Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells

Acute inflammation is a complex and tightly regulated homeostatic process that includes leukocyte migration from the vasculature into tissues to eliminate the pathogen/injury, followed by a pro-resolving response promoting tissue repair. However, if inflammation is uncontrolled as in chronic diseases such as Rheumatoid Arthritis (RA) it leads to tissue damage and disability. Synovial tissue inflammation in RA patients is maintained by sustained activation of multiple inflammatory positive-feedback regulatory pathways in a variety of cells including myeloid cells. In this review, we will highlight recent evidence uncovering biological mechanisms contributing to the aberrant activation of myeloid cells that contributes to perpetuation of inflammation in RA, and discuss emerging data on anti-inflammatory mediators contributing to sustained remission that may inform a novel category of therapeutic targets

Synovial tissue macrophages: friend or foe?

Healthy synovial tissue includes a lining layer of synovial fibroblasts and macrophages. The influx of leucocytes during active rheumatoid arthritis (RA) includes monocytes that differentiate locally into proinflammatory macrophages, and these produce pathogenic tumour necrosis factor. During sustained remission, the synovial tissue macrophage numbers recede to normal. The constitutive presence of tissue macrophages in the lining layer of the synovial membrane in healthy donors and in patients with RA during remission suggests that this macrophage population may have a role in maintaining and reinstating synovial tissue homeostasis respectively. Recent appreciation of the different origins and functions of tissue-resident compared with monocyte-derived macrophages has improved the understanding of their relative involvement in organ homeostasis in mouse models of disease. In this review, informed by mouse models and human data, we describe the presence of different functional subpopulations of human synovial tissue macrophages and discuss their distinct contribution to joint homeostasis and chronic inflammation in RA

Targeted delivery of anti-inflammatory therapy to rheumatoid tissue by fusion proteins containing an IL-4-linked synovial targeting peptide

We provide first-time evidence that the synovial endothelium-targeting peptide (SyETP) CKSTHDRLC successfully delivers conjugated IL-4 to human rheumatoid synovium transplanted into SCID mice. SyETP, previously isolated by in vivo phage display and shown to preferentially localize to synovial xenografts, was linked by recombinant technology to hIL-4 via an MMP-cleavable sequence. Both IL-4 and the MMP-cleavable sequence were shown to be functional. IL-4-SyETP augmented production of IL-1ra by synoviocytes stimulated with IL-1[beta] in a dose-dependent manner. In vivo imaging confirmed increased retention of SyETP-linked-IL-4 in synovial grafts which was enhanced by increasing number of copies (one to three) in the constructs. Strikingly, SyETP delivered bioactive IL-4 in vivo as demonstrated by increased pSTAT6 in synovial grafts. Thus, this study provides proof of concept for peptide-tissue-specific targeted immunotherapy in rheumatoid arthritis. This technology is potentially applicable to other biological therapies providing enhanced potency to inflammatory sites and reducing systemic toxicity

Expression of interleukin-1 and interleukin-1 receptor antagonist by human rheumatoid synovial tissue macrophages

Interleukin-1 (IL-1) has protean effects in the pathogenesis of rheumatoid arthritis (RA). These effects include production of prostaglandins and collagenase from rheumatoid fibroblasts as well as upregulation of adhesion molecule expression on these cells. IL-1 can activate monocytes and neutrophils, as well as promote the growth of fibroblasts and endothelial cells. Recently, a novel interleukin-1 receptor antagonist protein (IRAP) has been isolated, purified, cloned, and expressed, which may modulate the effects of IL-1. In this study, we present data demonstrating that macrophages isolated from human RA synovial tissues express both IL-1 and IRAP genes. In addition, RA synovial tissue macrophages and lining cells display IL-1 and IRAP antigenic expression by immunohistochemistry. In contrast, osteoarthritis synovial tissues, as compared to RA, have fewer IL-1 and IRAP-positive macrophages. Thus, the production of IL-1 balanced by IRAP may affect the joint destruction found in these diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29796/1/0000142.pd

IL-1β at the crossroad between rheumatoid arthritis and type 2 diabetes: may we kill two birds with one stone?

Although in the past the prevention of joint destruction in rheumatoid arthritis (RA) was strongly emphasized, now a great interest is focused on associated comorbidities in these patients. Multiple data suggest that a large percentage of RA patients are affected by Type 2 Diabetes (T2D), whose incidence has reached epidemic levels in recent years, thus increasing the health care costs. A better knowledge about the pathogenesis of these diseases as well as the mechanisms of action of drugs may allow both policy designers and physicians to choose the most effective treatments, thus lowering the costs. This review will focus on the role of Interleukin (IL)-1β in the pathogenesis of both the diseases, the efficacy of IL-1 blocking molecules in controlling these diseases, and will provide information suggesting that targeting IL-1β, in patients affected by both RA and T2D, may be a promising therapeutic choice

The pivotal role of interleukin-1 in the clinical manifestations of rheumatoid arthritis

The role of the cytokine network in mediating inflammation and joint destruction in rheumatoid arthritis (RA) has been investigated extensively in recent years. Interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFα) are two pivotal proinflammatory cytokines that have been shown to contribute to the clinical manifestations of RA. The ability of IL-1 to drive inflammation and joint erosion and to inhibit tissue repair processes has been clearly established in in vitro systems and animal models. Under physiological conditions, the activity of IL-1 is balanced by IL-1 receptor antagonist (IL-1Ra). Understanding of the respective roles of IL-1 and IL-1Ra in conditions of health and disease has led to the development of a recombinant IL-1ra, anakinra (Kineret®; Amgen Inc., Thousand Oaks, CA), which offers a new therapeutic modality for R

Pathogenesis of polymyalgia rheumatica

Polymyalgia rheumatica (PMR) is a chronic, inflammatory disorder of unknown cause, almost exclusively occurring in people aged over 50 and often associated with giant cell arteritis. The evidence that PMR occurs almost exclusively in individuals aged over 50 may indicate that age-related immune alterations in genetically predisposed subjects contribute to development of the disease. Several infectious agents have been investigated as possible triggers of PMR even though the results are inconclusive. Activation of the innate and adaptive immune systems has been proved in PMR patients as demonstrated by the activation of dendritic cells and monocytes/macrophages and the altered balance between Th17 and Treg cells. Disturbed B cell distribution and function have been also demonstrated in PMR patients suggesting a pathogenesis more complex than previously imagined. In this review we will discuss the recent findings regarding the pathogenesis of PMR

Evolving clinical profile of IL-1β, IL-10 and CTLA-4 gene in rheumatoid factor positive Caucasian population

Rheumatoid arthritis (RA), a systemic autoimmune condition, causes joint damage and sometimes extra-articular lesions (cutaneous vasculitis, neuropathy, Felty’s syndrome, pericarditis, intersticial lung disease) that may be life threatening. The reason why extra-articular features will develop in rare RA patients is unknown. Our study was aimed to find any disease correlation with respect to a few genetic loci implicated in rheumatoid arthritis. In our study no significant association was observed for Il-1β and IL-10. However CTLA-4 showed polymorphism in RA and controls. In our earlier article we reported polymorphism of HLA-DRB1 in Caucasian population. The study was conducted on 60 patients, where 30 were control and 30 were diseased. All the patients selected for the study were Rf (rheumatoid factor) positive. Therefore the studies need to be conducted on larger group of patients, so that the association can be verified in Caucasian population (Indian scenario)