Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

The Biology of Spondyloarthritis: Studies of the Host Immune Response in Experimental Chlamydia Infection and in Patients with Ankylosing Spondylitis.

Spondyloarthritis (SpA) refers to a family of related inflammatory diseases affecting axial and peripheral joints. Reactive arthritis (ReA) and ankylosing spondylitis (AS) are both subsets of SpA. Despite the important role of HLA-B27 in conferring risk for SpA, a multitude of environmental and other genetic factors contribute to these diseases. This thesis contains two distinct halves that examine unique aspects of the SpA family of disease. The general aim of this thesis is to better understand host immunity in the context of the SpA family of diseases. The first half, comprised of Chapters 1-5, examines immune alterations in patients with AS. The second half, comprised of Chapters 6-9, examines how macrophages control host immunity to the ReA-associated bacteria, Chlamydia. Each half contains a comprehensive literature review in addition to peer-reviewed, primary scientific publications. The thesis is tied off by chapter 10, which provides future directions and conclusions. AS, the most common subset of SpA and the subset with the strongest HLA-B27 link, typically affects males in young adulthood. The TNF-inhibitors (TNFi) have proven to be effective at controlling the symptoms of AS but are not curative. Genetic and immunological studies have implicated the Th17 axis of inflammation in the pathogenesis of AS. The first half of this thesis discusses potential non-canonical roles of HLA-B27, documents an abnormal expansion of T cells associated with prolonged TNFi use, details a male sex bias in the Th17-axis, and examines the role of novel factors in driving the Th17-axis in AS patients. ReA is triggered by a prior infection with bacteria such as Chlamydia. How Chlamydia infection causes sequelae like ReA is unknown as the basic biology of host-pathogen interactions is not well understood. The second half of this thesis dissects the interaction of Chlamydia with the host immune system, focusing on the specific role of the macrophage in murine models of infection. In conclusion, a better understanding of environmental and genetic factors that contribute to the chronic inflammation of SpA will aid in understanding and treating these common, disabling diseases.Ph.D

Crossing the boundaries : IL-23 and its role in linking inflammation of the skin, gut and joints

Several lines of evidence point towards the central role of interleukin 23 (IL-23) as a crucial inflammatory mediator in the pathogenesis of spondyloarthritis—a group of inflammatory arthritic diseases whose symptoms span the skin, gastrointestinal tract and joints. While therapeutic blockade of IL-23 proved successful in the treatment of inflammatory bowel disease, psoriatic skin disease and peripheral spondyloarthritis it failed in patients suffering from spondyloarthritis with predominantly axial involvement. Here we review state-of-the-art discoveries on IL-23 signalling pathways across target tissues involved in spondyloarthritis. We discuss the discrepancies in resident IL-23 responding cells and their downstream activities across skin, gut and joint that shape the unique immunological landscape of spondyloarthritis

From science to success? Targeting tyrosine kinase 2 in spondyloarthritis and related chronic inflammatory diseases

Spondyloarthritis (SpA) is a family of inflammatory arthritic diseases, which includes the prototypes of psoriatic arthritis and ankylosing spondylitis. SpA is commonly associated with systemic inflammatory diseases, such as psoriasis and inflammatory bowel disease. Immunological studies, murine models and the genetics of SpA all indicate a pathogenic role for the IL-23/IL-17 axis. Therapeutics targeting the IL-23/IL-17 pathway are successful at providing symptomatic relief, but may not provide complete protection against progression of arthritis. Thus there is still tremendous interest in the discovery of novel therapeutic targets for SpA. Tyrosine kinase 2 (TYK2) is a member of the Janus kinases, which mediate intracellular signaling of cytokines via signal transducer and activator of transcription (STAT) activation. TYK2 plays a crucial role in mediating IL-23 receptor signaling and STAT3 activation. A plethora of natural mutations in and around TYK2 have provided a wealth of data to associate this kinase with autoimmune/autoinflammatory diseases in humans. Induced and natural mutations in murine Tyk2 largely support human data; however, key inter-species differences exist, which means extrapolation of data from murine models to humans needs to be done with caution. Despite these reservations, novel selective TYK2 inhibitors are now proving successful in advanced clinical trials of inflammatory diseases. In this review, we will discuss TYK2 from basic biology to therapeutic targeting, with an emphasis on studies in SpA. Seminal studies uncovering the basic science of TYK2 have provided sound foundations for targeting it in SpA and related inflammatory diseases. TYK2 inhibitors may well be the next blockbuster therapeutic for SpA

The ties that bind : skin, gut and spondyloarthritis

Purpose of review: This article aims to review recent literature linking epithelial barrier inflammation and arthritis in spondyloarthritis (SpA), with a critical view on how they are bound by genetic, immunological and environmental ties. Recent findings The epithelia-joint axis has become an intense area of both basic and clinical SpA research. The penultimate goal is to understand the immunopathologic links between epithelial inflammation and arthritis in SpA. Inflammatory bowel disease (IBD) and psoriasis (PsO) have strong links to SpA at several levels. Clinically, there is a strong association of IBD, PsO and SpA. Genetically, there are many shared risk factors; however, there are also distinct differences in the genetics of the respective diseases. Immunologically, type 3 immunity, especially interleukin (IL)-17 and IL-23 dysregulation, has been shown to play a central role in IBD, PsO and SpA. Environmentally, a microbial dysbiosis has been noted in each of these diseases, but whether the microbial signature is similar between diseases is not clear, nor is the effect of dysbiosis on the immune response known. Summary: It will be crucial to determine whether the relationship between epithelia inflammation and SpA is truly causal for both the understanding of pathogenesis and for future treatment strategies

Intracellular Survival and Persistence of <i>Chlamydia muridarum</i> Is Determined by Macrophage Polarization

<div><p>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-<i>Chlamydia</i> interactions in the context of macrophage polarization. Here we use <i>Chlamydia muridarum</i> and murine bone-marrow derived macrophages to show <i>Chlamydia</i> 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 <i>Chlamydia</i>. 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 <i>16sRNA</i> in M2 macrophages with no change in M1 macrophages. Suppressed <i>Chlamydia</i> growth in M1 macrophages correlated with the induction of a bacterial gene expression profile typical of persistence as evident by increased <i>Euo</i> expression and decreased <i>Omp1</i> and <i>Tal</i> expression. Observations of permissive <i>Chlamydia</i> 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 <i>Chlamydia</i>. However, demonstration that the M1 macrophages, despite an antimicrobial signature, fail to eliminate intracellular <i>Chlamydia</i> 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.</p> </div

Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis

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 the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. 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.status: publishe

Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis

Mechanical loading is an important factor in the development of tendon and ligament disorders. In this Review, the authors discuss the evidence for the known role of mechanical loading in tendinopathy and its potential role in inflammatory arthritis. 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 the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. 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