This study reveals a potential role for MAIT cells in patients with AS and is the first linking IL-7 to the elevated IL-17 profile in patients through the AS-associated risk gene IL7R.

Over the past 5 years, advances in high-throughput techniques and studies involving large cohorts of patients have led to considerable advances in the identification of novel genetic associations and immune pathways involved in ankylosing spondylitis (AS). These discoveries include genes encoding cytokine receptors, transcription factors, signalling molecules and transport proteins. Although progress has been made in understanding the functions and potential pathogenic roles of some of these molecules, much work remains to be done to comprehend their complex interactions and therapeutic potential in AS. In this Review, we outline the current knowledge of AS pathogenesis, including genetic risk associations, HLA-B27-mediated pathology, perturbations in antigen-presentation pathways and the contribution of the type 3 immune response.

ObjectiveTo identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS).MethodsCohorts of male and female patients with AS and age‐ and sex‐matched healthy control subjects were selected, and the levels of serum cytokines (interferon‐γ [IFNγ], tumor necrosis factor α, interleukin‐17A [IL‐17A], and IL‐6) were examined by enzyme‐linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches.ResultsThe frequency of IL‐17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS‐associated alterations in the Th1 axis, such as the frequency of IFNγ and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex‐related immune profiles were independent of HLA–B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS.ConclusionThe results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex‐related differences in the clinical features of AS and could provide a rationale for sex‐specific treatment of AS.

Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and several mechanical stressrelated tendon and ligament disorders overlap anatomically with joints affected by chronic inflammatory arthritis. The role of mechanical stress in 'overuse' injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.

Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut-joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as α4β7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut-joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.

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Our findings indicate an unexplored pathogenic role of MIF in AS and a link between inflammation and new bone formation.

Macrophages can display a number of distinct phenotypes, known collectively as polarized macrophages. The best defined of these phenotypes are the classically-activated, interferon gamma (IFNγ)/LPS induced (M1) and alternatively-activated, IL-4 induced (M2) macrophages. The goal of this study is to characterize macrophage- Chlamydia interactions in the context of macrophage polarization. Here we use Chlamydia muridarum and murine bone-marrow derived macrophages to show Chlamydia does not induce M2 polarization in macrophages as a survival strategy. Unexpectedly, the infection of macrophages was silent with no upregulation of M1 macrophage-associated genes. We further demonstrate that macrophages polarized prior to infection have a differential capacity to control Chlamydia . M1 macrophages harbor up to 40-fold lower inclusion forming units (IFU) than non-polarized or M2 polarized macrophages. Gene expression analysis showed an increase in 16sRNA in M2 macrophages with no change in M1 macrophages. Suppressed Chlamydia growth in M1 macrophages correlated with the induction of a bacterial gene expression profile typical of persistence as evident by increased Euo expression and decreased Omp1 and Tal expression. Observations of permissive Chlamydia growth in non-polarized and M2 macrophages and persistence in M1 macrophages were supported through electron microscopy. This work supports the importance of IFNγ in the innate immune response to Chlamydia . However, demonstration that the M1 macrophages, despite an antimicrobial signature, fail to eliminate intracellular Chlamydia supports the notion that host–pathogen co-evolution has yielded a pathogen that can evade cellular defenses against this pathogen, and persist for prolonged periods of time in the host.