Arthritis induced in rats with non‐immunogenic adjuvants as models for rheumatoid arthritis

Holmdahl, Rikard; Lorentzen, Johnny C.; Lu, Shemin; Olofsson, Peter; Wester, Lena; Holmberg, Jens; Pettersson, Ulf

doi:10.1034/j.1600-065x.2001.1840117.x

Cited by 186 publications

(161 citation statements)

References 4 publications

(7 reference statements)

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“…The clinical manifestations of CIA are similar to those of PIA, although the genetic susceptibility and pathogenesis are slightly different (32). E3 rats are resistant to both PIA and CIA.…”

Section: Resultsmentioning

confidence: 83%

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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Section: Resultsmentioning

confidence: 83%

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

Olofsson¹,

Lu²,

Holmberg³

et al. 2003

Arthritis & Rheumatism

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“…5 Although the tested rheumatoid arthritis models depend on lymphocytes, they also rely on the use of injected adjuvant to break self-tolerance. [23][24][25][26] Log2 fold change (mean Relative mRNA levels (mean…”

Section: Discussionmentioning

confidence: 99%

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

Guo

Verdrengh²,

Tarkowski³

et al. 2009

Genes Immun

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Genetic variation in the antigen-presenting lectin-like receptor gene complex (APLEC) associates with autoimmunity and arthritis in rats and humans. We hypothesized that the encoded C-type lectin-like receptors might influence innate immunity and responses to infectious agents. To test this hypothesis, we compared in vivo and in vitro phenotypes in DA rats and APLEC-congenic rats. Survival rates following infection with Staphylococcus aureus and Herpes simplex virus differed significantly between the two strains. Likewise, differential delayed type hypersensitivity (DTH), an immunological reaction involving T lymphocytes and macrophages, was observed in response to provocation with the chemical oxazolone. Unstimulated bone marrow-derived macrophages from the two strains appeared to already have polarized activation states with different mRNA levels of CD163 and Dectin-1 receptors. Following stimulation with a panel of microbial agents, differences in induced mRNA and protein levels were shown for interleukin (IL)-6 and IL-10 following stimulation with lipopolysaccharide, mannan and b-glucan. Expression levels of APLEC gene mRNAs also differed, and both strains had a notably dichotomous expression of the genes, with general downregulation of all four Dcir genes and upregulation of Mincle and Mcl. We suggest that human APLEC genes may similarly regulate infectious diseases, DTH and general macrophage activation status.

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“…Such mechanisms have been implicated in the autoimmune susceptibility in type I diabetes and the NOD mouse [29]. In any case, these scenarios would require autoreactive T cells that escape negative selection in the thymus.There are good animal models for this scenario, for example, the PIA models in the rat [30] and the SKG model in the mouse [22] and even the CIA model, in which autoreactive T cells specific to glycosylated epitopes might not be properly deleted [31]. The lack of ACPAs in these models could be owing to the absence of relevant environmental factors combined with an inappropriate MHC class II allele.…”

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confidence: 99%

Autoimmune priming, tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

2014

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Extensive genome-wide association studies have recently shed some light on the causes of chronic autoimmune diseases and have confirmed a central role of the adaptive immune system. Moreover, better diagnostics using disease-associated autoantibodies have been developed, and treatment has improved through the development of biologicals with precise molecular targets. Here, we use rheumatoid arthritis (RA) as a prototype for chronic autoimmune disease to propose that the pathogenesis of autoimmune diseases could be divided into three discrete stages. First, yet unknown environmental challenges seem to activate innate immunity thereby providing an adjuvant signal for the induction of adaptive immune responses that lead to the production of autoantibodies and determine the subsequent disease development. Second, a joint-specific inflammatory reaction occurs. This inflammatory reaction might be clinically diagnosed as the earliest signs of the disease. Third, inflammation is converted to a chronic process leading to tissue destruction and remodeling. In this review, we discuss the stages involved in RA pathogenesis and the experimental approaches, mainly involving animal models that can be used to investigate each disease stage. Although we focus on RA, it is possible that a similar stepwise development of disease also occurs in other chronic autoimmune settings such as multiple sclerosis (MS), type 1 diabetes, and systemic lupus erythematosus.Keywords: Animal models r Autoimmunity r Rheumatology Revisiting past efforts of RA researchEven though much detail has been recently revealed on the genetics and epidemiology of autoimmune diseases, several concepts on autoimmunity have been around for a long time. Early rheumatology studies were already deeply engaged in analyzing rheumatoid factors (RFs), that is, autoantibodies to Ig, and the Correspondence: Dr. Rikard Holmdahl e-mail: Rikard.Holmdahl@ki.se strong genetic association of RA with the HLA-DR alloantigens. However, many of the underlying causes of RA and the different stages in the disease process are still unclear even with the most recent information and therefore many of the old conceptual questions remain.The main result of recent genome-wide association studies (GWAS) is the confirmation of the strong association between "classical" (RF-positive) RA and the "shared epitope" MHC class II alleles [1][2][3]. The shared epitope is a specific peptide-binding pocket, originally defined as a structure in the polymorphic DRB1 chain shared by many alleles with basic amino acids at positionwww.eji-journal.eu 1594 Rikard Holmdahl et al. Eur. J. Immunol. 2014. 44: 1593-1599 70 and 74 [2], to which one now also may add positions 11 and 13 that are also strongly associated with RA [3]. In addition, the identity of around hundred genetic loci, with minor contribution to RA susceptibility, strengthen the dogma that RA is caused by aberrant autoreactive T cells [4,5]. Even though the influence of MHC and CD4 + T cells are more validated than ever, we still search for th...

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Arthritis induced in rats with non‐immunogenic adjuvants as models for rheumatoid arthritis

Abstract: AcknowledgementsWe wish to thank Holger Luthman, Liselotte Bäckdahl and Ulrica Ribbhammar for critical reading of review text.

Cited by 186 publications

References 4 publications

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

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

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

Autoimmune priming, tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

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