Genetic and Molecular Basis of Quantitative Trait Loci of Arthritis in Rat: Genes and Polymorphisms

Xiong, Qing; Jiao, Yan; Hasty, Karen A.; Stuart, J.; Postlethwaite, Arnold E.; Kang, Andrew H.; Gu, Weikuan

doi:10.4049/jimmunol.181.2.859

Cited by 8 publications

(8 citation statements)

References 34 publications

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Section: Genetic Linkage Studies For Adjuvant Arthritis-linked Quantimentioning

confidence: 99%

“…Studies in experimental models have identified many quantitative trait loci (QTLs) that show a significant association with arthritis susceptibility and severity [ 3 - 6 ]. At least 52 QTLs have been identified in different rat models of arthritis, and these QTLs cover approximately 54% of the total rat genome [ 6 ]. These QTLs are distributed among various chromosomes (including the X chromosome), except for chromosomes 11, 13 and 17, but at present there is no information about QTLs on the Y chromosome [ 6 ].…”

Section: Genetic Linkage Studies For Adjuvant Arthritis-linked Quantimentioning

confidence: 99%

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The determinants of susceptibility/resistance to adjuvant arthritis in rats

Kim

Moudgil

2009

Arthritis Res Ther

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Adjuvant arthritis (AA) serves as an excellent model for human rheumatoid arthritis. AA is readily inducible in certain rat strains, but not in others. Susceptibility/resistance to AA is determined by multiple factors. Among the genetic factors, both MHC and non-MHC genes contribute to arthritis susceptibility, and specific quantitative trait loci show association with the severity of the disease. Differential T-cell proliferative and cytokine responses, as well as antibody responses, to heat-shock proteins are evident when comparing AA-susceptible and AA-resistant rats. In addition, neuroendocrine factors and the housing environment can further modulate arthritis susceptibility/severity in particular rat strains. IntroductionAdjuvant arthritis (AA) is inducible in susceptible rat strains, such as the Lewis (LEW) rat, by a single subcutaneous injection of heat-killed Mycobacterium tuberculosis H37Ra (Mtb) in oil. AA has been used extensively as an animal model of human rheumatoid arthritis (RA) for studies on the disease pathogenesis and for testing of new products for their therapeutic efficacy [1]. Various outbred and inbred rat strains differ in their relative susceptibility to AA (Table 1). Similarly, the prevalence of RA differs significantly among human populations living in different geographical regions of the world, and even among subpopulations within the same region [2]. Conducting well-controlled studies to unravel the mechanisms underlying the disease susceptibility in RA, however, is difficult for multiple reasons -including the genetic heterogeneity of human populations and the differences in the environmental influences. In this regard, studies in animal models of arthritis serve an invaluable purpose by providing information that is directly relevant to human RA.In the past 10 to 15 years, significant advances have been made in unraveling the mechanisms involved in the initiation of AA as well as the regulation of AA. Studies comparing the physiological characteristics as well as the immune responsiveness of AA-susceptible rat strains versus AAresistant rat strains have provided critical insights into the disease process and have thereby contributed to these advancements. In the present review we highlight the major factors determining the susceptibility/resistance to AA (Table 2). In a few places, studies from other models of arthritis are also included.The differential susceptibility to AA of inbred rat strains bearing different MHC haplotypes (for example, LEW rats and Brown Norway (BN) rats) as well as those possessing the same MHC haplotype but having disparate non-MHC (background) genes (for example, LEW rats and WistarKyoto (WKY) rats) (Table 1) underscores the significance of genetic factors in determining susceptibility/resistance to AA. These genetic factors mediate their effect in part via influencing the quantitative and qualitative aspects of immune response to the disease-related antigens (Table 2). Superimposed on this genetic predisposition is the modulation of disease su...

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Section: Genetic Linkage Studies For Adjuvant Arthritis-linked Quantimentioning

confidence: 99%

Section: Genetic Linkage Studies For Adjuvant Arthritis-linked Quantimentioning

confidence: 99%

The determinants of susceptibility/resistance to adjuvant arthritis in rats

Kim

Moudgil

2009

Arthritis Res Ther

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“…Though the genes in Group A3 are associated with arthritis-QTL, the expression level in LEW and WKY rats are comparable. In regard to the genes under Group B1 and B2 (differentially expressed between LEW and WKY rats, but not associated with arthritis QTL), we suggest that this group of DEG should also be considered for further evaluation for its likely contribution to disease susceptibility in AIA (Brenner et al, 2006; Remmers et al, 1996; Xiong et al, 2008). …”

