Wnt signaling genes of murine chromosome 15 are involved in sex-affected pathways of inflammatory arthritis

Autor: Andrew D. Pucker, Elena Kudryavtseva, Toni Forde, Vyacheslav A. Adarichev
Rok vydání: 2011
Předmět:
Zdroj: Arthritis and rheumatism. 64(4)
ISSN: 1529-0131
Popis: Rheumatoid arthritis (RA) is a progressive autoimmune inflammatory disease characterized by the complex interplay of genetics and environment (1–3). The influence of gender as non-genetic RA risk factor was recognized decades ago: women have worse RA symptoms than men, and represent the majority (approximately 75%) of RA patients (4, 5). Since the prognosis of arthritic patients has improved in the last few decades, gender disparities in RA were recently re-evaluated with the most up-to-date clinical parameters. The findings corroborated previous observations that women had worse arthritis than men for almost all clinical RA scores and also confirmed significant female to male preponderance in RA (6). Early linkage studies demonstrated the involvement of sex chromosomes in RA patients (7, 8), but recent genome-wide association studies (GWAS) have not found RA susceptibility genes on sex chromosomes (1, 3, 9) suggesting that the mainstream mode of gender-dependent RA regulation is hormonal rather than linked directly to sex chromosomes. However, genetic linkage analysis of animal models for RA have provided examples of significant gender influences on autosomal modifier loci (10–14). Murine chromosome 15 (ch15), particularly the Pgia8 genomic interval (13, 14), carries genes implicated in numerous autoimmune and inflammatory diseases including experimental autoimmune encephalitis, Theiler’s murine encephalomyelitis virus-induced demyelination, several types of rodent arthritides induced with either collagen type II (CIA) or aggrecan (PGIA) and Borrelia burgdorferi infection (14–16). In the human genome, ch15-syntenic region is associated with RA (9, 17), serum rheumatoid factor (18), and is associated with the efficacy of anti-TNF-α treatment in RA (19). Many of the murine ch15 loci were shown to be influenced by gender (14, 15, 20). Multiple murine models of RA emphasize the fact that inflammation could be provoked by numerous stimuli such as genetic alterations or immunization with cartilage-related antigens but lead to similar pathology, including inflamed synovium, pannus formation and bone and cartilage deterioration at the effector phase of the disease. Once arthritis is initiated, it tends to be self-perpetuating and could be transferred to a naive donor using serum or cells from an arthritic animal (21, 22), antibodies to type II collagen (CAIA), (23) or antibodies to glucose-6-phosphate isomerase (24). Antibody-mediated murine arthritides share similarities with the inflammatory effector phase of RA in humans. This phase is an important target for therapeutic interventions, such as anti-CD20 rituximab and anti-IL-1β canakinumab therapies (25, 26). We hypothesize that gender specific connective tissue remodeling might be a common point of convergence for the clustering of multiple inflammatory diseases within the Pgia8 congenic interval. In this study, we investigated the susceptibility to CAIA of BALB/c.DBA/2-Pgia8 (C.D2-Pgia8) congenic mice that carry a sex-affected arthritis-suppressive genomic interval previously found to be associated with PGIA (14). We used whole-genome transcriptome analysis of both congenic and wild-type males and females to address the major mechanisms/pathways that underlie the Pgia8 locus-specific anti-inflammatory effect.
Databáze: OpenAIRE
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