ORCID Profile
0000-0001-6924-6402
Current Organisations
University of Birmingham
,
University of Oxford
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Publisher: Proceedings of the National Academy of Sciences
Date: 21-09-2015
Abstract: Maintenance of vascular integrity during effector immune responses occurring in tissues is a prerequisite of a healthy immune response. The mechanism whereby the vascular endothelium remains undamaged while interacting with effector immune cells migrating to the site of inflammation is largely unknown. This study shows that signals mediated by CD31, a trans -homophilic receptor expressed at high levels by the endothelium, are both necessary and sufficient to prevent inflammation-induced endothelial cell death and confer immune privilege to the vascular endothelium. We also provide proof of principle that this property can be harnessed therapeutically in pancreatic β-cell transplantation, whereby CD31 gene transfer alone endows allogeneic targets with indefinite resistance to immune attack in vivo.
Publisher: BMJ
Date: 22-06-2009
Abstract: Synovial fibroblasts and osteoblasts generate active glucocorticoids by means of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. This activity increases in response to proinflammatory cytokines or glucocorticoids. During inflammatory arthritis synovium and bone are exposed to both these factors. This study hypothesised that glucocorticoids magnify the effects of inflammatory cytokines on local glucocorticoid production in both synovium and bone. The effects of inflammatory cytokines (IL-1β/tumour necrosis factor alpha TNFα) and glucocorticoids, alone or combined, were assessed on the expression and activity of 11β-HSD1 in primary synovial fibroblasts, primary human osteoblasts and MG-63 osteosarcoma cells. A range of other target genes and cell types were used to examine the specificity of effects. Functional consequences were assessed using IL-6 ELISA. In synovial fibroblasts and osteoblasts, treatment with cytokines or glucocorticoids in isolation induced 11β-HSD1 expression and activity. However, in combination, 11β-HSD1 expression, activity and functional consequences were induced synergistically to a level not seen with isolated treatments. This effect was seen in normal skin fibroblasts but not foreskin fibroblasts or adipocytes and was only seen for the 11β-HSD1 gene. Synergistic induction had functional consequences on IL-6 production. Combined treatment with inflammatory cytokines and glucocorticoids synergistically induces 11β-HSD1 expression and activity in synovial fibroblasts and osteoblasts, providing a mechanism by which synovium and bone can interact to enhance anti-inflammatory responses by increasing localised glucocorticoid levels. However, the synergistic induction of 11β-HSD1 might also cause detrimental glucocorticoid accumulation in bone or surrounding tissues.
Publisher: BMJ
Date: 30-11-2007
Publisher: Springer Science and Business Media LLC
Date: 19-01-2016
Publisher: Wiley
Date: 29-04-2021
DOI: 10.1002/ART.41593
Publisher: The American Association of Immunologists
Date: 11-2012
Abstract: Thymic atrophy is a frequent consequence of infection with bacteria, viruses, and parasites and is considered a common virulence trait between pathogens. Multiple reasons have been proposed to explain this atrophy, including premature egress of immature thymocytes, increased apoptosis, or thymic shutdown to prevent tolerance to the pathogen from developing. The severe loss in thymic cell number can reflect an equally dramatic reduction in thymic output, potentially reducing peripheral T cell numbers. In this study, we examine the relationship between systemic Salmonella infection and thymic function. During infection, naive T cell numbers in peripheral lymphoid organs increase. Nevertheless, this occurs despite a pronounced thymic atrophy caused by viable bacteria, with a peak 50-fold reduction in thymocyte numbers. Thymic atrophy is not dependent upon homeostatic feedback from peripheral T cells or on regulation of endogenous glucocorticoids, as demonstrated by infection of genetically altered mice. Once bacterial numbers fall, thymocyte numbers recover, and this is associated with increases in the proportion and proliferation of early thymic progenitors. During atrophy, thymic T cell maturation is maintained, and single-joint TCR rearrangement excision circle analysis reveals there is only a modest fall in recent CD4+ thymic emigrants in secondary lymphoid tissues. Thus, thymic atrophy does not necessarily result in a matching dysfunctional T cell output, and thymic homeostasis can constantly adjust to systemic infection to ensure that naive T cell output is maintained.
