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TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial or hostderived ligands found in arthritic joints. Here, we show that TLR2 and TLR4, but not TLR9, are involved in the pathogenesis of autoimmune arthritis and play distinct roles in the regulation of T cells and cytokines. We investigated the involvement of TLR2, TLR4, and TLR9 in the progression of arthritis using IL-1 receptor antagonist-knockout (IL1rn-/-) mice, which spontaneously develop an autoimmune T cell-mediated arthritis. Spontaneous onset of arthritis was dependent on TLR activation by microbial flora, as germ-free mice did not develop arthritis. Clinical and histopathological evaluation of IL1rn-/-Tlr2-/- mice revealed more severe arthritis, characterized by reduced suppressive function of Tregs and substantially increased IFN-[gamma] production by T cells. IL1rn-/-Tlr4-/- mice were, in contrast, protected against severe arthritis and had markedly lower numbers of Th17 cells and a reduced capacity to produce IL-17. A lack of Tlr9 did not affect the progression of arthritis. While any therapeutic intervention targeting TLR2 still seems complicated, the strict position of TLR4 upstream of a number of pathogenic cytokines including IL-17 provides an interesting potential therapeutic target for rheumatoid arthritis., Introduction RA is an autoimmune disease manifested by chronic inflammation and cartilage and bone destruction in multiple joints. Etiopathology of RA has been subjected to intensive research, resulting in the [...]

Leukotriene (LT) [B.sub.4] is a powerful chemotactic and immune modulating agent that signals via two receptors denoted [BLT.sub.1] and [BLT.sub.2]. Here we report that [BLT.sub.1] and [BLT.sub.2] are expressed at low levels in an apparently silent state in human umbilical vein endothelial cells (HUVEC). However, treatment with LPS leads to a > 10 fold increase in the levels of [BLT.sub.1] mRNA without any significant effects on [BLT.sub.2] mRNA. In parallel, LPS also increases the amounts of [BLT.sub.1] protein. Tumor necrosis factor-[alpha] (TNF-[alpha]) increases the expression of [BLT.sub.2] mRNA [approximately equal to] 6 times above basal levels with only a modest increase in [BLT.sub.1] mRNA. Interleukin-1 [beta] causes variable and parallel increases of both [BLT.sub.1] and [BLT.sub.2] mRNA. The natural ligand [LTB.sub.4] also increases [BLT.sub.1], but not [BLT.sub.2], mRNA and protein expression. Along with the induction of [BLT.sub.1] and/or [BLT.sub.2], HUVEC acquire the capacity to respond to [LTB.sub.4] with increased levels of intracellular calcium and these signals can be blocked by isotype selective BLT antagonists, CP-105696 and LY-255283. In addition, treatment of HUVEC with [LTB.sub.4] causes increased release of both nitrite, presumably reflecting nitric oxide (NO), and monocyte chemoattractant protein-1. Our data indicate that expression of functional BLT receptors may occur at the surface of endothelial cells in response to LPS, cytokines, and ligand, which in turn may have functional consequences during the early vascular responses to inflammation. Moreover, the results point to BLT receptors as potential targets for pharmacological intervention in LT-dependent inflammatory diseases such as asthma, rheumatoid arthritis, and arteriosclerosis. inflammation | arteriosclerosis | rheumatoid arthritis | asthma | nitric oxide

Rheumatoid arthritis (RA) is a common, chronic disease where health-related quality of life (HRQL) is one of the main goals of therapy. As such, instruments used to measure HRQL in RA must be able to discriminate across RA severity. The two basic categories of instruments used to measure HRQL are generic instruments and disease-specific instruments. Generic instruments can be further subdivided into preference-based measures which yield both single and multi-attribute utility values anchored at zero (death) and 1.00 (perfect health) as a measure of HRQL. The scores from these types of instruments can be integrated into cost-utility analyses as the weightings for quality adjusted life years. We assessed the construct validity of utility scores from four generic preference-based measures (the Health Utilities Index 2 and 3 (HUI2, HUI3), the EuroQol 5D (EQ-5D), and the Short Form 6-D (SF- 6D) and disease specific measures (the Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL) and the Health Assessment Questionnaire (HAQ)) in a sample of 313 RA patients in British Columbia, Canada. We also estimated the minimally important differences (MID) for each of the measures. Generally, as anticipated, the disease-specific measures were better able to discriminate across groups with higher RA severity: however, utility scores from each of the scales also appeared to discriminate well across RA severity categories. The MID values agreed with those previously reported in the literature for the HUI2, SF-6D and the HAQ and provided new information for the HUI3, EQ-5D and the RAQoL. We conclude that the all of the preference-based utility measures that were evaluated appear to adequately discriminate across levels of RA severity. Keywords: Utility; Rheumatoid arthritis; Construct validity; Canada