29 results found
Page TH, Chiappo D, Brunini F, et al., 2021, Danger-associated molecular pattern molecules and the receptor for advanced glycation end products enhance ANCA-induced responses, RHEUMATOLOGY, Vol: 61, Pages: 834-845, ISSN: 1462-0324
Page T, Brunini F, Caparros JG, et al., 2019, 210. The calprotectin/rage/ TLR4 axis in anca-associated vasculitis, Rheumatology, Vol: 58, Pages: ii91-ii91, ISSN: 1462-0324
Kraaij T, Kamerling SWA, van Dam LS, et al., 2018, Excessive neutrophil extracellular trap formation in ANCA-associated vasculitis is independent of ANCA, Kidney International, Vol: 94, Pages: 139-149, ISSN: 0085-2538
Neutrophil extracellular traps (NETs) are auto-antigenic strands of extracellular DNA covered with myeloperoxidase (MPO) and proteinase3 (PR3) that can be a source for the formation of anti-neutrophil cytoplasmic autoantibodies (ANCAs). The presence of NETs was recently demonstrated in renal tissue of patients with ANCA-associated vasculitis (AAV). NET formation was enhanced in AAV, suggesting that MPO-ANCA could trigger NET formation, supporting a vicious circle placing NETs in the center of AAV pathogenesis. Here we investigated NET formation in 99 patients with AAV by a novel highly sensitive and automated assay. There was a significant excess of ex vivo NET formation in both MPO-ANCA- and PR3-ANCA-positive patients with AAV compared to healthy individuals. Excessive NET formation did not correlate with serum ANCA levels. Likewise, immunoglobulin G depletion had no effect on excessive NET formation in patients with AAV, indicating an ANCA-independent process. Next, we explored the relation of excessive NET formation to clinical disease in ten patients with AAV and showed that excessive NET formation was predominantly found during active disease, more so than during remission. Excessive NET formation was found in patients with AAV hospitalized for disease relapse but not during severe infection. Thus, excessive NET formation in AAV is independent of ANCA, and an excess of ex vivo NET formation was related to active clinical disease in patients with AAV and a marker of autoimmunity rather than infection.
Page TH, Urbaniak AM, Espirito Santo AI, et al., 2018, Bruton's tyrosine kinase regulates TLR7/8-induced TNF transcription via nuclear factor-κB recruitment, Biochemical and Biophysical Research Communications, Vol: 499, Pages: 260-266, ISSN: 0006-291X
Tumour necrosis factor (TNF) is produced by primary human macrophages in response to stimulation by exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) via Toll-like receptor (TLR) signalling. However, uncontrolled TNF production can be deleterious and hence it is tightly controlled at multiple stages. We have previously shown that Bruton's tyrosine kinase (Btk) regulates TLR4-induced TNF production via p38 MAP Kinase by stabilising TNF messenger RNA. Using both gene over-expression and siRNA-mediated knockdown we have examined the role of Btk in TLR7/8 mediated TNF production. Our data shows that Btk acts in the TLR7/8 pathway and mediates Ser-536 phosphorylation of p65 RelA and subsequent nuclear entry in primary human macrophages. These data show an important role for Btk in TLR7/8 mediated TNF production and reveal distinct differences for Btk in TLR4 versus TLR7/8 signalling.
Brunini F, Cao JJL, Dudhiya F, et al., 2017, ANCA-ASSOCIATED VASCULITIS PATIENTS EXHIBIT REDUCED SERUM LEVELS OF SOLUBLE RAGE (SRAGE), Rheumatology, Vol: 56, Pages: 118-118, ISSN: 1462-0324
Brunini F, Page TH, Gallieni M, et al., 2016, The role of monocytes in ANCA-associated vasculitides, Autoimmunity Reviews, Vol: 15, Pages: 1046-1053, ISSN: 1873-0183
The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of diseases causing inflammation in small blood vessels and linked by the presence of circulating ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). These antigens are present both in the cytoplasmic granules and on the surface of neutrophils, and the effect of ANCA on neutrophil biology has been extensively studied. In contrast, less attention has been paid to the role of monocytes in AAV. These cells contain PR3 and MPO in lysosomes and can also express them at the cell surface. Monocytes respond to ANCA by producing pro-inflammatory and chemotactic cytokines, reactive-oxygen-species and by up-regulating CD14. Moreover, soluble and cell surface markers of monocyte activation are raised in AAV patients, suggesting an activated phenotype that may persist even during disease remission. The presence of monocyte-derived macrophages and giant cells within damaged renal and vascular tissue in AAV also attests to their role in pathogenesis. In particular, their presence in the tertiary lymphoid organ-like granulomas of AAV patients may generate an environment predisposed to maintaining autoimmunity. Here we discuss the evidence for a pathogenic role of monocytes in AAV, their role in granuloma formation and tissue damage, and their potential to both direct and maintain autoimmunity. ANCA-activation of monocytes may therefore provide an explanation for the relapsing–remitting course of disease and its links with infections. Monocytes may thus represent a promising target for the treatment of this group of life-threatening diseases.
