Rheumatoid Arthritis: Moots RJ

Dawson LJ, Smith PM, Moots RJ, Field EA. · No affiliation provided · Rheumatology (Oxford). · Pubmed #10788529 links to  free full text

This publication has no abstract.

Barnes T, Moots RJ, Goodacre J. · Department of Rheumatology, Academic Rheumatology Unit, University of Liverpool, UK. · Cytokine. · Pubmed #16188452 No free full text.

Abstract: Cytokine medicines have been licensed for the treatment of rheumatoid arthritis since 2000. The rheumatology community has accrued a large amount of experience in the use of these medications. This experience has led to the development of guidelines for their use that include ongoing vigilance for long term adverse events and efficacy using the Biologics Register. Delivery of these expensive therapies has prompted extensive system developments within rheumatology. The cytokine medicines have provided important tools to probe the pathogenesis of rheumatoid and other inflammatory diseases. Further cytokine medicines, in various stages of development, are on the horizon and continue to stimulate excitement within this fast expanding field.

Kaushik VV, Moots RJ. · University of Liverpool Academic Rheumatology Unit, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool, L97AL, UK. · Expert Opin Biol Ther. · Pubmed #15934837 No free full text.

Abstract: The development of biological anti-TNF-alpha therapy has revolutionised the treatment of rheumatoid arthritis and other inflammatory diseases, and has identified a worldwide market for expensive yet effective therapies for chronic diseases. Certolizumab (CDP-870) is a new agent that employs a novel strategy to neutralise TNF-alpha--namely the prokaryotic expression of TNF-alpha-specific Fab antibody fragments, coupled to polyethylene glycol--to produce a drug that is potentially less expensive to manufacture than other anti-TNF-alpha agents and which may be administered by subcutaneous injection once a month. The background to the ongoing development of this new agent and its clinical effects are discussed in this article.

Mpofu S, Fatima F, Moots RJ. · Academic Rheumatology Unit, University of Liverpool, Clinical Sciences Center, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK. · Rheumatology (Oxford). · Pubmed #15561736 links to  free full text

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Cross A, Barnes T, Bucknall RC, Edwards SW, Moots RJ. · Department of Medicine, School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, UK. · J Leukoc Biol. · Pubmed #16793915 links to  free full text

Abstract: Neutrophils are normally short-lived cells and die by apoptosis, but when recruited into tissues, their apoptosis is delayed, and they survive for much longer time periods. In inflammatory diseases, such as rheumatoid arthritis (RA), this delayed apoptosis may lead to increased tissue damage and a failure of the inflammation to resolve. However, there are conflicting reports in the literature as to whether neutrophil apoptosis is delayed or accelerated in rheumatoid joints. In this report, we show that neutrophils isolated from the synovial fluid (SF) of patients with RA show accelerated rates of apoptosis when incubated ex vivo and that SF, despite containing a variety of antiapoptotic cytokines, is proapoptotic. Paradoxically, levels of the key neutrophil survival protein Mcl-1 are elevated in freshly isolated SF neutrophils compared with matched peripheral blood samples from the same patients, indicating that delayed neutrophil apoptosis has been signaled in vivo as the cells enter the joints. However, when SF was added to neutrophils and incubated under hypoxia (1% O(2)), conditions known to exist in vivo within joints, the SF was antiapoptotic. These data reveal that the rheumatoid synovial joint contains a complex mixture of pro- and antiapoptotic factors and that the low, local oxygen tensions that exist within these joints can exert profound effects on neutrophil survival. These experiments also highlight the importance of performing in vitro experiments under laboratory conditions that closely mimic those that occur in vivo; otherwise, misleading conclusions may be drawn.

Cross A, Bakstad D, Allen JC, Thomas L, Moots RJ, Edwards SW. · School of Biological Sciences, Biosciences Building, University of Liverpool, Liverpool L69 7ZB, UK. · Pathophysiology. · Pubmed #16112850 No free full text.

Abstract: There is now a growing awareness that infiltrating neutrophils play an important role in the molecular pathology of rheumatoid arthritis. In part, this arises from the fact that neutrophils have potent cytotoxic activity, but additionally from the fact that inflammatory neutrophils can generate a number of cytokines and chemokines that can have a direct influence on the progress of an inflammatory episode. Furthermore, the molecular properties of inflammatory neutrophils are quite different from those normally found in the circulation. For example, inflammatory neutrophils, but not blood neutrophils, can express cell surface receptors (such as MHC Class II molecules and FcgammaRI) that dramatically alter the way in which these cells can interact with ligands to modulate immune function. Cytokine/chemokine expression and surface expression of these novel cell surface receptors is dependent upon the neutrophil responding to local environmental factors to selectively up-regulate the expression of key cellular components via signalling pathways coupled to transcriptional activation. However, major changes in the expression levels of some proteins are also regulated by post-translational modifications that alter rates of proteolysis, and hence changes in the steady-state levels of these molecules.

