Complex Genetic Control in a Rat Model for Rheumatoid Arthritis

Nordquist, Niklas; Olofsson, Peter; Vingsbo‐Lundberg, Carina; Petterson, Ulf; Holmdahl, Rikard

doi:10.1006/jaut.2000.0450

Cited by 36 publications

(47 citation statements)

References 27 publications

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“…Instead, qualitative differences in the immune response or CNS target factors could be considered. The location of the chromosome 1 locus differed from previously defined loci in rat inflammatory diseases, such as a locus regulating whole spinal cordinduced EAE in a E3 ϫ DA cross (18), although it colocalizes with a locus-regulating severity in pristane-induced arthritis (47).…”

Section: Figurecontrasting

confidence: 56%

New Loci Regulating Rat Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

Bečanović

Wallström

Kornek

et al. 2003

The Journal of Immunology

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Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in rats that closely mimics many clinical and histopathological aspects of multiple sclerosis. Non-MHC quantitative trait loci regulating myelin oligodendrocyte glycoprotein-induced EAE have previously been identified in the EAE-permissive strain, DA, on rat chromosomes 4, 10, 15, and 18. To find any additional gene loci in another well-known EAE-permissive strain and thereby to assess any genetic heterogeneity in the regulation of the disease, we have performed a genome-wide linkage analysis in a reciprocal (LEW.1AV1 × PVG.1AV1) male/female F2 population (n = 185). We examined reciprocal crosses, but no parent-of-origin effect was detected. The parental rat strains share the RT1av1 MHC haplotype; thus, non-MHC genes control differences in EAE susceptibility. We identified Eae16 on chromosome 8 and Eae17 on chromosome 13, significantly linked to EAE phenotypes. Two loci, on chromosomes 1 and 17, respectively showed suggestive linkage to clinical and histopathological EAE phenotypes. Eae16 and Eae17 differ from those found in previously studied strain combinations, thus demonstrating genetic heterogeneity of EAE. Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms.

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Section: Figurecontrasting

confidence: 56%

New Loci Regulating Rat Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

Bečanović

Wallström

Kornek

et al. 2003

The Journal of Immunology

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“…Previously published reports regarding linkages in crosses of the arthritissusceptible DA rat with the arthritis-resistant E3 rat have focused on PIA. Linkages identified in PIA involve regulation of the onset (Pia2 and Pia3), severity (Pia4, Pia7, and Pia8), and chronicity (Pia1, Pia5, and Pia6) of arthritis, as well as the acute inflammatory response, analyzed as plasma concentrations of acute-phase proteins (Apr1 and Apr2) (10,(16)(17)(18).…”

Section: Resultsmentioning

confidence: 99%

“…Two of the major QTLs that regulate arthritis severity are the Cia12/Pia4 locus on chromosome 12 and the Cia13/Pia7 locus on chromosome 4 (16,17). We or the Cia13/Pia7 locus, respectively, from the arthritisresistant E3 strain to the arthritis-susceptible DA strain.…”

Section: Resultsmentioning

confidence: 99%

“…We used 364 male rats of the (E3 ϫ DA)DA backcross and analyzed arthritis onset and severity as well as antibody levels, RF production, and acute-phase response. Since this has also been done in E3 ϫ DA crosses after injection with pristane (10,(16)(17)(18), a careful comparison between these arthritis models could be made. In the CIA linkage experiment, we were Figure 4.…”

Section: Discussionmentioning

confidence: 99%

“…Eight quantitative trait loci (QTLs) (Pia1-Pia8), including the MHC region on chromosome 20, have been found to be associated with the clinical manifestations of PIA (10,16,17). Two QTLs that control the acute-phase response (Apr1 and Apr2) have also been correlated with disease (18).…”

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

Olofsson¹,

Lu²,

Holmberg³

et al. 2003

Arthritis & Rheumatism

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Objective. To compare the genetic regulation of collagen-induced arthritis (CIA) with that of pristaneinduced arthritis (PIA) in rats.Methods. A genome-wide linkage analysis of an (E3 ؋ DA)DA backcross of rats with CIA (n ‫؍‬ 364 male rats; the same strain combinations as previously used to determine the genetic control of PIA) was performed. The strongest loci in both CIA and PIA (i.e., Cia12/Pia4 and Cia13/Pia7) were isolated in congenic strains. Susceptibility in both congenic strains was tested in rats with CIA and in rats with PIA.Results. We found a striking, although not complete, similarity of the arthritis-controlling loci in CIA and in PIA, as well as the previously defined loci associated with cartilage destruction, antibody production, and the acute-phase response. All major PIA quantitative trait loci (QTLs) identified in early severe arthritis were also strong regulators of CIA. The 2 strongest QTLs, Cia12/Pia4 on chromosome 12 and Cia13/Pia7 on chromosome 4, were also analyzed in congenic strains with DA or E3 as the background genome. Consistent with the results of linkage analysis, the congenic strain experiments showed that the chromosome 4 locus was more penetrant in CIA than in PIA, while the chromosome 12 locus almost completely dominated the control of PIA severity.Conclusion. The underlying genetic control of CIA was found to have many, but not all, pathogenic mechanisms in common with PIA, despite the use of a cartilage-specific antigen (type II collagen) to induce CIA but not PIA.

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Mapping and functional characterization of rat chromosome 4 regions that regulate arthritis models and phenotypes in congenic strains

Bäckdahl

Ribbhammar

Lorentzen

2003

Arthritis & Rheumatism

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Objective. DA rats are highly susceptible to experimental models of rheumatoid arthritis (RA). Linkage analyses in different models have identified several quantitative trait loci (QTLs) within a 70-cM region of DA rat chromosome 4 (C4). We produced congenic strains for these QTLs in order to map and characterize their impact on arthritis development.Methods. Selective breeding was used to transfer C4 intervals from arthritis-resistant PVG.1AV1 rats onto DA rats. These congenic strains were evaluated for susceptibility to arthritis induced by intradermal injection of rat type II collagen, pristane (a well-defined synthetic adjuvant oil), mycobacteria, or squalene (an endogenous adjuvant oil used in human vaccine).Results. Rats congenic for PVG.1AV1 genes in the 70-cM region were less susceptible than DA rats to collagen-induced arthritis (CIA), pristane-induced arthritis, adjuvant-induced arthritis, and squaleneinduced arthritis (SIA). Experiments in subcongenic strains indicated a gene regulating arthritis in males located in a 20-cM interval overlapping the QTL Pia5. A second gene, located in a 10-cM interval harboring the QTL Oia2, attenuated SIA and CIA. The latter caused a change in anticollagen antibody isotype levels toward a pattern similar to that seen in PVG.1AV1 rats. Conclusion.The QTL Oia2 regulates arthritis induced both by the nonimmunogenic immunostimulant squalene and by cartilage collagen. In CIA, it also skews anticollagen isotype profiles, suggesting qualitative regulation of autoimmunity. Interestingly, the homologous human chromosome region 12p12-p13 has also been linked to RA, suggesting that genetic and functional dissection of this locus will provide clues to disease pathways that lead to joint inflammation.

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Complex Genetic Control in a Rat Model for Rheumatoid Arthritis

Cited by 36 publications

References 27 publications

New Loci Regulating Rat Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

New Loci Regulating Rat Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

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

Mapping and functional characterization of rat chromosome 4 regions that regulate arthritis models and phenotypes in congenic strains

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