McAdoo SP, Bhangal G, Page T, et al., 2015, Correlation of disease activity in proliferative glomerulonephritis with glomerular spleen tyrosine kinase expression, Kidney International, Vol: 88, Pages: 52-60, ISSN: 0085-2538
Spleen tyrosine kinase (SYK) is an important component of the intracellular signaling pathway for various immunoreceptors. Inhibition of SYK has shown promise in preclinical models of autoimmune and glomerular disease. However, the description of SYK expression in human renal tissue, which would be desirable ahead of clinical studies, is lacking. Here we conducted immunohistochemical analysis for total and phosphorylated SYK in biopsy specimens from >120 patients with a spectrum of renal pathologies, including thin basement membrane lesion, minimal change disease, membranous nephropathy, IgA nephropathy, lupus nephritis, ANCA-associated glomerulonephritis, antiglomerular basement membrane disease, and acute tubular necrosis. We found significant SYK expression in proliferative glomerulonephritis and that glomerular expression levels correlated with presenting serum creatinine and histological features of disease activity that predict outcome in IgA nephropathy, lupus nephritis, ANCA-associated glomerulonephritis, and antiglomerular basement membrane disease. SYK was phosphorylated within pathological lesions, such as areas of extracapillary and endocapillary proliferation, and appeared to localize to both infiltrating leucocytes and to resident renal cells within diseased glomeruli. Thus SYK is associated with the pathogenesis of proliferative glomerulonephritides, suggesting that these conditions may respond to SYK inhibitor treatment.
Tarzi RM, Liu J, Schneiter S, et al., 2015, CD14 expression is increased on monocytes in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis and correlates with the expression of ANCA autoantigens, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 181, Pages: 65-75, ISSN: 0009-9104
Page TH, Charles PJ, Piccinini AM, et al., 2012, Raised circulating tenascin-C in rheumatoid arthritis, Arthritis Research and Therapy, Vol: 14, Pages: R260-R260, ISSN: 1478-6354
INTRODUCTION: The aim of this study was to examine whether circulating levels of the pro-inflammatory glycoprotein tenascin-C (TNC) are elevated in musculoskeletal disorders including rheumatoid arthritis (RA) and to assess in RA whether levels are related to clinical disease status and/or patient response to treatment. METHODS: TNC in serum or plasma was quantified by ELISA. Samples from 4 cohorts of RA patients were examined and compared to normal human subjects and to patients with other inflammatory diseases. RESULTS: Circulating TNC levels were significantly raised in patients with RA, as well as patients with systemic lupus erythematosus, idiopathic inflammatory myositis, psoriatic arthritis and ankylosing spondylitis, whilst patients with Sjogren's syndrome displayed levels similar to healthy controls. The highest levels of TNC were observed in RA patients with late stage disease. In early disease TNC levels correlated positively with ultrasound determined erosion scores. Treatment of early RA patients with infliximab plus methotrexate (MTX) resulted in a transient decrease in circulating TNC over the first year of therapy. In contrast, TNC levels increased over time in RA patients receiving MTX alone. In patients treated with infliximab plus MTX, baseline TNC levels significantly correlated with tender joint counts (TJC) at 18 and 54 weeks after initiation of infliximab therapy. CONCLUSIONS: Raised circulating TNC levels are detected in specific inflammatory diseases. Levels are especially high in RA where they may act as a biomarker of bone erosion and a predictor of the effect of infliximab on RA patient joint pain.
