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dc.contributor.advisorHessian, Paul A.
dc.contributor.authorKazantseva, Marina Grigorievna
dc.identifier.citationKazantseva, M. G. (2012). Smoking, genes and inflammation (Thesis, Doctor of Philosophy). University of Otago. Retrieved from
dc.description.abstractRheumatoid arthritis (RA) is an, autoimmune disease where genetic predisposition and environmental factors increase the risk of developing RA and the severity of the disease. Cigarette smoking is the major recognised environmental risk factor, and there is a combined effect from smoking and the human leukocyte antigen (HLA)-DRB1 shared epitope (SE) genotype on the risk of developing RA. This study sought to establish any direct effect of smoking and/or the genetic predisposition on the inflammation driving RA and to identify biological mechanism(s) that might explain epidemiological data linking smoking, genetics and RA. The aim of initial work was to establish any involvement of aryl hydrocarbon receptor (AHR)-mediated mechanisms within inflamed rheumatoid tissues. The expression of AHR, CYP1A1 and AHRR genes were quantified by real-time PCR in twenty synovial and eighteen subcutaneous nodule tissues. Patient’s smoking status was established at the time tissue was obtained. The results show smoking causes significant AHR activation in joint synovial tissue, but not in rheumatoid nodule tissues. A subset of synovial DCs show activated AHR in smokers, consistent with the sensitivity of human mo-DCs stimulated with the AHR agonist, benzo(a)pyrene (BaP) in vitro. It is concluded that DCs within the joint synovium are the principal immune cells that respond to cigarette smoke exposure. Microarray analysis revealed that the expression of 547 synovial genes was up-regulated by smoking, including folate receptor 1 (FOLR1), matrix metalloproteinases (MMP)9, MMP11 and MMP14, TNF-superfamily members, TNFSF10/TRAIL and TNFRSF10B/TRAILR2 and transcription factors, RUNX1 and RUNX2. Cell motility and adhesion were the biological processes in synovium most affected by smoking. The expression of 307 synovial genes was down-regulated by smoking, including the vascular “protective” genes, KLF2 and eNOS, suggesting that endothelial function is affected by smoking with implications for vasculitis and the development of rheumatoid nodules associated with severe RA. Any effect of smoking and SE copy number on genes associated with AHR signalling and other immune-inflammatory genes was established. Results suggest there are solitary, reciprocal or synergistic effects from smoking and the SE in rheumatoid inflammation, which are gene dependent. Thus, smoking increases AHR activation in synovium; the SE has no effect. Furthermore, while smoking reduces IL17A expression in synovial tissue, indications are that SE copy number increases IL17A expression. In combination, smoking and the SE increase synovial MMP9 gene expression. Human promonocytic U937 cells were used to model the effect of BaP exposure on MMP9 expression. PMA-activated U937 cells acquire an ability to respond to BaP, including with increased MMP9 gene expression. AHR-specific siRNA, confirmed that AHR regulates MMP9 gene expression. Further data implicate different MMPs in rheumatoid tissue destruction. High MMP7 expression by macrophages occurs in a subset of nodule tissues. This high MMP7 expression is associated with a -181G/G polymorphism within the MMP7 gene promoter but is reliant on the nodule environment for effect. Overall, the data presented in this thesis shows that smoking has a direct effect on rheumatoid synovial tissue. Gene-environment interactions are likely to determine the overall outcome for the inflammatory process in patients with RA.
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectrheumatoid arthritis
dc.subjectaryl hydrocarbon receptor
dc.subjectmatrix metalloproteinases
dc.titleSmoking, genes and inflammation
dc.language.rfc3066en of Philosophy of Otago
otago.openaccessAbstract Only
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