High-resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice

Ahlqvist, Emma; Ekman, Diana; Lindvall, Therese; Popovic, Marjan; Förster, Michael; Hultqvist, Malin; Klaczkowska, Dorota; Teneva, Ivanka; Johannesson, Martina; Flint, Jonathan; Valdar, William; Nandakumar, Kutty Selva; Holmdahl, Rikard

doi:10.1093/hmg/ddr206

Cited by 20 publications

(35 citation statements)

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“…After nine generations of backcross, a fragment of 15 mbp in chromosome 12 containing the targeted locus IgJ H was found. The genetic purity was confirmed using a 10k single nucleotide polymorphism chip (22) to scan genome of ACB and B10.Q strains.…”

Section: Methodsmentioning

confidence: 99%

Pathogenic Autoreactive B Cells Are Not Negatively Selected toward Matrix Protein Collagen II

Cao

Khmaladze

Jia

et al. 2011

The Journal of Immunology

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We have addressed the importance of B cell tolerance to collagen type II, a matrix protein, which is a target in rheumatoid arthritis (RA) and its mouse models. We generated a germline-encoded anti-collagen type II (CII) IgH replacement anti-C1 B cell mouse strain (ACB) to investigate how B cell tolerance to CII, a matrix protein, is subverted and to further understand pathogenesis of RA. Phenotypic analysis revealed that CII-specific B cells were surprisingly neither deleted nor anergized. Instead, they were readily detected in all lymphoid organs. Spontaneously produced autoantibodies could bind directly to cartilage surface without detectable pathology. However, exaggerated arthritis was seen after injection of anti-CII Abs specific for other epitopes. In addition, Abs from CII-specific hybridomas generated from ACB mice induced arthritis. Interestingly, IgH/L chain sequence data in B cell hybridomas revealed a lack of somatic mutations in autoreactive B cells. The ACB model provides the first possibility, to our knowledge, to study B cell tolerance to a matrix protein, and the observations made in the study could not be predicted from previous models. B cell-reactive epitopes on CII are largely shared between human RA and rodent CII-induced arthritis; this study, therefore, has important implications for further understanding of pathological processes in autoimmune diseases like RA.

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Section: Methodsmentioning

confidence: 99%

Pathogenic Autoreactive B Cells Are Not Negatively Selected toward Matrix Protein Collagen II

Cao

Khmaladze

Jia

et al. 2011

The Journal of Immunology

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“…3). In mice, both AILs and HSs have been used for the high-resolution mapping of QTLs associated with different arthritis traits, including disease onset, severity, incidence and antibody production (Ahlqvist et al, 2011; Förster et al, 2012; Yu et al, 2006). HSs have also been developed in rats from eight inbred progenitor strains – ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N (Johannesson et al, 2009) – and have been successfully used to map QTLs contributing to different phenotypic traits (Baud et al, 2013).…”

Section: Different Strategies Of Disease Gene Identificationmentioning

confidence: 99%

“…The use of these models in laboratory animals overcomes the challenges of genetic heterogeneity and environmental effects that feature in human studies. Animal models can also be used to identify disease loci, which can then be isolated on a fixed genetic background so that conclusive experiments can be performed to investigate specific disease pathways in vivo (Ahlqvist et al, 2011; Aitman et al, 2008; Baud et al, 2013; Vingsbo et al, 1996; Moreno-Moral and Petretto, 2016). …”

Section: Introductionmentioning

confidence: 99%

Rheumatoid arthritis: identifying and characterising polymorphisms using rat models

Yau

Holmdahl

2016

Disease Models &Amp; Mechanisms

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Rheumatoid arthritis is a chronic inflammatory joint disorder characterised by erosive inflammation of the articular cartilage and by destruction of the synovial joints. It is regulated by both genetic and environmental factors, and, currently, there is no preventative treatment or cure for this disease. Genome-wide association studies have identified ∼100 new loci associated with rheumatoid arthritis, in addition to the already known locus within the major histocompatibility complex II region. However, together, these loci account for only a modest fraction of the genetic variance associated with this disease and very little is known about the pathogenic roles of most of the risk loci identified. Here, we discuss how rat models of rheumatoid arthritis are being used to detect quantitative trait loci that regulate different arthritic traits by genetic linkage analysis and to positionally clone the underlying causative genes using congenic strains. By isolating specific loci on a fixed genetic background, congenic strains overcome the challenges of genetic heterogeneity and environmental interactions associated with human studies. Most importantly, congenic strains allow functional experimental studies be performed to investigate the pathological consequences of natural genetic polymorphisms, as illustrated by the discovery of several major disease genes that contribute to arthritis in rats. We discuss how these advances have provided new biological insights into arthritis in humans.

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“…PMA and ionomycin were then added as a positive control. The ratio of emission of Fluo-4 divided by Fura Scandinavian Journal of Immunology, 2016, 84, [3][4][5][6][7][8][9][10][11] Red was calculated to best estimate calcium influx in gated CD4 + CD19 neg . The difference between baseline and the peak value of antibody stimulated cells was used as main parameter.…”

Section: Methodsmentioning

confidence: 99%

“…Other commonly used genetic backgrounds, including C57BL/B6 (B6) and C57BL/B10 (B10), which normally express a different MHC haplotype, are resistant to CIA. However, using a disease-promoting congenic MHC such as MHC H2-A q from DBA/1, susceptibility to CIA can be transferred to B6 and B10 mice [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

The SKG Mutation in ZAP‐70 also Confers Arthritis Susceptibility in C57 Black Mouse Strains

et al. 2016

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Various rodent models of arthritis are essential to dissect the full complexity of human rheumatoid arthritis (RA), a common autoimmune disease affecting joints. The SKG model of arthritis originates from a spontaneous mutation in ZAP-70 found in a BALB/c colony. This mutation affects T cell selection due to reduced TCR signalling, which allows leakage of self-reactive T cells from the thymus. To further expand the practical applicability of this unique model in arthritis research, we investigated the arthritogenicity of the SKG mutation in two common black mouse strains C57BL/6.Q and C57BL/10.Q and compared to BALB/c.Q. Mice retained the reduced TCR signalling characteristic of SKG.BALB/c mice, which leads to similar alteration in thymic selection. Importantly, mice also retained susceptibility to chronic arthritis after a single injection of mannan from Saccharomyces cerevisiae, with comparable prevalence and severity regardless of the genetic background. Further characterization of CD4(+) T cells revealed a similar bias towards IL-17 production and activated T cell phenotype in all SKG strains compared to respective wild type controls. Finally, transfer of SKG thymocytes conferred susceptibility to recipients, which confirm the intrinsic defect and pathogenicity of T cells. Overall, these results underline the strong impact that the W163C ZAP-70 mutation has on T cell-driven arthritis, and they support the use of the SKG model in black mice, which is useful for further investigations of this distinctive arthritis model to better understand autoimmunity.

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High-resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice

Cited by 20 publications

References 50 publications

Pathogenic Autoreactive B Cells Are Not Negatively Selected toward Matrix Protein Collagen II

Pathogenic Autoreactive B Cells Are Not Negatively Selected toward Matrix Protein Collagen II

Rheumatoid arthritis: identifying and characterising polymorphisms using rat models

The SKG Mutation in ZAP‐70 also Confers Arthritis Susceptibility in C57 Black Mouse Strains

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