Section: Discussionmentioning

confidence: 94%

Comparative antigen-induced gene expression profiles unveil novel aspects of susceptibility/resistance to adjuvant arthritis in rats

Yu¹,

Lu²,

Tan³

et al. 2013

Molecular Immunology

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Lewis (LEW) and Wistar Kyoto (WKY) rats of the same major histocompatibility complex (MHC) haplotype (RT.1l) display differential susceptibility to adjuvant-induced arthritis (AIA). LEW are susceptible while WKY are resistant to AIA. To gain insights into the mechanistic basis of these disparate outcomes, we compared the gene expression profiles of the draining lymph node cells (LNC) of these two rat strains early (day 7) following a potentially arthritogenic challenge. LNC were tested both ex vivo and after restimulation with the disease-related antigen, mycobacterial heat-shock protein 65. Biotin-labeled fragment cRNA was generated from RNA of LNC and then hybridized with an oligonucleotide-based DNA microarray chip. The differentially expressed genes (DEG) were compared by limiting the false discovery rate to <5% and fold change ≥2.0, and their association with quantitative trait loci (QTL) was analyzed. This analysis revealed a more active immune response overall in WKY than LEW rats. Important differences were observed in the association of DEG with QTL in LEW vs. WKY rats. Both the number of upregulated DEG associated with rat arthritis-QTL and their level of expression were relatively higher in LEW when compared to WKY rat; however, the number of downregulated DEG-associated with rat arthritis-QTL as well as AIA-QTL were found to be higher in WKY than in LEW rats. In conclusion, distinct gene expression profiles define arthritis-susceptible versus resistant phenotype of MHC-compatible inbred rats. These results would advance our understanding of the pathogenesis of autoimmune arthritis and might also offer potential novel targets for therapeutic purposes.

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“…The procedures used were to that previous published [12]. Briefly, query terms were the combination of the name of the gene with any of these key words: arthritis, inflammation, anti-inflammatory, inflammatory mediator, inflammatory cytokine, autoimmune, immune, joint damage, T-cell, macrophage, neutrophil, angiogenesis, synovial, synovial hyperplasia, synovial fibroblast, lymphocytic infiltrate, and cartilage degradation.…”

Section: Methodsmentioning

confidence: 99%

Congenic Mice Provide Evidence for a Genetic Locus That Modulates Spontaneous Arthritis Caused by Deficiency of IL-1RA

et al. 2013

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To understand the role of genetic factors involved in the development of spontaneous arthritis in mice deficient in IL-1 receptor antagonist protein (IL_1RA), we have identified a genomic region containing a major quantitative trait locus (QTL) for this disease. The QTL is on chromosome 1 and appears to be the strongest genetic region regulating arthritis. To confirm the importance of the QTL and to identify potential candidate genes within it, we conducted speed congenic breeding to transfer the QTL region from DBA/1 mice that are resistant to spontaneous arthritis into BALB/c−/− which are susceptible. Genetic markers along every chromosome were used to assist in the selection of progeny in each generation to backcross to BALB/c−/−. By the 6th generation we determined that all of the chromosomes in the progeny were of BALB/c origin with the exception of portions of chromosome 1. At this stage we intercrossed selected mice to produce homozygous strains containing the genomic background of BALB/c−/− except for the QTL region on chromosome 1, which was from DBA/1. We were able to establish two congenic strains with overlapping DBA/1 DNA segments. These strains were observed for the development of spontaneous arthritis. Both congenic strains were relatively resistant to spontaneous arthritis and had delayed onset and reduced severity of disease. The gene/s that regulates this major QTL would appear to be located in the region of the QTL that is shared by both strains. The common transferred region is between D1Mit110 and D1Mit209 on chromosome 1. We evaluated this region for candidate genes and have identified a limited number of candidates. Confirmation of the identity and precise role of the candidates will require additional study.

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Genetic and Molecular Basis of Quantitative Trait Loci of Arthritis in Rat: Genes and Polymorphisms

Cited by 8 publications

References 34 publications

The determinants of susceptibility/resistance to adjuvant arthritis in rats

The determinants of susceptibility/resistance to adjuvant arthritis in rats

Comparative antigen-induced gene expression profiles unveil novel aspects of susceptibility/resistance to adjuvant arthritis in rats

Congenic Mice Provide Evidence for a Genetic Locus That Modulates Spontaneous Arthritis Caused by Deficiency of IL-1RA

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