Human autoimmune diseases are hallmarked by inappropriate loss-of-tolerance and self-attacking response of the immune system. Studies included in this thesis are focusing on the implication and functional impact of genetic factors in three autoimmune diseases rheumatoid arthritis (RA), asthma, and systemic lupus erythematosus (SLE). Using genetic association studies, we found in study I and II that sequence variants of the interferon regulatory factor 5 (IRF5) gene were associated with RA and asthma, and the associations were more pronounced in certain disease subtypes. Distinct association patterns or risk alleles of the IRF5 gene variants were revealed in different diseases, indicating that IRF5 contributes to disease manifestations in a dose-dependent manner. In study III, we found that seven out of eight genetic risk loci for SLE, which were originally identified in East Asian populations, also conferred disease risk with the same risk alleles and comparable magnitudes of effect sizes in Caucasians. Remarkable differences in risk allele frequencies were observed for all associated loci across ethnicities, which seems to be the major source of genetic heterogeneity for SLE. In study IV we explored an exhaustive spectrum of sequence variants in the genes inhibitor of kappa light polypeptide gene enhancer in B-cells kinase epsilon (IKBKE) and interferon induced with helicase C domain 1 (IFIH1) by gene resequencing, and identified nine variants in IKBKE and three variants in IFIH1 as genetic risk factors for SLE. One of the associated variants may influence splicing of IKBKE mRNA. In study V we provided genome-wide transcriptional regulatory profiles for IRF5 and signal transducer and activator of transcription 4 (STAT4) using chromatin immunoprecipitation-sequencing (ChIP-seq). The target genes of IRF5 and STAT4 were found to play active roles in pathways related with inflammatory response, and their expression patterns were characteristic for SLE patients. We also identified potential cooperative transcription factors for IRF5 and STAT4, and disease-associated sequence variants which may affect the regulatory function of IRF5 and STAT4. In conclusion, this thesis illuminates the contribution of several genetic risk factors to susceptibility of human autoimmune diseases, which facilitates our understanding of the genetic basis of their pathogenesis.

Bibliography: leaves 172-185. / xii, 185 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Investigates the induction of heat shock protein (HSP) by some of the anti-inflammatory agents and antirheumatic agents used in the management of rheumatoid arthritis. Presents HSP induction in peripheral white blood cells cultured in vitro. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1995?

Copy of author's previously published article. / Bibliography: leaves 189-219. / ix, 219, [69] leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Explores pathways by which therapeutic agents may affect the inflammatory reaction in rheumatoid arthritis and confirms and expands observation on anti-rheumatic agents that are capable of regulating the activity as well as the expression and production of a variety of inflammatory mediators related to tissue destruction in the inflamed joint. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1997

Copies of author's previously published articles in back-cover pocket. / Bibliography: leaves 180-205. / x, 205 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines aspects of the potential enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in humans, and develops methods for quantifying total (bound plus unbound) and unbound ketoprofen enantiomers in plasma. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1993?

Rheumatoid arthritis is a chronic inflammatory autoimmune disease. Measurement of the level of serum markers (sRAGE, S100A9, S100A8 and S100A12) and genetic testing for the presence of the PTPN22 genetic polymorphism could help elucidate the underlying cause of inflammation and complications in RA, such as atherosclerosis. Therefore, serum levels of sRAGE, S100A9, S100A8 and S100A12 were measured by ELISA in patients with established RA (n=138). The associations between the serum levels of these molecules; and inflammatory markers and RA complications were analysed by multiple linear regression modelling. Established RA patients (n=192) were investigated for the PTPN22 C1858T genetic polymorphism by PCR-RFLP. Multiple logistic regression modelling was used to examine the association between PTPN22 C1858T genetic polymorphism and inflammatory markers and RA complications. In RA patients, we found that serum levels of S100A9 were associated with the body mass index (BMI); and the presence of S100A8 and S100A12. The serum levels of S100A8 in RA patients were associated with the presence of anti-citrullinated peptide antibodies, rheumatoid factor and S100A9. The serum levels of S100A12 in RA patients were associated with the presence of anti-citrullinated peptide antibodies and S100A9; and a history of diabetes. Inflammatory markers and RA complications were not associated with the PTPN22 genetic polymorphism in established RA patients; serum level of triglyceride was the only variable associated with PTPN22 C1858T in multiple logistic regression analysis. Taken together, these data suggest that serum levels of sRAGE, S100A9 and S100A12 protein may be useful correlates of inflammation and autoantibody production in RA patients. Further studies are recommended to determine whether these markers predict clinical outcomes when measured at the onset of RA.

