Genetic control of antibody production during collagen‐induced arthritis development in heterogeneous stock mice

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

doi:10.1002/art.34658

Cited by 19 publications

(16 citation statements)

References 78 publications

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“…The only exception was the lack of response to the J1 epitope in the common marmoset. This lack is in fact similar to the mouse in which the response to J1 is strain specific [28]. Interestingly, the heterogeneity in the mouse has been mapped to the variable heavy chain locus, indicating that constraints of the binding structures lead to restrictions in using allele-specific V genes [7].…”

Section: Discussionmentioning

confidence: 91%

Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice

et al. 2014

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IntroductionAntibodies towards type II collagen (CII) are detected in patients with rheumatoid arthritis (RA) and in non-human primates and rodents with collagen induced arthritis (CIA). We have previously shown that antibodies specific for several CII-epitopes are pathogenic using monoclonal antibodies from arthritic mice, although the role of different anti-CII epitopes has not been investigated in detail in other species. We therefore performed an inter-species comparative study of the autoantibody response to CII in patients with RA versus monkeys and mice with CIA.MethodsAnalysis of the full epitope repertoire along the disease course of CIA was performed using a library of CII triple-helical peptides. The antibody responses to the major CII epitopes were analyzed in sera and synovial fluid from RA patients, and in sera from rhesus monkeys (Macaca mulatta), common marmosets (Callithrix jacchus) and mice.ResultsMany CII epitopes including the major C1, U1, and J1 were associated with established CIA and arginine residues played an important role in the anti-CII antibody interactions. The major epitopes were also recognized in RA patients, both in sera and even more pronounced in synovial fluid: 77% of the patients had antibodies to the U1 epitope. The anti-CII immune response was not restricted to the anti-citrulline protein antibodies (ACPA) positive RA group.ConclusionCII conformational dependent antibody responses are common in RA and are likely to originate from rheumatoid joints but did not show a correlation with ACPA response. Importantly, the fine specificity of the anti-CII response is similar with CIA in monkeys and rodents where the recognized epitopes are conserved and have a major pathogenic role. Thus, anti-CII antibodies may both contribute to, as well as be the consequence of, local joint inflammation.

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Section: Discussionmentioning

confidence: 91%

Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice

et al. 2014

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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%

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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“…Indeed peptidyl arginine deiminase (PAD) that generates citrullinated peptides, is expressed in CIA synovia, and citrullination of CII enhances the arthritogenic activity (Lundberg et al, 2005). Both ACPA and RF have been described in the CIA model in C57BL/6Q mice (Forster et al, 2012) and in SKG mice (Hsu et al, 2009) (Keith et al, 2013) but there are no reports of ACPA in KxB/N or hTNF mice.…”

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Animal models of rheumatoid arthritis: How informative are they?

McNamee

Williams

Seed

2015

European Journal of Pharmacology

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Animal models of arthritis are widely used to de-convolute disease pathways and to identify novel drug targets and therapeutic approaches. However, the high attrition rates of drugs in Phase II/III rates means that a relatively small number of drugs reach the market, despite showing efficacy in pre-clinical models. There is also increasing awareness of the ethical issues surrounding the use of animal models of disease and it is timely, therefore, to review the relevance and translatability of animal models of arthritis. In this paper we review the most commonly used animal models in terms of their pathological similarities to human rheumatoid arthritis as well as their response to drug therapy. In general, the ability of animal models to predict efficacy of biologics in man has been good. However, the predictive power of animal models for small molecules has been variable, probably because of differences in the levels of target knockdown achievable in vivo.3

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Genetic control of antibody production during collagen‐induced arthritis development in heterogeneous stock mice

Cited by 19 publications

References 78 publications

Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice

Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice

Rheumatoid arthritis: identifying and characterising polymorphisms using rat models

Animal models of rheumatoid arthritis: How informative are they?

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