Publisher: American Society of Hematology
Date: 07-05-2009
DOI: 10.1182/BLOOD-2008-06-162958
Abstract: Hematopoiesis is a carefully controlled process that is regulated by complex networks of transcription factors that are, in part, controlled by signals resulting from ligand binding to cell-surface receptors. To further understand hematopoiesis, we have compared gene expression profiles of human erythroblasts, megakaryocytes, B cells, cytotoxic and helper T cells, natural killer cells, granulocytes, and monocytes using whole genome microarrays. A bioinformatics analysis of these data was performed focusing on transcription factors, immunoglobulin superfamily members, and lineage-specific transcripts. We observed that the numbers of lineage-specific genes varies by 2 orders of magnitude, ranging from 5 for cytotoxic T cells to 878 for granulocytes. In addition, we have identified novel coexpression patterns for key transcription factors involved in hematopoiesis (eg, GATA3-GFI1 and GATA2-KLF1). This study represents the most comprehensive analysis of gene expression in hematopoietic cells to date and has identified genes that play key roles in lineage commitment and cell function. The data, which are freely accessible, will be invaluable for future studies on hematopoiesis and the role of specific genes and will also aid the understanding of the recent genome-wide association studies.
Publisher: Wiley
Date: 27-07-2012
DOI: 10.1002/ART.34474
Abstract: Several studies suggest that bone mineral density (BMD) is reduced in chronic inflammatory diseases. Higher serum levels of C-reactive protein (CRP) have been associated with lower BMD in women and older adults. However, it is not clear whether this association holds in a representative s le of the general population. The purpose of this study was to examine the relationship between BMD and CRP level in a large representative US population-based s le from the National Health and Nutrition Examination Survey (NHANES). We included participants age ≥20 years with BMD (total and subregions) measured by dual x-ray absorptiometry scans and complete information on covariates from NHANES. The association between CRP level and BMD was evaluated using multivariate linear regression models, adjusting for potential confounders and further adjusting for comorbid diseases, medications, and serum vitamin D levels. The study s le included 10,475 participants (53% Caucasian, 22% Mexican American, 18% African American, and 7% other races). Men had higher BMD and lower CRP concentrations than women. BMD (total body BMD as well as subtotal BMD and BMD of the extremities, ribs, and trunk subregions) was inversely associated with quintiles of CRP concentration both in men and in women in a dose-dependent manner (for total BMD, P for trend < 0.0001 for men, P for trend = 0.0005 for women). The associations were independent of medications, comorbidities, and other potential confounders. The results remained largely unchanged with further adjustment for serum vitamin D levels. Among men and women in a large representative population-based s le, the CRP level was inversely and independently associated with total BMD in a dose-dependent manner.
Publisher: Wiley
Date: 28-10-2011
DOI: 10.1002/ART.30570
Abstract: Interleukin-6 (IL-6) is a proinflammatory cytokine with regulatory effects on the survival and differentiation of T cells. It exerts its biologic function in 2 ways: by directly binding to the IL-6 receptor (IL-6R CD126) or via trans-signaling, in which soluble IL-6R/IL-6 complexes bind to the signaling component CD130. This study was undertaken to assess the expression and regulation of CD126 and CD130 and determine how these affect the response of CD4+ T cells to IL-6 in the joints of patients with rheumatoid arthritis (RA). Flow cytometry and immunofluorescence microscopy were used to determine the expression, function, and regulation of CD126 and CD130 in CD4+ T cells from the peripheral blood (PB), synovial fluid (SF), and synovial tissue of RA patients. Compared to the findings in RA PB, CD4+ T cells in the SF and synovial tissue expressed low levels of CD126. In contrast, whereas CD4+ T cell expression of CD130 was minimal in the SF, its level in the synovial tissue was high. Consistent with this phenotype, synovial tissue T cells responded to trans-signaling by soluble IL-6R/IL-6 complexes, whereas no response was evident in CD4+ T cells from the SF. Down-regulation of both receptor components in SF T cells could be explained by exposure to high levels of IL-6. Increased levels of CD130 messenger RNA and protein in synovial tissue CD4+ T cells suggested that CD130 is up-regulated locally. Among a range of cytokines tested, only IL-10 induced CD130 expression in T cells. The inflamed microenvironment in the synovial tissue maintains responsiveness to IL-6 trans-signaling through the up-regulation of CD130 expression in CD4+ T cells, and this process may be driven by IL-10.