Steele JC, Dawson LJ, Moots RJ, Field EA. · Department of Oral Medicine, University of Liverpool Dental Hospital & School, Pembroke Place, Liverpool, UK. · Oral Dis. · Pubmed #15888112 No free full text.

Abstract: Congenital heart block (CHB) has been linked with Sjögren's Syndrome. This paper reports a case of previously undiagnosed maternal Primary Sjögren's Syndrome (1 degrees SS) that was only discovered following the birth of the patient's first child with CHB. The possible pathophysiological mechanisms underlying CHB associated with 1 degrees SS are discussed.

Cross A, Edwards SW, Bucknall RC, Moots RJ. · Academic Rheumatology Unit, University of Liverpool, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK. · Arthritis Rheum. · Pubmed #15146412 links to  free full text

Abstract: OBJECTIVE: Neutrophils are known to express and release a large number of proinflammatory cytokines when they are stimulated by inflammatory stimuli. The objective of this study was to determine whether neutrophils express oncostatin M (OSM), a member of the interleukin-6 family of cytokines that has been implicated in the pathogenesis of inflammatory joint disease. METHODS: Neutrophils were isolated from the blood of healthy volunteer donors and from the blood and synovial fluid of patients with rheumatoid arthritis (RA). OSM levels were measured in cell extracts and in culture supernatants by Western blotting. Total RNA was isolated from control and granulocyte-macrophage colony-stimulating factor (GM-CSF)-treated neutrophils, and OSM messenger RNA levels were quantified by hybridization of a radiolabeled probe. RESULTS: GM-CSF stimulated a rapid and transient expression and release of OSM from blood neutrophils, which was more rapid than the expression and release from blood monocytes. A 28-kd protein was identified in cell extracts, but an additional 25-kd isoform was detected in culture supernatants. Synovial fluid neutrophils could not be stimulated to express OSM, but this cytokine was detected in cell-free supernatants at various levels. CONCLUSION: Blood neutrophils can be stimulated to express and rapidly release large quantities of OSM. We propose that this important cytokine is released from neutrophils as they infiltrate rheumatoid joints and, thus, contribute to the complex cytokine network that characterizes RA.

Cross A, Bucknall RC, Cassatella MA, Edwards SW, Moots RJ. · University of Liverpool, Liverpool, UK. · Arthritis Rheum. · Pubmed #14558085 links to  free full text

Abstract: OBJECTIVE: To investigate a potential interaction between neutrophils and T cells in rheumatoid arthritis (RA), by defining the optimal conditions for induction of class II major histocompatibility complex (MHC) expression on peripheral blood neutrophils in vitro and investigating the capacity for neutrophils to express class II MHC molecules in RA. METHODS: Surface expression of class II MHC and costimulatory molecules by peripheral blood and synovial fluid (SF) neutrophils obtained from healthy controls and patients with RA was measured by flow cytometry and fluorescence microscopy. Intracellular class II MHC protein and messenger RNA (mRNA) were detected by Western blotting and Northern blotting, respectively. RESULTS: Freshly isolated peripheral blood neutrophils from controls did not express surface class II MHC; expression was induced by culture with appropriate cytokines. Freshly isolated peripheral blood neutrophils from patients with RA expressed mRNA, but there was no surface expression of class II MHC. Freshly isolated SF neutrophils from patients with RA contained high levels of class II MHC mRNA, did not express surface class II MHC, but did have large intracellular amounts of this protein as detected by Western blotting. After culture for 20 hours in vitro, SF neutrophils from RA patients expressed large amounts of surface class II MHC but very low levels of costimulatory molecules CD80 and CD86. Fluorescence microscopy localized surface class II MHC to discrete areas on the neutrophil. Class II MHC-expressing neutrophils stimulated T cell proliferation. CONCLUSION: Peripheral blood neutrophils from patients with RA but not healthy controls express class II MHC mRNA. SF neutrophils in RA synthesize and express large amounts of class II MHC but not costimulatory molecules. This might underlie a novel interaction with T cells that is important in terms of disease pathology.

Pridgeon C, Lennon GP, Pazmany L, Thompson RN, Christmas SE, Moots RJ. · Academic Rheumatology Unit and Department of Immunology, University of Liverpool, UK. · Rheumatology (Oxford). · Pubmed #12730548 links to  free full text

Abstract: BACKGROUND: Natural killer (NK) cells play an important role in several animal models of autoimmunity by modulating T-cell responses, but it is unclear whether human NK cells have similar functions. METHODS: We characterized the phenotype of NK cells in synovial fluid (SF) and peripheral blood (PB) of patients with rheumatoid arthritis (RA) and in healthy control subjects using flow cytometry and quantitative PCR. RESULTS: The proportions of NK cells in PB and SF of RA patients were not significantly different from those in healthy PB. However, the SF NK cell phenotype was strikingly different, with increased CD94 and CD56 densities and greatly reduced proportions of cells expressing CD158a/b. These cells also had reduced mRNAs coding for CD158a/b and low perforin levels compared with RA PB and healthy PB NK cells. CONCLUSIONS: We identified a novel phenotype of SF NK cells that is of potential significance in RA. Experiments are now under way to determine the function of these SF NK cells and their potential role in RA.

