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STEP INTO THE FIRST AXSPA EXHIBIT

Explore the pathobiology of axSpA

The chronic inflammatory pathogenesis of axSpA is complex, multifactorial, and arises from external factors

…that involve multiple adaptive and innate immune cells and pro-inflammatory cytokines.1-3

The pathologic processes leading to axSpA

The pathologic processes leading to axSpA are not yet completely understood. However, recent studies have revealed insights into the pathways responsible for initiating and maintaining inflammation leading to various clinical manifestations, and some of the key adaptive and innate immune cells and cytokines involved.1,3-7

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The role of cytokines in driving inflammation

The latest evidence shows that several different cytokines, including IL-17A, IL-17F, TNF, IL-12, IL-23, as well as direct or indirect involvement of the JAK/STAT pathway, have distinct roles in driving inflammation in different tissues in SpA. Although the relative contributions of each are complex, important distinctions are emerging about which cytokines contribute to various clinical manifestations and SpA disease phenotypes.3-5,7,8

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IL-17 family

The IL-17 cytokine family consists of six members that include IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F.9,13

IL-17A and IL-17F share ~50% structural homology and have a similar pro-inflammatory function, signaling via the same receptor complex.12 IL-17A and IL-17F exist as both homo- and heterodimers, meaning three cytokines exist (IL-17A/A, IL-17A/F, and IL-17F/F), all of which have been shown to contribute to inflammation in axSpA.12,14

There are 5 members of the IL-17 receptor family. Two IL-17 receptors (IL-17RC and IL-17RA) are thought to act in concert to mediate signaling by IL-17A/A, IL-17F/F, and IL-17A/F.11,13

Studies have shown that IL-17A and IL-17F cooperate with other mediators of inflammation, such as TNF, to amplify inflammatory responses.12 The contribution of IL-17A and IL-17F to pathological bone formation has been shown in a human periosteum-derived stem cell model of osteogenic differentiation, indicating the importance of IL-17A and IL-17F in bone pathogenesis.10

The IL-17A and IL-17F
Receptor Complex

Evidence suggests IL-17 is regulated by IL-23-dependent and IL-23-independent pathways in axSpA

The IL-17 Family in axSpA

The IL-23–IL-17 axis process

IL-23 is responsible for promoting the expansion and survival of Th17 subsets, including the production of IL-17A and IL-17F from Th17 cells. This process is commonly referred to as the IL-23–IL-17 axis, and has been implicated in several inflammatory diseases, including axSpA.13,14,18,19

Recent evidence suggests that the IL-23–IL-17 axis is not a linear “cascade” in axSpA. IL-23 and IL-17 display partially overlapping but distinct biology and pathobiology.20 Although the IL-23–IL-17 adaptive immunity pathway is still thought to play a role in driving inflammation in axSpA, cells of the innate immune system can also produce IL-17A and IL-17F independently of IL-23.18,20 This aspect of the pathobiology of axSpA may be distinct from PsA, where the IL-23–IL-17 axis still appears to play an integral role in disease.4,19-21

The role of IL-23 in the pathobiology of axSpA is unclear, as clinical trials of biologics blocking this cytokine have failed.

IL-23

An important upstream regulator of IL-1713,20

IL-23 is a member of the IL-12 superfamily and is a heterodimer consisting of both a p40 and p19 chain.13,20 It is an important cytokine involved in the pathogenesis of several immune-mediated inflammatory diseases, including psoriasis, PsA, axSpA, and IBD.20 However, its interaction with different cells and downstream cytokine pathways may be different across diseases.20

Some evidence shows that IL-23 can migrate from barrier sites such as the gut and skin, where dendritic cells have been activated, and travel to sites of disease pathogenesis in axSpA, although this needs to be further explored.20 A key pro-inflammatory role of IL-23 is stimulation of Th17 cells to produce IL-17, IL-22, and TNF, which leads to inflammation, bone formation, and bone erosion.4,13,20

Historically, the IL-23–IL-17 axis has been deemed a central component driving pathological bone formation in SpA diseases, but as evidence evolves, it’s becoming clear that the pathological processes leading to bone loss or formation may vary at different bone sites and across different disease types.4,20

