A comparative genetic analysis between collagen‐induced arthritis and pristane‐induced arthritis

Olofsson, Peter; Lu, Shemin; Holmberg, Jens; Song, Taek Lyul; Wernhoff, Patrik; Pettersson, Ulf; Holmdahl, Rikard

doi:10.1002/art.11100

Cited by 19 publications

(29 citation statements)

References 43 publications

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“…First, results from the linkage study as well as from previously published and unpublished experiments with larger congenic fragments showed a clear dominant inheritance, with one E3 allele protecting from pristaneinduced arthritis. 6,7,17 In this study however, PIA was only reduced in rats with two E3 alleles, thus showing a clear recessive mode of inheritance. Although linkage peaks most often do not very precisely predict the position of a QTN, it is still notable that both the LOD score interval as well as the maximum peak from Pia7 is centromeric from Oia2.…”

Section: Discussioncontrasting

confidence: 64%

Finemapping of the arthritis QTL Pia7 reveals co-localization with Oia2 and the APLEC locus

et al. 2010

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In this study, we sought to determine the effect of the quantitative trait locus Pia7 on arthritis severity. The regulatory locus derived from the arthritis-resistant E3 rat strain was introgressed into the arthritis-susceptibility DA strain through continuous backcrossing. Congenic rats were studied for their susceptibility to experimental arthritis using pristane and adjuvant oil. In addition, cell number and function of various leukocyte populations were analyzed either under naive or stimulated conditions. We found that the minimal congenic fragment of DA.E3-Pia7 rats overlapped with the minimal fragment in DA.PVG-Oia2 congenic rats, which has been positionally cloned to the antigen-presenting lectin-like receptor complex (APLEC) genes. DA.E3-Pia7 congenic rats were protected from both PIA and OIA, but the protection was more pronounced in OIA. In adoptive transfer experiments we observed that the Pia7 locus controlled the priming of arthritogenic T cells and not the effector phase. In addition, Pia7 congenic rats had a significant higher frequency of B cells and granulocytes as well as TNFa production after stimulation, indicating a higher activation state of cells of the innate immune system. In conclusion, this study shows that the APLEC locus is a major locus regulating the severity of experimentally induced arthritis in rats.

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Section: Discussioncontrasting

confidence: 64%

Finemapping of the arthritis QTL Pia7 reveals co-localization with Oia2 and the APLEC locus

et al. 2010

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“…To localize and to narrow the intervals containing the two arthritis-regulatory genes, and to comprehensively characterize their regulatory effects in arthritis severity, joint histology, and synovial tissue cytokine gene expression, Cia5 subcongenics were generated and studied for their susceptibility to and severity of pristaneinduced arthritis (PIA) and CIA, two well-established models of autoimmune erosive arthritis that share certain similarities in their pathogenesis and genetic regulation, but also have differences (23,25,33,39,40). We determined that Cia5 contains three different QTLs that regulate arthritis severity.…”

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confidence: 99%

The Non-MHC Quantitative Trait LocusCia5Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis

Meng

Yarlett

Joe

et al. 2005

The Journal of Immunology

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Cia5 is a locus on rat chromosome 10 which regulates the severity of collagen- and pristane-induced arthritis (CIA and PIA). To refine the region toward positional identification, Cia5 subcongenic strains were generated and studied in PIA and CIA. The protective effect of the telomeric locus Cia5a was confirmed in both models. A second arthritis severity locus (Cia5d) was identified within the most centromeric portion of Cia5. DA.F344(Cia5d) rats had a significantly lower median arthritis severity index in PIA, but not in CIA, compared with DA. On histologic analyses DA.F344(Cia5a) and DA.F344(Cia5d) congenics with PIA preserved a nearly normal joint architecture compared with DA, including significant reduction in synovial hyperplasia, pannus, angiogenesis, inflammatory infiltration, bone and cartilage erosions. Cia5 and Cia5a synovial levels of IL-1β mRNA were reduced. Although both DA.F344(Cia5) and DA.F344(Cia5a) rats were protected in CIA, the arthritis scores of DA.F344(Cia5) were significantly higher than those of DA.F344(Cia5a), suggesting the existence of a third locus where F344-derived alleles centromeric from Cia5a contribute to increased arthritis severity. The existence of the third locus was further supported by higher levels of autoantibodies against rat type II collagen in DA.F344(Cia5) congenics compared with DA.F344(Cia5a). Our results determined that Cia5 contains three major arthritis severity regulatory loci regulating central events in the pathogenesis of arthritis, and differentially influencing CIA and PIA. These loci are syntenic to regions on human chromosomes 17q and 5q implicated in the susceptibility to rheumatoid arthritis, suggesting that the identification of these genes will be relevant to human disease.

