Arthritis deformans in its atrophic form (rheumatoid arthritis) is, perhaps, best defined as a chronic disease affecting many joints, principally the smaller ones. It occurs chiefly in the female sex, is due probably to the action of a toxin, and is characterised by changes in the cartilages and the soft structures surrounding the joints, thus causing great immobility and deformity. That arthritis is a disease of great antiquity is borne out by the fact that recently-unearthed bones from tombs of about 3700-1300 B.C. showed unmistakable evidence of the affection. In exarnination of remains in Egypt, remains representative of all periods from early predynastic times dovm to the Fifth Dynasty after Christ, "the disease which showed itself with by far the greatest frequency in the bodies of all periods is rheumatoid arthritis". Virchow has left records describing the affection in bones unearthed from Pompeii. From these remote times onwards through the Middle Ages to the present day, an almost continuous series of historical records testifies that the disease has always been with us, and also that its clinical characters have remained unaltered through all the ages. The aetiology and pathology of the disease have, however, been so shrouded in darkness that we find the various writers, in their information on the subject, making indiscriminate use of the terms rheumatism, gout and arthritis to designate this affection.

Omega-3 fatty acids (ω-3 FA, including eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]), are essential polyunsaturated fatty acids which are correlated with lower incidence of chronic diseases. DHA and EPA can be enzymatically converted to resolvins, protectins and maresins, which play important roles in resolution of inflammation. Additionally, ω-3 FA can also directly activate surface receptors, namely the long-chain free fatty acid receptors GPR40 and GPR120, two GPCRs with poorly investigated biology. Using real-time PCR analysis, GPR40 transcript in human neutrophils was detected; the protein expression was also confirmed by flow cytometry and image stream analysis. Expression of GPR40 protein was up-regulated after stimulation with platelet-activating factor (PAF, 10nM) or leukotriene B4 (LTB4, 10nM) for 10 minutes. I utilised the selective agonist GW9508 to investigate the biology of GPR40. Tested on human neutrophils, GW9508 elevated intracellular calcium when applied within the 0.1-10μM range. The up-regulation of GPR40 expression by pro-inflammatory stimuli suggested to us potential regulatory roles for this receptor during inflammation. I then showed that 1 and 10μM GW9508 increased neutrophil chemotaxis in response to the cytokine IL-8 (30ng/ml). In addition, GPR40 activation by GW9508 enhanced phagocytosis of E. coli by human neutrophils by approximately 50% when tested at 0.1 and 1μM. Moreover, GW9508-neutrophil stimulation augmented microvesicle release and delayed apoptosis after stimulation. Finally, I demonstrated that GPR40 is expressed in inflammatory cells isolated from murine arthritic joints, such as neutrophils, macrophages and inflammatory monocytes. KBN-serum induced arthritic mice developed a more severe disease when treated prophylactically with GW9508 (10mg/kg, i.p. treated from day 0, daily), characterized by a higher clinical score and increased oedema when compared to vehicle control mice. Therapeutic intervention with GW9508 at the peak of the disease (day 5) delayed the resolution of arthritis. In summary, the data suggest that activation of GPR40 by GW9508 enhances neutrophil activation, up regulating the pro-inflammatory properties of this cell type, and therefore, exacerbating experimental inflammatory arthritis.

Diss. (sammanfattning) Umeå : Umeå universitet, 2008. / Härtill 3 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Inflammatory arthritis (IA) types such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and psoriatic arthritis (PsA) have been shown to exhibit common clinical features. As complex diseases they have a known genetic component, some of which is known to be shared. The aim of this study was to assess the genetic overlap between 3 types of IA (RA, JIA and PsA) using genotype data generated on the Immunochip array and to select a biologically promising overlapping region for further genetic and functional investigation. Overlap analysis was performed using association data generated for a large cohort of inflammatory arthritis cases and shared controls (11,475 RA; 2816 JIA; 929 PsA respectively). 50 genetic regions were identified as being associated with more than 1 type of IA (p < 1x10-3), with several interesting similarities and differences observed between the diseases. As several of the overlapping regions detected represented novel disease associations, they required replication in an independent sample cohort. 12 variants were selected for replication in an independent RA cohort of 3879 cases and 2561 controls. Of these, 2 variants in the CTLA4 and MTMR3 regions were successfully replicated in RA at p<0.05. Bioinformatics analysis was performed for the 50 overlapping regions, with one particularly promising region, RUNX1, selected for further investigation. In this region, the same variant (rs9979383) is associated across the 3 diseases, with similar odds ratios (OR 0.8-0.9) observed in each disease. As this region represented both a novel IA association and had not been densely genotyped on the Immunochip array, fine mapping was performed by genotyping 51 SNPS in 3491 cases and 2359 controls. This resulted in replication of the association at rs9979383 (p=0.02) with no additional significant genetic effects detected, therefore this variant was selected for further functional analysis. As rs9979383 lies ~280kb upstream of the RUNX1 gene, a cis-eQTL analysis was performed to identify if the variant acts by regulation of RUNX1 gene expression. This was performed in whole blood, CD4+ and CD8+ lymphocytes from 75 (and a subset of 23) healthy volunteers respectively. No significant eQTLs were detected between rs9979383 and RUNX1 in whole blood (p =0.9) or RUNX1/LOC100506403 CD4+ and CD8+ lymphocytes (p=0.1). This study has provided insight into the genetic similarities and differences between different types of inflammatory arthritis, which can be applied to further investigations into disease susceptibility. Although no significant cis-eQTL was detected in any of these tissues with either RUNX1 or the nearby lnc-RNA LOC100506403, in cells from healthy volunteers under unstimulated conditions, these findings will direct future functional investigations into the role of this overlapping region in the susceptibility of IA.

Abstract not available

Mia Alessandra Nieto is an 8-year old living with Juvenile Idiopathic Arthritis (JIA) in Austin, Texas. When she was diagnosed at 10 months, she was the youngest child ever diagnosed with JIA in the state of Texas. However, it took 37 days to confirm her condition because there is an immense lack on knowledge in the field of pediatric rheumatology among general practitioners despite the fact that JIA is the most prevalent chronic condition in children in the United States with over 300,000 diagnosed. This is an overview of Mia’s story, along with information regarding the lack of knowledge on the condition not only in the general population but mainly and more importantly among the medical professionals in the United States. / text

Diss. (sammanfattning) Uppsala : Univ., 2005. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Michigan, 1991.

Thesis (M.S.)--University of Michigan, 1991.