Fossati G, Moots RJ, Bucknall RC, Edwards SW. · University of Liverpool, Liverpool, UK. · Arthritis Rheum. · Pubmed #12115243 links to  free full text

Abstract: OBJECTIVE: To determine the roles played by the neutrophil Fcgamma receptor type II (FcgammaRII) (CD32) and FcgammaRIIIb (CD16) in phagocytosis, bacterial killing, and activation by immune complexes (ICs) and to test the hypothesis that inhibition of pathologic effector neutrophil function is possible without compromising host defense. METHODS: Receptor function was probed by enzymic removal of FcgammaRIIIb from the cell surface and by use of Fab/F(ab')(2) fragments of monoclonal antibodies to block receptor-ligand binding. Cells were challenged with (a) serum-opsonized Staphylococcus aureus, (b) serum- and IgG-opsonized latex particles, and (c) synthetic soluble and insoluble ICs to mimic bacterial and inflammatory stimuli. RESULTS: Phosphatidylinositol-phospholipase C treatment removed >97% of surface FcgammaRIIIb from neutrophils previously treated with tumor necrosis factor alpha to mobilize intracellular stores of receptor. This treatment profoundly inhibited activation of primed neutrophils by soluble ICs of the type found in diseased rheumatoid joints, but had no effect on phagocytosis and killing of serum-opsonized S aureus. CONCLUSION: FcgammaRIIIb plays a major role in the secretion of toxic products in response to ICs, but little or no role in the phagocytosis and killing of serum-opsonized bacteria. The selective suppression of effector neutrophil function is therefore possible. FcgammaRIIIb, or its intracellular signaling pathway, is a potential therapeutic target in inflammatory diseases such as rheumatoid arthritis, because disruption of its function should decrease inflammatory tissue damage, but not jeopardize host protection against infection.

Moots RJ, Al-Saffar Z, Hutchinson D, Golding SP, Young SP, Bacon PA, McLaughlin PJ. · Rheumatology Research Group, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL. · Ann Rheum Dis. · Pubmed #10460194 links to  free full text

Abstract: OBJECTIVES: It was noted that treatment of a patient with acute mania by haloperidol was associated with marked improvement in activity of rheumatoid arthritis. The objective of this study was to examine the effects of haloperidol on inflammatory cytokine release in vitro, as a potential mechanism to explain the in vivo anti-inflammatory effects of haloperidol. METHODS: The effect of haloperidol on the production of inflammatory cytokines interleukin 1beta (IL1beta) and tumour necrosis factor alpha (TNFalpha) was measured in bacterial lipopolysaccharide stimulated whole blood cultures and on the promonocyte cell line THP-1, using commercial and in house enzyme linked immunosorbent assays to measure cytokine concentrations. RESULTS: Haloperidol inhibited lipopolysaccharide stimulated production of both IL1beta and TNFalpha in vitro in a dose dependent manner and over a prolonged time period. Marked inhibition was seen over a range of concentrations of haloperidol from 0.5 microgram/ml to 50 microgram/ml, including those predicted to occur in the patient's blood. CONCLUSIONS: Haloperidol treatment seemed to alleviate inflammation in rheumatoid arthritis. In vitro experiments would suggest that the mechanism is by direct inhibition of proinflammatory cytokine release. This phenomenon requires further investigation and may potentially lead to the development of novel treatment.

Chauhan S, Kamal A, Thompson RN, Estrach C, Moots RJ. · No affiliation provided · Br J Ophthalmol. · Pubmed #19553514 No free full text.

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Mpofu S, Kaushik VV, Grundy G, Moots RJ. · No affiliation provided · Rheumatology (Oxford). · Pubmed #15024150 links to  free full text

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Estrach C, Mpofu S, Thompson RN, Williams E, Abernethy VE, Moots RJ. · No affiliation provided · Arthritis Rheum. · Pubmed #14674016 links to  free full text

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Mpofu S, Moots RJ. · No affiliation provided · Ann Rheum Dis. · Pubmed #12634248 links to  free full text

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Hutchinson D, Lynch MP, Moots RJ, Thompson RN, Williams E. · No affiliation provided · Rheumatology (Oxford). · Pubmed #11561124 links to  free full text

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Hutchinson D, Moots RJ. · No affiliation provided · Ann Rheum Dis. · Pubmed #10836957 links to  free full text

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