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“…Although each experimental model appears to involve different physiologic pathways in the introduction of arthritis, they share a high similarity in their genetic control, as has been observed in linkage analyses in which a strikingly high number of QTLs were found to be overlapping and the effects of isolated loci were observed to be similar between CIA and PIA in congenic rats (7,21). Congenic strains have a great potential for use in the identification of arthritis-regulatory genes.…”

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confidence: 90%

“…We have previously reported the location of 12 non-major histocompatibility complex (MHC) loci (Pias 2-8, Pia10, and Pias [12][13][14][15] that regulate the severity of pristane-induced arthritis (PIA) in F 2 offspring of the 100%-susceptible DA and 100%-resistant E3 inbred rat strains (6)(7)(8). To positionally clone the underlying gene and study the effect of an arthritis-regulating quantitative trait locus (QTL), we have produced congenic strains in which the regulatory loci were transferred from the arthritisresistant E3 strain into the arthritis-susceptible DA strain.…”

mentioning

confidence: 99%

“…In the present study, we constructed congenic rat strains in which 3 major arthritis-promoting QTLs from the DA strain (Pia4/Cia12, Pia5/Cia3, and Pia7/Cia13) (6,(10)(11)(12) were transferred into the completely arthritisresistant E3 rat strain (7). These congenic rats were evaluated for the susceptibility to and severity of arthritis, which was induced by 2 different arthritogenic agents: native type II rat collagen emulsified in Freund's incomplete adjuvant (IFA), and the mineral oil pristane (13,14).…”

mentioning

confidence: 99%

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Detection of arthritis‐susceptibility loci, including Ncf1, and variable effects of the major histocompatibility complex region depending on genetic background in rats

Rintisch

Förster

Holmdahl

2009

Arthritis & Rheumatism

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Objective. To characterize the arthritismodulating effects of 3 non-major histocompatibility complex (MHC) quantitative trait loci (QTLs) in rat experimental arthritis in the disease-resistant E3 strain, and to investigate the disease-modulating effects of the MHC region (RT1) in various genetic backgrounds.Methods. A congenic fragment containing Ncf1 along with congenic fragments containing the strongest remaining loci, Pia5/Cia3 and Pia7/Cia13 on chromosome 4, were transferred from the arthritis-susceptible DA strain into the background of the completely resistant E3 strain. The arthritis-regulatory potential of the transferred alleles was evaluated by comparing the susceptibility to experimental arthritis in congenic rats with that in E3 rats. The RT1 u haplotype from the E3 strain was transferred into the susceptible DA strain (RT1 av1 ), and various F 1 and F 2 hybrids were generated to assess the effects of RT1 on arthritis susceptibility.Results. The DA allele of Ncf1 did not break the arthritis resistance of the E3 rats, although it led to enhanced autoimmune B cell responses, as indicated by significantly elevated levels of anticollagen antibodies in congenic rats. Introgressing Pia5 and Pia7 loci on chromosome 4 broke the resistance to arthritis, and the MHC locus on chromosome 20 in DA rats enhanced arthritis when RT1 interacted with E3 genes.Conclusion. The findings in these congenic lines confirm the existence of 3 major QTLs that regulate the severity of arthritis and are sufficient to induce the transformation of a completely arthritis-resistant rat strain into an arthritis-susceptible strain. This study also reveals a dramatic difference in the arthritisregulatory potential of the rat MHC depending on genetic background, suggesting that strong epistatic interactions occur between MHC and non-MHC genes.

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A comparative genetic analysis between collagen‐induced arthritis and pristane‐induced arthritis

Cited by 19 publications

References 43 publications

Finemapping of the arthritis QTL Pia7 reveals co-localization with Oia2 and the APLEC locus

Finemapping of the arthritis QTL Pia7 reveals co-localization with Oia2 and the APLEC locus

The Non-MHC Quantitative Trait LocusCia5Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis

Detection of arthritis‐susceptibility loci, including Ncf1, and variable effects of the major histocompatibility complex region depending on genetic background in rats

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