Page TH, D'Souza Z, Nakanishi S, et al., 2012, Role of Novel Rat-specific Fc Receptor in Macrophage Activation Associated with Crescentic Glomerulonephritis, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 5710-5719
Page TH, Midwood KS, 2012, Targeting DAMP Activation of Toll-Like Receptors: Novel Pathways to Treat Rheumatoid Arthritis?, Rheumatoid Arthritis - Treatment, Publisher: InTech, Pages: 211-232, ISBN: 978-953-307-850-2
Smolinska MJ, Page TH, Urbaniak AM, et al., 2011, Hck tyrosine kinase regulates TLR4-induced TNF and IL-6 production via AP-1., J Immunol, Vol: 187, Pages: 6043-6051
The TLRs play a key role in host defense against infection and injury, and mounting evidence suggests that these receptors may also play a role in diseases such autoimmunity, atherosclerosis, and cancer. Activation of TLRs on macrophages results in the production of multiple soluble mediators including the key inflammatory cytokines, TNF and IL-6. Thus, the intracellular signaling mechanism by which TLRs signal is a subject of great interest. As well as activating the NF-κB and MAPK pathways, TLR engagement leads to tyrosine kinase activation within minutes. Src family kinases (SFKs) are the largest nonreceptor tyrosine kinase family with nine members: Src, Hck, Lyn, Fyn, Fgr, Blk, Lck, Yes, and Ylk. The role of the SFKs in TLR signaling has been an area of much controversy, with conflicting findings between studies using chemical inhibitors and knockout mice. Using primary human macrophages in combination with adenoviral overexpression and small interfering RNA knockdown studies, we show that the SFK, Hck, has a pre-eminent role in LPS/TLR4-induced TNF and IL-6 production. Hck kinase mediates TLR4-induced transcription of both TNF and IL-6 by a mechanism that involves neither the NF-κB nor the MAPK pathways, but rather leads to AP-1 binding with a complex of c-fos and JunD. These data highlight the importance of Hck as an active component in LPS-induced TLR signaling and suggest the possibility of targeting this kinase for the alleviation of excessive inflammation.
Page TH, Brown A, Timms EM, et al., 2010, Inhibitors of p38 Suppress Cytokine Production in Rheumatoid Arthritis Synovial Membranes Does Variable Inhibition of Interleukin-6 Production Limit Effectiveness In Vivo?, ARTHRITIS AND RHEUMATISM, Vol: 62, Pages: 3221-3231, ISSN: 0004-3591
Page TH, Turner JJO, Brown AC, et al., 2010, Nonsteroidal Anti-Inflammatory Drugs Increase TNF Production in Rheumatoid Synovial Membrane Cultures and Whole Blood, JOURNAL OF IMMUNOLOGY, Vol: 185, Pages: 3694-3701, ISSN: 0022-1767
Palmer CD, Mutch BE, Page TH, et al., 2008, Bmx regulates LPS-induced IL-6 and VEGF production via mRNA stability in rheumatoid synovial fibroblasts, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 370, Pages: 599-602, ISSN: 0006-291X
Smolinska MJ, Horwood NJ, Page TH, et al., 2008, Chemical inhibition of Src family kinases affects major LPS-activated pathways in primary human macrophages, MOLECULAR IMMUNOLOGY, Vol: 45, Pages: 990-1000, ISSN: 0161-5890
Page TH, Brown AC, Timms EM, et al., 2007, Treatment with non-steroidal anti-inflammatory drugs increases TNF production in rheumatoid arthritis, 15th Annual Meeting of the International-Cytokine-Society, Publisher: ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD, Pages: 32-32, ISSN: 1043-4666
Horwood NJ, Page TH, McDaid JP, et al., 2006, Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production, J Immunol, Vol: 176, Pages: 3635-3641, ISSN: 0022-1767
Page TH, Lali FV, Groome N, et al., 1997, Association of the common gamma-chain with the human IL-7 receptor is modulated by T cell activation., J Immunol, Vol: 158, Pages: 5727-5735, ISSN: 0022-1767
IL-7 acts on both resting and activated T cells. The functional IL-7R is reported to consist of two subunits, the ligand binding IL-7R and the common gamma-chain (gamma c chain), where IL-7R:gamma c chain association is driven solely by ligand binding. However, we now demonstrate that in primary T cells this event is also controlled by cellular activation. We show that IL-7R:gamma c chain complexes are detected in activated, but not in resting, T cells despite similar levels of gamma c chain expression, implying that the gamma c chain is not associated with the IL-7R in unstimulated T cells. Furthermore, IL-7R:gamma c chain association correlates with the expression of JAK-3 in T cells, but not in transfected COS-7 cells. The finding that IL-7R:gamma c chain assembly is controlled at a level beyond that of receptor expression has important implications for the control of cytokine function in T cells.
