Research in this division covers the basic mechanisms underlying inflammatory arthritis and metabolic bone disease.
Prof Gaston and Dr Goodall study the immunologic basis of inflammatory arthritis, and the factors which influence differentiation of pro-inflammatory T lymphocytes, particularly the role of dendritic cells in integrating signals from pathogens and cellular stress to alter cytokine production. We have a special interest in the IL-17/IL-23 cytokine axis, since this has been implicated in inflammatory arthritis, with very strong genetic evidence for a critical role in one form of joint disease, spondyloarthritis. Reactive arthritis, which is a member of the spondyloarthritis family, is triggered by specific infections, one of which is the important genitor-urinary tract pathogen, Chlamydia trachomatis (CT). Accordingly, we study the ability of CT infection to induce cytokines in dendritic cells, and the mechanisms underlying this; recent work has shown a crucial role for the cytoplasmic danger-sensing kinase, PKR. We also collaborate with colleagues at the Wellcome Trust Genome Campus on the genetics of CT and their relevance to the pathogenic properties of the organism. Recent work has examined the cytokine TSLP which also shows, like IL-23, major up-regulation by cellular stress. This is in dendritic cells by fungi and yeast which are in turn implicated in inflammatory arthritis in a major murine model of spondyloarthritis. Whereas TSLP production by epithelial cells has previously been mainly shown to be involved in allergic asthma in humans, this new work on dendritic cell production raises the possibility of its involvement in joint inflammation. Lastly, we work on human regulatory T cells (“Treg”) and have recently developed a reliable way of identifying them ex vivo without destroying the cells. Using these techniques we have also shown that non-regulatory cells (which would previously not been reliably distinguished from Treg) are major producers of IL-17 (Figure). Furthermore, some appear to be “ex-Treg” cells based on expressing the same T cell receptor. In spondyloarthritis there is a relative deficit of Treg and an excess of IL-17 producing cells.
Dr Poole’s group applies novel imaging techniques, including high resolution CT, to investigate human bone diseases. With the Engineering for Clinical Practice team of Graham Treece and Andrew Gee, they have studied focal thinning as a cause of femoral neck fracture and have discovered that bone building drugs have targeted effects at key sites within the osteoporotic femur and vertebrae. Research into prediction of future osteoarthritis by automated mapping of subchondral sclerosis and the joint space width is also pursued, using large cohorts of patients with imaging, genetic and outcome data in Iceland. Dr. Poole and colleagues recently developed a technique for extracting bone mineral density data from routine CT scans such as those used to screen for malignancy, and this has been recognized by an NHS Innovation 2014 award. Dr. Poole and NHS colleagues run a tertiary service for the diagnosis and management of rare metabolic bone diseases.
Goodall JC, Wu C, Zhang Y, Ellis L, O’Brien L, Saudek V, Gaston JSH. Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendric cell IL-23 expression. Proc Natl Acad Sci USA 2010; 107:17698-703.
Evans DM, Spencer CC, Pointon JJ, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat. Genet. 43: 761-767 (2011).
Prevosto C, Goodall JC. and Gaston JSH. Cytokine secretion by Pathogen Recognition Receptor-stimulated dendritic cells in rheumatoid arthritis and ankylosing spondylitis. J. Rheumatol. 39:1918-28 (2013).
Poole KE, Treece GM, Mayhew PM, Vaculik J, Dungl P, Horak M, et al. Cortical thickness mapping to identify focal osteoporosis in patients with hip fracture. PloS ONE. 2012; 7(6): e38466http://www.ncbi.nlm.nih.gov/pubmed/22701648.
Gregson CL, Poole KE, McCloskey EV, Duncan EL, Rittweger J, Fraser WD, et al. Elevated circulating sclerostin concentrations in individuals with High Bone Mass, with and without LRP5 mutations. J Clin Endocrinol Metab. 2014: jc20133958.http://www.ncbi.nlm.nih.gov/pubmed/24606091.
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