Positional identification of Ncf1 as a gene that regulates arthritis severity in rats

Olofsson, Peter; Holmberg, Jens; Tordsson, Jesper; Lu, Shemin; Åkerström, Bo; Holmdahl, Rikard

doi:10.1038/ng1058

Cited by 337 publications

(368 citation statements)

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“…This locus also showed a strong effect on disease, since the E3 allele of this locus conferred 90% protection against arthritis severity in PIA (Figure 3). Recently, the Cia12/Pia4 QTL was found to confer structural polymorphism in the Ncf1 gene (35). The effect of this genetic variation resulted in differential production of free radicals by the NADPH oxidase complex (36).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

Olofsson¹,

Lu²,

Holmberg³

et al. 2003

Arthritis & Rheumatism

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“…Lack of oxygen radicals promotes inflammation by breaking T-cell tolerance to CII, 29 and the inflammation is probably mediated via CD68 ϩ cells during the process of antigen presentation, 56 which in turn could affect APC-T-cell interactions and the resulting T-cell priming and activation. 27,57 We also reported that Ncf1-associated, reduced oxidative environment promotes IL33 ϩ -dependent, T cell-mediated, adjuvant-free arthritis in mice. 58 In the present study, we found that PNiPAAm-CII immunization led to significantly enhanced incidence and severity of arthritis in the Ncf1 mutated mice compared with wild-type littermate controls.…”

Section: Discussionmentioning

confidence: 78%

“…Furthermore, our recent studies demonstrated Ncf1 (coding p47 phox subunit of the NA-DPH oxidase complex, which is a multicomponent electron carrier that is responsible for the reduction of oxygen, resulting in the production of ROS) polymorphism as one of the major genetic factors that control arthritis severity and chronicity, regulating autoimmune reactions and impaired tolerance to CII. [27][28][29] In addition, we have also observed a high frequency of arthritis after CII immunization without any adjuvant in a transgenic mice expressing a CII-specific TCR V␤12 chain that recognizes the immunodominant glycosylated CII260Ϫ270 peptide that is dependent on eosinophilic inflammation. 30 Hence, in the present study, we tested various mouse strains using PNiPAAm-CII immunization to find genetic restriction of arthritis development in the absence of a classical adjuvant.…”

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confidence: 67%

“…Earlier we identified Ncf1 as an arthritis susceptibility gene in rats and mice, 27,28 which provided evidence for the importance of the dysfunctional NADPH oxidase complex and reduced reactive oxygen species (ROS) production in arthritis development. The Ncf1 protein (also known as p47 phox ) is an essential organizing subunit of the NADPH oxidase complex that is responsible for the production of ROS in phagocytic cells (NOX2).…”

Section: Discussionmentioning

confidence: 99%

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Collagen Type II and a Thermo-Responsive Polymer of N-Isopropylacrylamide Induce Arthritis Independent of Toll-Like Receptors

Shakya

Kumar

Klaczkowska

et al. 2011

The American Journal of Pathology

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We established and characterized an arthritis mouse model using collagen type II (CII) and a thermo-responsive polymer, poly(N-isopropylacrylamide) (PNiPAAm). The new PNiPAAm adjuvant is TLR-independent, as all immunized TLR including MyD88-deficient mice developed an anti-CII response. Unlike other adjuvants, PNiPPAm did not skew the cytokine response (IL-1␤, IFN-␥, IL-4, and IL-17), as there was no immune deviation towards any one type of immune spectrum after immunization with CII/ PNiPPAm. Hence, using PNiPAAm, we studied the actual immune response to the self-protein, CII. We observed arthritis and autoimmunity development in several murine strains having different major histocompatibility complex (MHC) haplotypes after CII/ PNiPAAm immunization but with a clear MHC association pattern. Interestingly, C57Bl/6 mice did not develop CII-induced arthritis, with PNiPAAm demonstrating absolute requirement for a classical adjuvant. Presence of a gene (Ncf1) mutation in the NADPH oxidation complex has a profound influence in arthritis and using PNiPAAm we could show that the high CIA severity in Ncf1 mutated mice is independent of any classical adjuvant. Macrophages, neutrophils, eosinophils, and osteoclasts but not mast cells dominated the inflamed joints. Furthermore, arthritis induction in the adjuvant-free, eosinophil-dependent V␤12 DBA/1 mice could be shown to develop arthritis independent of eosinophils using CII/PNiPAAm. Thus, biocompatible and biodegradable PNiPAAm offers unique opportunities to study actual autoimmunity independent of TLR and a particular cytokine phenotype profile.

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“…15 Based on their thought role in protecting cells from oxidative stress, several GSTs have been suggested as candidate genes for cancer, 16 arthritis, 17 hypertension 18 and asthma. 19 However, the lower levels of Gstm1 and Gstm2 in the congenic strain might play a protective role during the induction phase of CIA, since reduced oxidative burst response has been shown to promote activation of arthritogenic T cells, both in pristane-induced arthritis (PIA) in rats 20 and in CIA in mice. 21 Tspan-2, which is one of the candidates for Cia21, 5 is also a possible candidate for the insulin-dependent diabetes loci 10, Idd10, mapped to the same region.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice

et al. 2005

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One of the major quantitative trait loci (QTLs) associated with arthritis in crosses between B10.RIII and RIIIS/J mice is the Cia5 on chromosome 3. Early in the congenic mapping process it was clear that the locus was complex, consisting of several subloci with small effects. Therefore, we developed two novel strategies to dissect a QTL: the partial advanced intercross (PAI) strategy, with which we recently found the Cia5 region to consist of three loci, Cia5, Cia21 and Cia22, and now we introduce the QTL-chip strategy, where we have combined congenic mapping with a QTL-restricted expression profiling using a novel microarray design. The expression of QTL genes was compared between parental and congenic mice in lymph node, spleen and paw samples in five biological replicates and in dye-swapped experiments at three time points during the induction phase of arthritis. The QTL chip approach revealed 4 genes located in Cia21, differently expressed in lymph nodes, and 14 genes in Cia22, located within two clusters. One cluster contains six genes, differently expressed in spleen, and the second cluster contains eight genes, differently expressed in paws. We conclude the QTL-chip strategy to be valuable in the selection of candidate genes to be prioritized for further investigation.

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Positional identification of Ncf1 as a gene that regulates arthritis severity in rats

Cited by 337 publications

References 50 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

Collagen Type II and a Thermo-Responsive Polymer of N-Isopropylacrylamide Induce Arthritis Independent of Toll-Like Receptors

Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice

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