Crawley JB, Rawlinson L, Lali FV, et al., 1997, T cell proliferation in response to interleukins 2 and 7 requires p38MAP kinase activation., J Biol Chem, Vol: 272, Pages: 15023-15027, ISSN: 0021-9258
Interleukin-2 (IL-2) is a potent T cell mitogen. However, the signaling pathways by which IL-2 mediates its mitogenic effect are not fully understood. One of the members of the mitogen-activated protein kinase (MAPK) family, p42/44MAPK (ERK2/1), is known to be activated by IL-2. We have now investigated the response to IL-2 of two other members of the MAP kinase family, p54MAP kinase (stress-activated protein kinase (SAPK)/Jun-N-terminal kinase (JNK)) and p38MAP kinase (p38/Mpk2/CSBP/RK), which respond primarily to stressful and inflammatory stimuli (e.g. tumor necrosis factor-alpha, IL-1, and lipopolysaccharide). Here we show that IL-2, and another T cell growth factor, IL-7, activate both SAPK/JNK and p38MAP kinase. Furthermore, inhibition of p38MAP kinase activity with a specific pyrinidyl imidazole inhibitor SB203580 that prevents activation of its downstream effector, MAPK-activating protein kinase-2, correlated with suppression of IL-2- and IL-7-driven T cell proliferation. These data indicate that in T cells p38MAP kinase has a role in transducing the mitogenic signal.
Page TH, Lali FV, Foxwell BM, 1995, Interleukin-7 activates p56lck and p59fyn, two tyrosine kinases associated with the p90 interleukin-7 receptor in primary human T cells., Eur J Immunol, Vol: 25, Pages: 2956-2960, ISSN: 0014-2980
We have investigated signaling events associated with the cloned 90-kDa (p90) interleukin-7 receptor (IL-7R) to determine whether changes in the signaling pathways initiated by this molecule can explain the ability of T cells to proliferate to IL-7 following activation. Using in vitro kinase assays we find that the p90 IL-7R in both unstimulated and activated human T cells is physically associated with two molecules with intrinsic kinase activity. Western blotting analysis reveals these proteins to be the src kinase enzymes, p59fyn and p56lck. Binding of human recombinant IL-7 to the p90 IL-7R results in increased activity of both receptor-associated kinases in both resting and activated mature T cells. Thus, the signaling pathways initiated via the p90 IL-7R-associated src kinases are unlikely to be solely responsible for the proliferation of only activated T cells in response to IL-7. Additional signals, which may derive from other IL-7R-associated molecules such as the gamma c, are clearly required for IL-7-driven proliferation of activated primary T cells.
Page TH, Willcocks JL, Taylor-Fishwick DA, et al., 1993, Characterization of a novel high affinity human IL-7 receptor. Expression on T cells and association with IL-7 driven proliferation., J Immunol, Vol: 151, Pages: 4753-4763, ISSN: 0022-1767
Although both unstimulated and activated human T cells express high affinity IL-7R, only activated T cells can proliferate to IL-7. This responsiveness may occur as a direct result of changes in the structure of the IL-7R during T-cell activation. We have previously demonstrated such changes by affinity cross-linking studies, and have shown that unstimulated human T cells express a single IL-7R of 90 kDa, whereas activated T cells express an additional 76-kDa IL-7 binding protein. In this study the origin and function of the p90 and p76 molecules have been investigated. To determine the role of each of these receptors in IL-7 driven proliferation, IL-7R expression and proliferative capacity were monitored during mitogenic stimulation. These analyses showed that the ability of PBMC to proliferate to IL-7 correlated with expression of the p76 IL-7R, and not with expression of the p90 IL-7R. IL-7-driven proliferation is mediated via high affinity IL-7R, and accordingly, Scatchard analysis revealed that, like the p90 IL-7R, the p76 IL-7R bound IL-7 with dual (high; Kd 38 pM and low; Kd 360 pM) affinity. Deglycosylation studies showed that the p90 and p76 IL-7R are not simply differently glycosylated isoforms of a single receptor. In agreement, mAb to the previously cloned IL-7R were found to stain unstimulated T cells that express only the p90 IL-7R but not T-cell clones that express predominantly the p76 IL-7R. These antibodies also immunoprecipitated the cloned IL-7R as a 90-kDa species from both 125-I-surface-labeled resting and activated T cells, but were unable to precipitate the 76-kDa IL-7R. In addition, PCR analysis of p76-expressing cells could not detect splicing of the extracellular domain of the cloned IL-7R, thereby excluding the possibility that the p76 IL-7R is a previously undescribed splice variant of the cloned IL-7R. These data demonstrate that the p90 IL-7R is the T-cell homologue of the cloned IL-7R, and imply that the p90 and p76 IL-7R have differe
