Abstract
Murine collagen-induced arthritis (CIA) is a chronic inflammatory disease bearing all the hallmarks of rheumatoid arthritis. CIA has been widely used to study the etiology, pathogenesis and new therapeutic approaches of rheumatoid arthritis. Previous studies have identified multiple quantitative trait loci (QTL) controlling different aspects of disease pathogenesis. However, progress in identifying the new susceptibility genes outside the MHC locus has been slow. With the advent of new global methods for genetic analysis such as large-scale sequencing, gene expression profiling, combined with classical linkage analysis, congenic and physical and in silico fine mapping, progress is considerably accelerating. Here we present preliminary data using an integrative genomics strategy to identify new putative susceptibility genes contributing to the pathogenesis of CIA. The strategy is based on integrating a genome scan to identify QTLs linked to clinical disease phenotypes and subtraits in a cross between the CIA-susceptible DBA1/J and resistant FVB/NJ mouse strains. Additionally, gene expression profiling in target tissues and immune cells in parental strains and their F2 progeny is performed. Numerous classical QTL and expression QTL were identified. Master QTLs/expression QTLs controlling basic disease traits and subtraits were selected for further analysis using in silico tools; for example, haplotype sharing analysis, interspecies synteny analysis, congenic mapping, and pathway construction. So far we have confirmed C5 as a putative susceptibility gene for the Cia2 locus on chromosome 2. We also identified the mitochondrial ATP8 as a novel susceptibility gene. We are also pursuing three additional QTLs on chromosomes 1, 5, 18 controlling leukocyte–endothelial cell adhesion, anticollagen antibody production and arthritis severity. Functional analysis of candidate genes for those loci is underway.
Highlights
Rheumatoid arthritis is a chronic inflammatory disorder that primarily affects the joints and results in the destruction of cartilage and subchondral bone by the inflamed synovium
peripheral blood mononuclear cells (PBMC) from systemic sclerosis (SSc) patients responded to TNFα with significantly higher production of leukotriene E4 (LTE4) in comparison with healthy controls (P < 0.05 at 1 hour), while there were no significant differences in TNFα-induced production of 15-hydroxyeicosatetraenoic acid (15-HETE) between SSc patients and controls
It was shown that attachment of synovial fibroblasts (SF) that this association was completely dependent on concomitant from rheumatoid arthritis patients to laminin-111 (LM-111) induced carriage of the PSORS1 risk allele
Summary
Rheumatoid arthritis is a chronic inflammatory disorder that primarily affects the joints and results in the destruction of cartilage and subchondral bone by the inflamed synovium. A observed in affected joints of rheumatoid arthritis (RA) patients, as tourniquet was not used during the procedures and the skin portal well as extensive synovial infiltration of inflammatory cells. These conflicting observations suggest that the regulation of IL-7 expression is tightly controlled at the level of tissue specificity To support this hypothesis, we showed that several cytokines have a different effect on IL-7 production in BM StrC, epithelial cells from the liver and gut. TRU-015 is a CD20-directed small modular immunopharmaceutical drug candidate that effectively depletes B lymphocytes in cynomolgus monkeys in a dose-dependent manner, and improves survival in mouse xenograft tumor models [4,5].
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