Showing papers by "Peter C. Taylor published in 2005"

Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis.

Abstract: Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis (RA), but little is understood about their citrullinated target antigens. We have detected a candidate citrullinated protein by immunoblotting lysates of monocytic and granulocytic HL-60 cells treated with peptidylarginine deiminase. In an initial screen of serum samples from four patients with RA and one control, a protein of molecular mass 47 kDa from monocytic HL-60s reacted with sera from the patients, but not with the serum from the control. Only the citrullinated form of the protein was recognised. The antigen was identified by tandem mass spectrometry as α-enolase, and the positions of nine citrulline residues in the sequence were determined. Serum samples from 52 patients with RA and 40 healthy controls were tested for presence of antibodies against citrullinated and non-citrullinated α-enolase by immunoblotting of the purified antigens. Twenty-four sera from patients with RA (46%) reacted with citrullinated α-enolase, of which seven (13%) also recognised the non-citrullinated protein. Six samples from the controls (15%) reacted with both forms. α-Enolase was detected in the RA joint, where it co-localised with citrullinated proteins. The presence of antibody together with expression of antigen within the joint implicates citrullinated α-enolase as a candidate autoantigen that could drive the chronic inflammatory response in RA.

Hypoxia and angiogenesis in rheumatoid arthritis.

Abstract: Purpose of reviewAngiogenesis is a prominent feature of rheumatoid synovitis. Although new blood vessels deliver oxygen to the augmented inflammatory cell mass, the neovascular network is dysfunctional and fails to restore tissue oxygen homeostasis, so that the rheumatoid joint remains a markedly hy

Serum vascular markers and vascular imaging in assessment of rheumatoid arthritis disease activity and response to therapy

Abstract: Vascular pathology, in the form of angiogenesis, is important in the perpetuation of rheumatoid arthritis (RA) and, in the form of endothelial dysfunction, contributes to associated cardiovascular co-morbidity. Emerging evidence suggests that TNFa blockade may modify vascular pathology in RA. Serum concentrations of vascular endothelial growth factor (VEGF), a potent endothelial cell-specific growth factor that is up-regulated by pro-inflammatory cytokines and by hypoxia, are elevated in RA and correlate with disease activity. Serum levels of VEGF at first presentation in RA predict radiographic progression of the disease over the subsequent year. Power Doppler ultrasonography is a sensitive method for demonstrating the presence of blood flow in small vessels and the vascular signal correlates with histopathological quantification of the vascular density of synovial tissue. Recent data indicate that high-frequency ultrasound and power Doppler are sensitive tools for evaluation of disease activity and assessment of response to therapy. Power Doppler imaging may also have the potential to predict those patients most at risk of accelerated joint destruction. However, much work has yet to be done to standardize the use of these imaging technologies.

Molecular therapeutic targets in rheumatoid arthritis

Abstract: In an attempt to combat the pain and damage generated by rheumatoid arthritis (ra), new drugs are being developed to target molecular aspects of the disease process. Recently, a major development has been the use of biologicals (antibodies and soluble receptors) that neutralise the activity of tumour necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1), both of which are involved in disease progression. An increase in our understanding of cell and molecular biology has resulted in the identification and investigation of potential new targets, and also the refinement and improvement of current therapeutic modalities. This review describes therapies that are approved, in clinical trials or under pre-clinical investigation at the laboratory level, particularly focusing on cytokines, although other therapeutic targets of interest are mentioned.

Lymphocytes treated by extracorporeal photopheresis can down-regulate cytokine production in untreated monocytes.

Abstract: BACKGROUND Pro-inflammatory cytokines are actively involved in graft-versus host-disease (GvHD) aetiology. Treatment of GvHD, using extracorporeal photopheresis (ECP), has demonstrated clinical efficacy. ECP rapidly reduces the number of T cells that produce tumour necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma) and interleukin (IL)2. ECP-treated cells are re-infused immediately after completion of treatment. This study attempted to determine the influence that ECP-treated cells would have on untreated cells following re-infusion. METHODS Heparinized samples were taken from 10 chronic GvHD patients, pre-ECP and immediately prior to re-infusion (post-ECP). Lymphocytes and monocytes were isolated using magnetic separation. The post-ECP lymphocytes were mixed with pre-ECP monocytes, while the post-ECP monocytes and pre-ECP lymphocytes were combined. After suitable stimulation, the T cells were tested for intracellular TNFalpha, IFNgamma and IL2, while the monocytes were evaluated for TNFalpha, IL1alpha, IL1beta, IL6 and IL8. RESULTS Although cytokine secretion is decreased in T cells exposed to ECP, pre-ECP T cells were unaffected by post-ECP monocytes. Post-ECP monocytes demonstrated a reduction in cytokine secretion. Furthermore, untreated monocytes down-regulated cytokine production following exposure to ECP-treated lymphocytes. CONCLUSION ECP has both a direct and indirect immunosuppressive action, both of which may be beneficial in the treatment of GvHD.

Citrullinated α enolase, a novel citrullinated autoantigen in rheumatoid arthritis, upregulated by chronic inflammation

Abstract: Antibodies to citrullinated proteins are the most specific serological marker for rheumatoid arthritis (RA). They are associated with severity of disease and may occur years before clinical manifestations. It is unclear whether antibodies to citrullinated proteins react with any citrullinated protein or whether there are specific citrullinated proteins driving the autoimmune response. In this study we use the HL60 cell line as a substrate for identifying autoantigens in myelomonocytic cells, the major cell type present in the rheumatoid joint.

Chapter 42 – Autoimmunity – Rheumatoid Arthritis

Abstract: This chapter discusses autoimmunity in rheumatoid arthritis (RA). The clinical presentation of RA is heterogeneous with a wide spectrum of age of onset, degree of joint involvement, and severity. Although the cause of RA remains unknown, advances in molecular technology have facilitated identification of cell subsets and cytokines contributing to the inflammatory and destructive components of the disease. The majority of biologic markers of potential value in the diagnosis and assessment of outcome in RA are measured in peripheral blood or urine. Although, in general, cytokines and immune cell subsets within the peripheral blood compartment are not measured clinically they are considered to be important in the pathogenesis of RA. In terms of RA diagnosis, rheumatoid factors remain the sole serological measure included in the widely used American College of Rheumatology classification criteria for RA. However, there is currently increasing interest in the measurement of antibodies to cyclic citrullinated peptides (anti-CCP) as a more specific marker of RA. The chapter discusses principles behind the measurement of biologic markers and the markers under investigation in the diagnosis and assessment of outcome in RA.