Willcocks JL, Hales A, Page TH, et al., 1993, The murine T cell line CT6 provides a novel bioassay for interleukin-7., Eur J Immunol, Vol: 23, Pages: 716-720, ISSN: 0014-2980
Like interleukin (IL)-2 and IL-4, IL-7 can act as a growth factor for activated T lymphocytes. Upon screening a panel of growth factor-dependent T cell lines, we found that only the cell line CT6 responded to IL-7, indeed as vigorously as to IL-2. Obviously, these findings challenge the validity of previous results on IL-2 production obtained using the CT6 cell line. However, they also demonstrate a novel and sensitive system for the bioassay of IL-7. The ability of the surveyed T cell lines to proliferate to IL-7 corresponded with the expression of IL-7 receptors (IL-7R) on the cell surface. The murine IL-7R on CT6 was shown to bind IL-7 with dual affinity and was visualized as an affinity cross-linked complex of 93 kDa. This IL-7R appears similar to that seen on murine splenic T cells and on 70Z/3, the pre-B cell line from which the murine IL-7R was cloned.
PAGE TH, TAYLORFISHWICK D, WILLCOCKS JL, et al., 1993, CHARACTERIZATION OF A NOVEL HIGH-AFFINITY IL-7 RECEPTOR - EXPRESSION ON T-CELLS AND ROLE IN IL-7 DRIVEN PROLIFERATION, JOURNAL OF CELLULAR BIOCHEMISTRY, Pages: 80-80, ISSN: 0730-2312
WILLCOCKS JL, HALES A, PAGE TH, et al., 1993, THE MURINE T-CELL LINE CT6 PROVIDES A NOVEL BIOASSAY FOR INTERLEUKIN-7, JOURNAL OF CELLULAR BIOCHEMISTRY, Pages: 101-101, ISSN: 0730-2312
FOXWELL BMJ, TAYLORFISHWICK DA, SIMON JL, et al., 1992, ACTIVATION INDUCED CHANGES IN EXPRESSION AND STRUCTURE OF THE IL-7 RECEPTOR ON HUMAN T-CELLS, INTERNATIONAL IMMUNOLOGY, Vol: 4, Pages: 277-282, ISSN: 0953-8178
PAGE TH, DALLMAN MJ, 1991, MOLECULAR-CLONING OF CDNAS FOR THE RAT INTERLEUKIN-2 RECEPTOR ALPHA-CHAIN AND BETA-CHAIN GENES - DIFFERENTIALLY REGULATED GENE ACTIVITY IN RESPONSE TO MITOGENIC STIMULATION, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 21, Pages: 2133-2138, ISSN: 0014-2980
DALLMAN MJ, SHIHO O, PAGE TH, et al., 1991, Peripheral tolerance to alloantigen results from altered regulation of the interleukin-2 pathway, Journal of Experimental Medicine, Vol: 173, Pages: 79-87, ISSN: 0022-1007
Tolerance to alloantigen may be induced in rats by administration of blood followed by transplantation of a renal allograft. The mechanism of this tolerance was investigated by directly analyzing the functional activity of graft-infiltrating cells. We have previously shown cytotoxic T lymphocyte infiltration of, and major histocompatibility complex induction on, grafts of tolerant animals. We now report that cells isolated from the grafts of tolerant rats show a reduced expression of the p55 interleukin 2 receptor (IL-2R) chain on the cell surface compared with that seen on the cells of untreated animals. Scatchard analysis further reveals low expression of high affinity IL-2R. This is due to reduced transcription of both IL-2R alpha and beta chain mRNAs and results in a reduced ability of cells to proliferate in response to IL-2. Cells isolated from tolerant animals are unable to make biologically active IL-2 in culture, whereas cells from untreated animals make high levels. This is not reflected at the mRNA level as the IL-2 gene is induced in both tolerant and untreated animals to similar levels. The induction of tolerance is abrogated by administration of recombinant IL-2 to animals at the time of transplantation. Thus, we conclude that an altered regulation of the IL-2 pathway results in tolerance in these alloantigen-treated and transplanted animals.
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