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- Ahlqvist, Emma, et al.
(författare)
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High-resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice
- 2011
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Ingår i: Human Molecular Genetics. - Oxford : Oxford University Press. - 0964-6906 .- 1460-2083. ; 20:15, s. 3031-3041
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Tidskriftsartikel (refereegranskat)abstract
- Resolving the genetic basis of complex diseases like rheumatoid arthritis will require knowledge of the corresponding diseases in experimental animals to enable translational functional studies. Mapping of quantitative trait loci in mouse models of arthritis, such as collagen-induced arthritis (CIA), using F(2) crosses has been successful, but can resolve loci only to large chromosomal regions. Using an inbred-outbred cross design, we identified and fine-mapped CIA loci on a genome-wide scale. Heterogeneous stock mice were first intercrossed with an inbred strain, B10.Q, to introduce an arthritis permitting MHCII haplotype. Homozygous H2(q) mice were then selected to set up an F(3) generation with fixed major histocompatibility complex that was used for arthritis experiments. We identified 26 loci, 18 of which are novel, controlling arthritis traits such as incidence of disease, severity and time of onset and fine-mapped a number of previously mapped loci. © The Author 2011. Published by Oxford University Press. All rights reserved.
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| 4. |
- Klaczkowska, Dorota
(författare)
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Finding genes controlling arthritis in mice-Fcγ receptors and complement C5
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmune diseases are dependent on multifactorial factors including genes, environment and interactions between them. This thesis is focused on a chronic inflammatory disorder, Rheumatoid arthritis (RA). So far only very few genes and environmental factors have been identified reflecting the complexity of the autoimmune processes. Identification of new genes and the underlying mechanisms leading to disease progression is absolutely crucial for finding more specific therapies. Understanding the pathogenic events causing chronic joint destruction can be best done using animal models. The work in this thesis focused on well-defined mouse models of autoimmune diseases: collagen induced arthritis (CIA), collagen antibody induced arthritis (CAIA) and experimental autoimmune encephalomyelitis (EAE). We have used two different strategies to map the genes that influence arthritis development: congenic strains and heterogeneous stock inbred-outbred cross. Of particular interest in this thesis are gene regions previously identified in two-generation crosses between B10.Q and NOD strains; Cia9 and Cia2 loci that carry promising candidate genes such as FcγR cluster region and complement C5 respectively. To be able to elucidate the role of underlying genes in arthritis in both the loci, we generated sub-interval congenic lines (paper III and IV). We found that FcγRIIb and FcγRIII are most likely candidates for the original Cia9 locus (paper III). Moreover, we were able to show that systemic rather than local production of complement C5 is crucial in arthritis development (paper IV). In order to identify additional loci controlling arthritis in mice we have used another genetic approach – using heterogeneous stock mice, a cross between eight different founders. At first, HS mice were screened for susceptibility to different animal models (paper II) and then CIA permissive H2q haplotype has been introduced and a large cohort of heterogeneous stock inbred-outbred cross was investigated for arthritis susceptibility (paper I). We found 18 new arthritis loci and fine mapped several already known loci including Cia9 and Cia2. The last part of this thesis describes the prospect of using a thermo-responsive polymer as an adjuvant (paper V). These results suggest mapping of causative genes in a complex disease is multifaceted and a challenging task.
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| 5. |
- Shakya, Akhilesh Kumar, et al.
(författare)
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Collagen type II and a thermo-responsive polymer of N-isopropylacrylamide induce arthritis independent of Toll-like receptors : a strong influence by major histocompatibility complex class II and Ncf1 genes
- 2011
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Ingår i: American Journal of Pathology. - New York : Elsevier. - 0002-9440 .- 1525-2191. ; 179:5, s. 2490-2500
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Tidskriftsartikel (refereegranskat)abstract
- 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-1beta, IFN-gamma, 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 Vbeta12 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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| 6. |
- Vaartjes, Daniëlle, et al.
(författare)
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Genetic dissection of a major haplotype associated with arthritis reveal FcγR2b and FcγR3 to act additively
- 2021
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 51:3, s. 682-693
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Tidskriftsartikel (refereegranskat)abstract
- A haplotype with tightly linked Fc gamma receptor (FcγR) genes is known as a major locus controlling immune responses and autoimmune diseases, including arthritis. Here, we split a congenic fragment derived from the NOD mouse (Cia9) to study its effect on immune response and arthritis in mice. We found that arthritis susceptibility was indeed controlled by the FcγR gene cluster and a recombination between the FcγR2b and FcγR3 loci gave us the opportunity to separately study their impact. We identified the NOD-derived FcγR2b and FcγR3 alleles as disease-promoting for arthritis development without impact on antibody secretion. We further found that macrophage-mediated phagocytosis was directly correlated to FcγR3 expression in the congenic mice. In conclusion, we positioned FcγR2b and FcγR3 alleles as disease regulatory and showed that their genetic polymorphisms independently and additively control innate immune cell activation and arthritis.
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