IL-23 in axSpA

IL-12

Role of IL-12 in axSpA

IL-12 is a pro-inflammatory cytokine composed of two subunits (p35 and p40), resulting in an active heterodimer p70.24 Produced by innate immune cells, it induces naïve T cell differentiation into IFN-gamma producing Th1 cells and prevents T cell exhaustion.24,25

IL-12 and IL-23 activity are tightly linked. Both of these inflammatory cytokines share the p40 subunit and a receptor chain (IL-12R1), which controls distinct IL-12 and IL-23 signaling pathways.24

In axSpA, over-activation of IL-12 and IL-23 increases the number of circulating Th1 and Th17 cells. This activates signaling from cytokines and proteins, which promotes monocyte differentiation into osteoclasts and contributes to sacroiliac and peripheral joint damage.1,26,27

The role of IL-12 in the pathobiology of axSpA is unclear, as axSpA clinical trials of biologics blocking this cytokine have failed.

IL-12 Pathways in axSpA

TNF

TNF signaling plays a role in the pathogenic processes in axSpA

The TNF superfamily (TNFSF) consists of 19 structurally related pleotropic cytokines.29,30 TNFSF proteins are key drivers of inflammation and play roles in the mediation of apoptosis, angiogenesis, cell proliferation, and other critical biologic functions.29

TNF-α exists in transmembrane and soluble forms and is mostly created by T-cells, NK cells, and macrophages.31 TNF-α cellular signaling occurs through two receptors—TNF-receptor1 (TNFR1) and TNFR2—which have differing mechanisms of cellular signaling, ligand affinity, and patterns of expression.32,33 TNFR1 is the dominant receptor involved in inflammatory and innate immune responses.28

TNF-mediated pro-inflammatory TNFR1 signals can increase catabolic bone resorption in the spine by means of osteoclast formation and matrix metalloproteinase production, causing bone erosion.28 Furthermore, TNFR1 and TNFR2 signaling (with other cytokine involvement) can lead to pathogenic bone formation indicative of spinal fusion through increased osteoblast activity.28

In axSpA, TNF-mediated signaling plays an important role in disease progression.

Activated dendritic cells can secrete TNF-α, which leads to increased T-cell signaling and Th cell differentiation.30 Elevated levels of TNF can be found in the synovium and other locations on the body such as the sera and aqueous humor of patients with anterior uveitis.34

In axSpA, TNF can synergize with IL-17 and IL-23 pathways.

  • IL-23 stimulates Th17 cell differentiation, which leads to the production of cytokines such as IL-17 and causes further upregulation of TNF.1
  • IL-17 can combine with TNF, leading to stronger pro-inflammatory cytokine expression (e.g., IL-6 and IL-8) than either cytokine can enact alone.35

TNF=tumor necrosis factor.

TNF in axSpA

JAK-STAT

JAK-STAT pathways may play an important role in the pathogenesis of axSpA

JAK molecules are a group of intracellular tyrosine kinases, comprising four isoforms: JAK1, JAK2, JAK3, and tyrosine kinase (TYK) 2.37 These groups are coupled to signal transducer and activator of transcription (STAT) molecules.5 Many immune cells and effector molecules use different combinations of JAK and STAT molecules to convert signals from the cell surface to the nucleus, where they activate transcription and induce gene activation. This downstream gene activation has a role in regulating different biological processes, including the activation of pathological pathways in axSpA.5,36,38 Many SpA-associated cytokines are mediated either directly or indirectly via JAK-STAT pathways.36

JAK=Janus kinase.

JAK-STAT Pathways in axSpA

Take your seats in the Animated Science Theatre

Uncover the mechanisms driving axSpA, including the role of IL-17A and IL-17F

Discover how several different cytokines have distinct roles in driving inflammation in PsA

Gaze upon the PsA Gallery of Cytokines

NEXT ROOM IN THE PATHOBIOLOGY EXHIBIT

Immune dysregulation

Explore how cytokine dysregulation drives inflammation in axSpA.

Continue axSpA tour

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