Publisher: Elsevier BV
Date: 08-2018
Publisher: Public Library of Science (PLoS)
Date: 20-06-2013
Publisher: Wiley
Date: 07-04-2005
DOI: 10.1016/J.FEBSLET.2005.03.071
Abstract: Fibroblasts are a erse cell type and display clear topographic differentiation and positional memory. In a screen for fibroblast specific markers we have characterized four monoclonal antibodies to endosialin (TEM1/CD248). Previous studies have reported that endosialin is a tumour endothelium marker and is localized intracellularly. We demonstrate conclusively that endosialin is a cell surface glycoprotein and is predominantly expressed by fibroblasts and a subset of pericytes associated with tumour vessels but not by tumour endothelium. These novel antibodies will facilitate the isolation and classification of fibroblast and pericyte lineages as well as the further functional analysis of endosialin.
Publisher: Wiley
Date: 26-06-2012
DOI: 10.1002/ART.34414
Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism
Date: 03-2017
Publisher: Wiley
Date: 28-09-2012
DOI: 10.1002/ART.34556
Publisher: Proceedings of the National Academy of Sciences
Date: 16-06-2009
Abstract: Invasive nontyphoidal Salmonella (NTS), including Salmonella typhimurium (STm), are major yet poorly-recognized killers of infants in sub-Saharan Africa. Death in these children is usually associated with bacteremia, commonly in the absence of gastrointestinal symptoms. Evidence from humans and animal studies suggest that severe infection and bacteremia occur when specific Ab is lacking. Understanding how Ab responses to Salmonella are regulated will help develop vaccines against these devastating infections. STm induces atypical Ab responses characterized by prominent, accelerated, extrafollicular T-independent (TI) Ab against a range of surface antigens. These responses develop without concomitant germinal centers, which only appear as infection resolves. Here, we show STm rapidly induces a population of TI B220 + CD5 − B1b cells during infection and TI Ab from B1b cells targets the outer membrane protein (Omp) porins OmpC, OmpD and OmpF but not flagellin. When porins are used as immunogens they can ablate bacteremia and provide equivalent protection against STm as killed bacterial vaccine and this is wholly B cell-dependent. Furthermore Ab from porin-immunized chimeras, that have B1b cells, is sufficient to impair infection. Infecting with porin-deficient bacteria identifies OmpD, a protein absent from Salmonella Typhi, as a key target of Ab in these infections. This work broadens the recognized repertoire of TI protein antigens and highlights the importance of Ab from different B cell subsets in controlling STm infection. OmpD is a strong candidate vaccine target and may, in part, explain the lack of cross-protection between Salmonella Typhi and STm infections.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2021
DOI: 10.1038/S41467-021-22365-Z
Abstract: In healthy joints, synovial fibroblasts (SFs) provide the microenvironment required to mediate homeostasis, but these cells adopt a pathological function in rheumatoid arthritis (RA). Carbohydrates (glycans) on cell surfaces are fundamental regulators of the interactions between stromal and immune cells, but little is known about the role of the SF glycome in joint inflammation. Here we study stromal guided pathophysiology by mapping SFs glycosylation pathways. Combining transcriptomic and glycomic analysis, we show that transformation of fibroblasts into pro-inflammatory cells is associated with glycan remodeling, a process that involves TNF-dependent inhibition of the glycosyltransferase ST6Gal1 and α2-6 sialylation. SF sialylation correlates with distinct functional subsets in murine experimental arthritis and remission stages in human RA. We propose that pro-inflammatory cytokines remodel the SF-glycome, converting the synovium into an under-sialylated and highly pro-inflammatory microenvironment. These results highlight the importance of glycosylation in stromal immunology and joint inflammation.
