Innate Cells: The Alternative Source of IL-17 in Axial and Peripheral Spondyloarthritis?

Abstract

Spondyloarthritis (SpA) is a chronic inflammatory rheumatism characterized by inflammation of sacroiliac joints, peripheral joints, and spine. The Assessment of SpondyloArthritis Society describes three disease forms: axial (axSpA), peripheral, and enthesitic SpA. Each may be associated with extra-articular manifestations: psoriasis, inflammatory bowel disease, and acute anterior uveitis. Genome-wide association studies performed in axSpA and psoriatic arthritis (PsA) have shown a shared genetic background, especially the interleukin 23 (IL-23)/IL-17 pathway, which suggests pathophysiological similarities. The convincing positive results of clinical trials assessing the effect of secukinumab and ixekizumab (anti-IL-17A monoclonal antibodies) in axSpA and PsA have reinforced the speculated crucial role of IL-17 in SpA. Nevertheless, and obviously unexpectedly, the differential efficacy of anti-IL-23–targeted treatments between axSpA (failure) and PsA (success) has profoundly disrupted our presumed knowledge of disease pathogeny. The cells able to secrete IL-17, their dependence on IL-23, and their respective role according to the clinical form of the disease is at the heart of the current debate to potentially explain these observed differences in efficacy of IL-23/IL-17–targeted therapy. In fact, IL-17 secretion is usually mainly related to T helper 17 lymphocytes. Nevertheless, several innate immune cells express IL-23 receptor and can produce IL-17. To what extent these alternative cell populations can produce IL-17 independent of IL-23 and their respective involvement in axSpA and PsA are the crucial scientific questions in SpA. From this viewpoint, this is a nice example of a reverse path from bedside to bench, in which the results of therapeutic trials allow for reflecting more in depth on the pathophysiology of a disease. Here we provide an overview of each innate immunity-producing IL-17 cell subset and their respective role in disease pathogeny at the current level of our knowledge.

Clinical Phenotypes of Adult-Onset Still’s Disease: New Insights from Pathophysiology and Literature Findings

“…These cells play a particularly important role in the peripheral form of SpA and psoriatic arthritis. An increase of IL-17 in SJIA/AOSD has also been reported [1,16], while it is the determining cytokine in the axial form of SpA [36]. One could imagine that the "cytokine burst" during an SJIA/AOSD flare up could trigger, through an overexpression of these cytokines, a form of SpA, and could thus be considered more a shift than an overlap.…”

“…The main cytokines produced during SJIA/AOSD flares are IL-1β, IL-18 and IL-6 [1,35]. Along with IL-23, these cytokines participate in the differentiation of Th17 cells [36]. These cells play a particularly important role in the peripheral form of SpA and psoriatic arthritis.…”

“…Interestingly, if NUD shares common clinical and biological features with AOSD, the treatment may also be based on the same principle, with a notably very good response to anti-IL1 agents [59]. All these observations suggest a common pathophysiological background and pathways between AOSD and other inflammatory diseases, which need to be clarified: involvement of innate immune cells, especially neutrophils in AOSD [1,17], NUD [58,59] and SpA [37]; the central role of the NLRP3 inflammasome leading to caspase activation and overproduction of active IL-1β in AOSD, NUD and Schnitzler syndrome [1,17,59,60]; involvement of cytokines such as IL-18 and IL-6 in AOSD and Crohn's disease [1,16,17,61,62] or IL-17 in AOSD and SpA [1,36], etc. Figure 2 shows the continuum between AOSD and the other polygenic autoinflammatory disorders.…”

Specialized subsets of innate-like T cells and dendritic cells protect from lethal pneumococcal infection in the lung

“…Considering that the capacity for IL-17A synthesis is found in several types of innate or innate-like cells, including ILC3 (Cua and Tato, 2010; Rosine and Miceli-Richard, 2020) as well as T cells, there could be functional redundancy for these cell types. In agreement with a previous publication (Hassane et al, 2020), we found that lung γδ T cells were more numerous than iNKT cells, and a higher percentage of them produced IL-17A compared to iNKT cells after S. pneumoniae infection.…”

Using secukinumab in a patient with endplate inflammation complicated by hepatitis B virus infection

“…According to present studies, the activation of T helper 17 (Th17) lymphocytes and dendritic cells and the release of cytokines, such as IL-17 and tumor necrosis factor (TNF)-α, play important roles in the pathogenesis of both diseases. [ 1 , 2 ] The increased levels of inflammatory cytokines, such as IL-6, IL-1, IL-17, and TNF-α, in the intervertebral discs of patients with endplate inflammation suggest the significance of the inflammatory response in disease pathogenesis. [ 2 ] Among these key cytokines, IL-17 can mediate the migration and activation of immune cells and aggravate the inflammatory response.…”