Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis

Otto, Jeffrey M.; Cs‐Szabó, Gabriella; Gallagher, Jodi; Velins, Sonja; Mikecz, Katalin; Buzás, Edit I.; Enders, Jill T.; Li, Yefu; Olsen, Bjørn R.; Glant, Tibor T.

doi:10.1002/1529-0131(199912)42:12<2524::aid-anr4>3.0.co;2-0

Cited by 68 publications

(81 citation statements)

References 23 publications

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“…Amd1 and Asm1 may be a common locus for the same etiology of these 2 kinds of diseases. This is also the first study to map a gene locus for susceptibility to spontaneous arthropathy in DBA/1 mice, Amd2, on chromosome 3 in the region of a DBA/1 (14,22) and other mouse and rat models (23)(24)(25). However, the region of Amd2 did not share any of the loci involving the MHC.…”

Section: Discussionmentioning

confidence: 85%

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

Oishi¹,

Miyazaki²,

Mizuki³

et al. 2005

Arthritis & Rheumatism

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Objective. To analyze the influence of the genetic background of an arthritis-prone strain of mice, MRL, on the spontaneous development of arthropathy in DBA/1 mice, which histopathologically resembles enthesopathy in humans, and to clarify the strain-specific gene loci and their interactions that confer susceptibility to arthropathy.Methods. MRL, DBA/1, (MRL ؋ DBA/1)F 1 , and (MRL ؋ DBA/1)F 2 intercross mice were prepared, and the severity and onset of arthropathy of the ankle joints in individual mice were quantified (0-3 and 0-5 scale, respectively). A genome-wide scan of 271 male F 2 intercross mice with polymorphic microsatellite markers was performed.Results. Only male DBA/1, (MRL ؋ DBA/1)F 1 , and (MRL ؋ DBA/1)F 2 mice developed arthropathy. The macroscopic and histopathologic findings of arthropathy in the F 2 mice were similar to those in the parental DBA/1 mice, but the onset was significantly earlier. In the quantitative trait locus analysis of male F 2 mice, 1 susceptibility locus for both the severity and early onset of the disease in the region of an MRL allele, Amd1, was located at marker D10Mit259 (map position 40.0 cM), which was common to 1 of the sialadenitis susceptibility loci in MRL mice, Asm1. Another susceptibility locus for the severity and early onset of arthropathy in the region of a DBA allele, Amd2, was located at D3Mit46 (29.5 cM). These loci manifested an additive effect on the development of arthropathy.Conclusion. Arthropathy in DBA/1 mice is under the control of an allelic combination of gene loci, one of which is common to the locus for sialadenitis in MRL/ MpJ-lpr/lpr mice.

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Section: Discussionmentioning

confidence: 85%

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

Oishi¹,

Miyazaki²,

Mizuki³

et al. 2005

Arthritis & Rheumatism

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“…In contrast, Milt4 could not be confirmed using the respective consomic mice, probably because it is involved in an epistatic relationship with other genes. Previous studies have mapped QTL to the same region on mouse Chr 8 for susceptibility to arthritis (20), colitis (21,22), and experimental allergic encephalomyelitis (23). It is likely that these diseases share an inflammatory component with endotoxemia.…”

Section: Discussionmentioning

confidence: 99%

A Quantitative Trait Loci Analysis to Map Genes Involved in Lipopolysaccharide-Induced Inflammatory Response: Identification of Macrophage Scavenger Receptor 1 as a Candidate Gene

Fulton¹,

Reeves

Takeya

et al. 2006

The Journal of Immunology

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Septic shock, which is a major complication observed after trauma and other human diseases, is likely the product of a prolonged and poorly controlled systemic inflammatory response. Symptoms of sepsis can be partially reproduced by injection of bacterial LPS in mice. Differences in mortality between C57BL/6Jhigh and A/Jlow mice after LPS injection have been previously observed and correlated with differences in the inflammatory response between these two inbred strains. In the present study, we have mapped four loci responsible for differences in levels of LPS-induced IL-10, named modifier of IL-10, between the two strains. A locus within mouse chromosome 8 was confirmed using chromosome 8 consomic mice. This locus was further reduced in size by haplotype analysis and evaluated by the presence of potential candidate genes. The macrophage scavenger receptor 1 (Msr1) within this locus emerged as a candidate gene based on differences at the expression and structural levels between C57BL/6J and A/J mice. In comparison with wild-type (C57BL/6J) mice, Msr1 knockout mice displayed reduced levels of LPS-induced IL-10, but not of TNF-α or IL-6, confirming a specific role for this gene in the regulation of IL-10. These results suggest that Msr1 is involved in the regulation of the anti-inflammatory process, thus offering a new perspective on the molecular mechanisms involved in endotoxemia and sepsis.

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“…Multiple genetic loci regulate adenovirus clearance H-G Zhang et al (BALB/c Â DBA/2)F 2 mice 48 and also the duration and onset of experimental allergic encephalomyelitis in (SJL/J Â B10.S/DvTe)F 2 mice. 49 Similarly, the QTL influencing IL-6 on Chr 6 (41.5 cM) is close to a previously mapped QTL on Chr 6 (44 cM) for autoimmune gastritis, 50 collagen II-induced arthritis (Chr 6, 48.7 cM), 51 and cutaneous hypersensitivity (Chr 6, 45.5 cM).…”

Section: (C) Ifn-g Is Plotted Against Tnf-a As Described In (B) (D) mentioning

confidence: 99%

Identification of multiple genetic loci that regulate adenovirus gene therapy

et al. 2003

Gene Ther

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A key aspect of the immune response to adenovirus (Ad) gene therapy is the generation of a cytotoxic T-cell (CTL) response. To better understand the genetic network underlying these events, 20 strains of C57BL/6 Â DBA/2 (BXD) recombinant inbred (RI) mice were administered with AdLacZ and analyzed at days 7, 21, 30, and 50 for liver b-galactosidase (LacZ) expression and CTL response. Sera levels of interferon gamma (IFN-g), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) were analyzed at different times after AdLacZ. There was a distinct strain-dependent expression of LacZ, which was strongly correlated with the CTL response. Among the five BXD RI strains that exhibited significantly prolonged LacZ expression, four also exhibited a marked defect in the production of Ad-specific CTL. There was a strong correlation between the sera levels of IFN-g, TNF-a, and IL-6, but cytokine responses were not significantly correlated with LacZ expression or the CTL response. Quantitative trait loci regulating LacZ on day 30 were found on chromosome (Chr) 19 (33 cM) and Chr 15 (42.8 cM). Cytotoxicity mapped to Chr 7 (41.0 and 57.4-65.2 cM), Chr 15 (61.7 cM), and Chr X (27.8 cM). IFN-g production mapped to Chr 18 (22, 27, and 32 cM) and Chr 11 (64.0 cM). TNF-a and IL-6 production mapped to Chr 6 (91.5 cM) Chr 9 (42.0 cM) and Chr 8 (52 and 73.0 cM). These results indicate that different strains of mice exhibit different pathways for effective clearance of AdLacZ depending on genetic polymorphisms and interactions at multiple genetic loci.

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Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis

Cited by 68 publications

References 23 publications

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

A Quantitative Trait Loci Analysis to Map Genes Involved in Lipopolysaccharide-Induced Inflammatory Response: Identification of Macrophage Scavenger Receptor 1 as a Candidate Gene

Identification of multiple genetic loci that regulate adenovirus gene therapy

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