Publisher: American Society of Hematology
Date: 02-10-2014
DOI: 10.1182/BLOOD-2014-05-572818
Abstract: CLEC-2 activation induces proteolytic cleavage of GPVI and FcγRIIa but not itself. CLEC-2 but not GPVI is detected on platelet-derived microparticles.
Publisher: Wiley
Date: 11-06-2014
Publisher: The American Association of Immunologists
Date: 15-08-2011
Abstract: Hematopoietic cells constitutively express CD31/PECAM1, a signaling adhesion receptor associated with controlling responses to inflammatory stimuli. Although expressed on CD4+ T cells, its function on these cells is unclear. To address this, we have used a model of systemic Salmonella infection that induces high levels of T cell activation and depends on CD4+ T cells for resolution. Infection of CD31-deficient (CD31KO) mice demonstrates that these mice fail to control infection effectively. During infection, CD31KO mice have diminished numbers of total CD4+ T cells and IFN-γ–secreting Th1 cells. This is despite a higher proportion of CD31KO CD4+ T cells exhibiting an activated phenotype and an undiminished capacity to prime normally and polarize to Th1. Reduced numbers of T cells reflected the increased propensity of naive and activated CD31KO T cells to undergo apoptosis postinfection compared with wild-type T cells. Using adoptive transfer experiments, we show that loss of CD31 on CD4+ T cells alone is sufficient to account for the defective CD31KO T cell accumulation. These data are consistent with CD31 helping to control T cell activation, because in its absence, T cells have a greater propensity to become activated, resulting in increased susceptibility to become apoptotic. The impact of CD31 loss on T cell homeostasis becomes most pronounced during severe, inflammatory, and immunological stresses such as those caused by systemic Salmonella infection. This identifies a novel role for CD31 in regulating CD4 T cell homeostasis.
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1186/AR4065
Publisher: Wiley
Date: 18-10-2016
DOI: 10.1002/PATH.4806
Publisher: American Society for Clinical Investigation
Date: 16-11-2015
DOI: 10.1172/JCI79070
Publisher: BMJ
Date: 06-03-2017
DOI: 10.1136/ANNRHEUMDIS-2016-210715
Abstract: Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine) glucocorticoids (GC) biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at % improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.
Publisher: Springer Science and Business Media LLC
Date: 06-05-2019
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.1186/AR1993
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/AR4288
Publisher: BMJ
Date: 02-01-2014
DOI: 10.1136/ANNRHEUMDIS-2013-203926
Abstract: To determine the relationship between inflammation and glucocorticoid metabolism in vivo, in a clinical study of patients with inflammatory arthritis treated with anti-TNFα therapy. Urine s les were collected from patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as part of a multicentre study assessing responses to infliximab and etanercept. Systemic measures of glucocorticoid metabolism were assessed by gas chromatography/mass spectrometry at weeks 0 (baseline), 4 and 12 after anti-TNFα therapy. Clinical data including DAS28 and C-reactive protein were also collected. Systemic measures of 11β-HSD1 activity in patients with inflammatory arthritis decreased significantly following anti-TNFα therapy in patients with RA and PsA. Additionally, the activity of the glucocorticoid inactivating enzyme 5α-reductase appeared to increase significantly. This study demonstrates, for the first time, that the increased 11β-HSD1 activity seen in patients with inflammatory arthritis is mediated through TNFα. Furthermore, the changes in related glucocorticoid metabolising enzymes suggest that there is a coordinated change in glucocorticoid metabolism which promotes higher tissue glucocorticoid levels.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2015
Publisher: Springer Science and Business Media LLC
Date: 16-08-2019
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Christopher Dominic Buckley.