Arthritis is a debilitating disease of the joints caused by the accelerated breakdown of cartilage, resulting in painful, swollen joints. Cartilage protects the joint by absorbing the shock that would otherwise be transferred directly to the underlying bone. One crucial component of cartilage is a specialised molecule known as aggrecan. Aggrecan consists of a core protein with three globular domains (G1, G2 and G3) and is modified with over one hundred highly sulphated glycosaminoglycan chains. Two types of glycosaminoglycans are substituted along the length of the protein, chondroitin sulphate and keratan sulphate. The glycosaminoglycans impart a highly negative charge to the tissue, giving it the ability to retain water and resist compressive forces. / Aggrecan is lost from cartilage following cleavage by aggrecanases. Too little aggrecan in cartilage destabilises the structural integrity of the tissue and is associated with arthritis. Of the five known aggrecanase cleavage sites, it is cleavage within the interglobular domain (IGD) between the G1 and G2 domains at NITEGE373 - 374ARGSVI that directly contributes to loss of aggrecan function. / The chondroitin sulphate and keratan sulphate located between the G2 and G3 domains is responsible for maintaining the biomechanical properties of aggrecan. The role of keratan sulphate within the G1-G2 domain is unknown, but it is not thought to be essential for aggrecan function. However the literature suggests a possible role of keratan sulphate in facilitating aggrecanase cleavage of NITEGE373 - 374ARGSVI in the IGD. The aim of my project was to examine the role of keratan sulphate in aggrecanase-mediated cleavage of aggrecan in the IGD. Three major goals have been accomplished in this thesis: 1) Identification of a cell type capable of sustained keratan sulphate synthesis. 2) Expression of a recombinant G1-G2 protein substituted with keratan sulphate (rG1-G2). 3) Demonstration that endogenous N-linked keratan sulphate is sufficient to potentiate aggrecanase cleavage of rG1-G2 in the IGD. / Cultured cells do not synthesise keratan sulphate. Therefore identifying a cell type, and culture conditions to maximise keratan sulphate synthesis, was a major undertaking. Conditions were identified which allowed for maximal keratan sulphate synthesis, albeit on a small scale, in primary bovine keratocytes. Using a Vaccinia virus expression system, recombinant G1-G2 was expressed in primary bovine keratocytes. / Analysis of the rG1-G2 revealed that it was substituted with 5 kDa of keratan sulphate. One important aspect of the study was that the keratan sulphate was all N-linked to the core protein. Subsequent aggrecanase digests, comparing substrates before and after removal of keratan sulphate, showed that aggrecanase cleavage was markedly more efficient when keratan sulphate was present. The results contained in this thesis add significantly to the established literature by providing a greater understanding of the mechanisms involved in aggrecanase-mediated cleavage of aggrecan and cartilage destruction. The results suggest that aggrecan substitution with N-linked keratan sulphate potentiates aggrecanase activity. The results from this study identify N-linked keratan sulphate as a possible target for the development of new drugs for the management of arthritis.

Tez (Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dalı, 2001. / Bibliyografya var.

Thesis (Ph. D.)--University of Adelaide, Dept. of Pathology, 1986. / Includes bibliographical references (leaves 211-260).

Thesis (Ph.D.)--McMaster University (Canada), 1994. / Source: Dissertation Abstracts International, Volume: 56-01, Section: B, page: 0252. Adviser: C. J. L. Lock.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dalı, 2006. / Bibliyografya var.