The genetic control of rheumatoid factor production in a rat model of rheumatoid arthritis

Wernhoff, Patrik; Olofsson, Peter; Holmdahl, Rikard

doi:10.1002/art.11342

“…Even though the sensitivity and specificity of RF for identification of patients with RA is relatively low compared with the more recently discovered autoantibodies, several studies show that RF predisposes to the development of RA (38,43,44). Increased levels of RF in symptom-free individuals greatly increase the risk of acquiring RA, and high titers predict persistent radiographic damage in inflammatory polyarthritis (38,43,44). Moreover, RF levels are also elevated in relatives of RA patients and RA-prone rats, providing evidence of an independent genetic control of RF production (38,43,44).…”

Section: Discussionmentioning

confidence: 99%

Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis

Quinones¹,

Ahuja²,

Jiménez³

et al. 2004

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The prevailing paradigm is that in human rheumatoid arthritis (RA), the accumulation of monocytes and T cells in the joint, mediated in part by such CC chemokine receptors (CCRs) as CCR2 and CCR5, respectively, plays a central role in disease pathogenesis. To further validate this paradigm, we conducted proof-of-principle studies and tested the hypothesis that gene inactivation of Ccr2 or Ccr5 will ameliorate experimental RA. Contrary to our expectations, we found that in two well-established murine models of experimental RA, CCR2 expression in the hematopoietic cell compartment served as a negative regulator of autoantibody production as well as arthritic disease onset, severity, and resolution. In contrast, the RA phenotype in Ccr5-null mice was similar to that of WT mice. Remarkably, the collagen-induced arthritis phenotype of Ccr2 -/-mice mimicked closely that of severe human RA, including production of rheumatoid factor, enhanced T cell production, and monocyte/macrophage accumulation in the joints. Our findings demonstrate an essential protective role of CCR2 expression in RA, indicate the existence of alternative receptors responsible for monocyte/macrophage accumulation to inflamed joints, and emphasize the need to clarify carefully the complex effects of the chemokine system in RA before they can be considered as therapeutic targets.Nonstandard abbreviations used: activation-induced cell death (AICD); alkaline phosphatase (AKP); antigen (Ag); chemokine receptor (CCR); collagen Ab-induced arthritis (CAIA); collagen-induced arthritis (CIA); draining lymph nodes (DLN); graft-versus-host-disease (GVHD); macrophage inflammatory protein (MIP); monocyte chemoattractant protein (MCP); p-nitrophenyl phosphate (pNPP); receptor activator NF-κB ligand (RANKL); rheumatoid arthritis (RA); rheumatoid factor (RF); ribonuclease protection assay (RPA); single-stranded DNA (ssDNA); tartrate-resistant acid phosphatase (TRAP); type II collagen (CII).

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“…However, RF was detected in the sera of Ccr2 -/-mice ( Figure 3C), thus reproducing one of the characteristic features of human RA, and notably, a feature of only a handful of other rodent models of RA (Table 1, and refs. [38][39][40][42][43][44][45][46]. Furthermore, compared with WT mice, higher levels of circulating anti-single-stranded DNA (anti-…”

Section: Figurementioning

confidence: 99%

Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis

Quinones¹,

Ahuja²,

Jiménez³

et al. 2004

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The prevailing paradigm is that in human rheumatoid arthritis (RA), the accumulation of monocytes and T cells in the joint, mediated in part by such CC chemokine receptors (CCRs) as CCR2 and CCR5, respectively, plays a central role in disease pathogenesis. To further validate this paradigm, we conducted proof-of-principle studies and tested the hypothesis that gene inactivation of Ccr2 or Ccr5 will ameliorate experimental RA. Contrary to our expectations, we found that in two well-established murine models of experimental RA, CCR2 expression in the hematopoietic cell compartment served as a negative regulator of autoantibody production as well as arthritic disease onset, severity, and resolution. In contrast, the RA phenotype in Ccr5-null mice was similar to that of WT mice. Remarkably, the collagen-induced arthritis phenotype of Ccr2 -/-mice mimicked closely that of severe human RA, including production of rheumatoid factor, enhanced T cell production, and monocyte/macrophage accumulation in the joints. Our findings demonstrate an essential protective role of CCR2 expression in RA, indicate the existence of alternative receptors responsible for monocyte/macrophage accumulation to inflamed joints, and emphasize the need to clarify carefully the complex effects of the chemokine system in RA before they can be considered as therapeutic targets.Nonstandard abbreviations used: activation-induced cell death (AICD); alkaline phosphatase (AKP); antigen (Ag); chemokine receptor (CCR); collagen Ab-induced arthritis (CAIA); collagen-induced arthritis (CIA); draining lymph nodes (DLN); graft-versus-host-disease (GVHD); macrophage inflammatory protein (MIP); monocyte chemoattractant protein (MCP); p-nitrophenyl phosphate (pNPP); receptor activator NF-κB ligand (RANKL); rheumatoid arthritis (RA); rheumatoid factor (RF); ribonuclease protection assay (RPA); single-stranded DNA (ssDNA); tartrate-resistant acid phosphatase (TRAP); type II collagen (CII).

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“…The study of rat models of arthritis in inbred strains that differ in their susceptibility to and severity of arthritis reduces several of these confounding variables (17,18), thus facilitating the identification of loci regulating arthritis-related phenotypes, including disease severity (19 -28), chronicity (23,29,30), as well as specific disease features, such as the production of rheumatoid factors (31). Once identified, these rat arthritis genes will provide novel targets for focused candidate gene (or candidate pathway) analysis in RA case-control studies.…”

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confidence: 99%

The Non-MHC Quantitative Trait LocusCia5Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis

Meng

¹

,

Yarlett

²

,

Joe

³

et al. 2005

The Journal of Immunology

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Cia5 is a locus on rat chromosome 10 which regulates the severity of collagen- and pristane-induced arthritis (CIA and PIA). To refine the region toward positional identification, Cia5 subcongenic strains were generated and studied in PIA and CIA. The protective effect of the telomeric locus Cia5a was confirmed in both models. A second arthritis severity locus (Cia5d) was identified within the most centromeric portion of Cia5. DA.F344(Cia5d) rats had a significantly lower median arthritis severity index in PIA, but not in CIA, compared with DA. On histologic analyses DA.F344(Cia5a) and DA.F344(Cia5d) congenics with PIA preserved a nearly normal joint architecture compared with DA, including significant reduction in synovial hyperplasia, pannus, angiogenesis, inflammatory infiltration, bone and cartilage erosions. Cia5 and Cia5a synovial levels of IL-1β mRNA were reduced. Although both DA.F344(Cia5) and DA.F344(Cia5a) rats were protected in CIA, the arthritis scores of DA.F344(Cia5) were significantly higher than those of DA.F344(Cia5a), suggesting the existence of a third locus where F344-derived alleles centromeric from Cia5a contribute to increased arthritis severity. The existence of the third locus was further supported by higher levels of autoantibodies against rat type II collagen in DA.F344(Cia5) congenics compared with DA.F344(Cia5a). Our results determined that Cia5 contains three major arthritis severity regulatory loci regulating central events in the pathogenesis of arthritis, and differentially influencing CIA and PIA. These loci are syntenic to regions on human chromosomes 17q and 5q implicated in the susceptibility to rheumatoid arthritis, suggesting that the identification of these genes will be relevant to human disease.

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The genetic control of rheumatoid factor production in a rat model of rheumatoid arthritis

Cited by 31 publications

References 65 publications

Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis

Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis

Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis

The Non-MHC Quantitative Trait LocusCia5Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis

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