detrimental to Crohn’s disease [36–39].