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Sökning: WFRF:(Holmdahl Rikard) > Andersson Åsa

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1.
  • Andersson, Åsa, et al. (författare)
  • A genetic basis for shared autoimmunity in mouse models.
  • 2005
  • Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 38:3, s. 209-217
  • Forskningsöversikt (refereegranskat)abstract
    • Development of autoimmune disease is the result of activation of the immune system that subsequently leads to tissue destruction. Although the clinical outcome significantly differs between autoimmune diseases, some pathogenic pathways could be shared. During the recent years, intense efforts to find the genetic factors behind development of the complex and polygenic autoimmune diseases have been undertaken. The difficulties in addressing what genetic factors predispose for autoimmunity in humans underline the importance of animal models in the understanding of the general mechanisms behind the initiation of disease. Interestingly, it has been observed in studies of experimental models of autoimmune diseases, that many of the genetic linkages to disease development are located in the same genetic regions and potentially could be controlled by the same gene. Furthermore, comparison of the mouse/rat genetic regions with regions of association to human inflammatory diseases, also demonstrates some homologous loci between species. Some mouse strains can develop disease in more than one model for autoimmunity. This not only argues for some general mechanisms, but it also supports mechanisms related to the specific tissues attacked in the various autoimmune diseases. Here, we will discuss some aspects of shared autoimmunity in mouse models from a genetic point of view.
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2.
  • Jirholt, Johan, et al. (författare)
  • Identification of susceptibility genes for experimental autoimmune encephalomyelitis that overcome the effect of protective alleles at the eae2 locus.
  • 2002
  • Ingår i: International Immunology. - : Oxford University Press (OUP). - 1460-2377 .- 0953-8178. ; 14:1, s. 79-85
  • Tidskriftsartikel (refereegranskat)abstract
    • We have previously identified a locus on mouse chromosome 15 (eae2) that regulates susceptibility to experimental autoimmune encephalomyelitis in a cross between the susceptible strain B10.RIII and the resistant strain RIIIS/J. In an effort to verify the protective effect from having two RIIIS/J alleles at eae2, the resistant locus was bred into the susceptible strain in homozygous form. However, the expected effect was not as clear as in the original study. This might be due to an epistatic effect conferred by several unidentified genes in the genome of the resistant strain or due to the environment by genotype interactions, possibly overcoming the effect of protective alleles at eae2. To further the genetic understanding in this disease, a genome-wide linkage screening approach was employed on an F(2) intercross that carried the protective allele at eae2in homozygous form while the rest of the genome segregated between the B10.RIII and RIIIS/J strains as in the original investigation. In the present study we find one region on chromosome 7, not previously identified in this strain combination, that affects the disease at significant logarithm of the odds score and six regions showing suggestive evidence for linkage to disease phenotypes.
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3.
  • Johannesson, Martina, et al. (författare)
  • Identification of epistasis through a partial advanced intercross reveals three arthritis loci within the Cia5 QTL in mice
  • 2005
  • Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 6:3, s. 175-185
  • Tidskriftsartikel (refereegranskat)abstract
    • Identification of genes controlling complex diseases has proven to be difficult; however, animal models may pave the way to determine how low penetrant genes interact to promote disease development. We have dissected the Cia5/Eae3 susceptibility locus on mouse chromosome 3 previously identified to control disease in experimental models of multiple sclerosis and rheumatoid arthritis. Congenic strains showed significant but small effects on severity of both diseases. To improve the penetrance, we have now used a new strategy that defines the genetic interactions. The QTL interacted with another locus on chromosome 15 and a partial advanced intercross breeding of the two congenic strains for eight generations accumulated enough statistical power to identify interactions with several loci on chromosome 15. Thereby, three separate loci within the original QTL could be identified; Cia5 affected the onset of arthritis by an additive interaction with Cia31 on chromosome 15, whereas the Cia21 and Cia22 affected severity during the chronic phase of the disease through an epistatic interaction with Cia32 on chromosome 15. The definition of genetic interactions was a prerequisite to dissect the Cia5 QTL and we suggest the partial advanced intercross strategy to be helpful also for dissecting other QTL controlling complex phenotypes.
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4.
  • Karlsson, Jenny C, et al. (författare)
  • Genetic Interactions in Eae2 Control Collagen-Induced Arthritis and the CD4+/CD8+ T Cell Ratio.
  • 2005
  • Ingår i: Journal of Immunology. - 1550-6606. ; 174:1, s. 533-541
  • Tidskriftsartikel (refereegranskat)abstract
    • The Eae2 locus on mouse chromosome 15 controls the development of experimental autoimmune encephalomyelitis (EAE); however, in this study we show that it also controls collagen-induced arthritis (CIA). To find the smallest disease-controlling locus/loci within Eae2, we have studied development of CIA in 676 mice from a partially advanced intercross. Eae2 congenic mice were bred with mice congenic for the Eae3/Cia5 locus on chromosome 3, previously shown to interact with Eae2. To create a large number of genetic recombinations within the congenic fragments, the offspring were intercrossed, and the eight subsequent generations were analyzed for CIA. We found that Eae2 consists of four Cia subloci (Cia26, Cia30, Cia31, and Cia32), of which two interacted with each other, conferring severe CIA. Genes within the other two loci independently interacted with genes in Eae3/Cia5. Investigation of the CD4/CD8 T cell ratio in mice from the partially advanced intercross shows that this trait is linked to one of the Eae2 subloci through interactions with Eae3/Cia5. Furthermore, the expression of CD86 on stimulated macrophages is linked to Eae2.
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5.
  • Karlsson, Jenny C, et al. (författare)
  • Novel quantitative trait Loci controlling development of experimental autoimmune encephalomyelitis and proportion of lymphocyte subpopulations.
  • 2003
  • Ingår i: Journal of Immunology. - 1550-6606. ; 170:2, s. 1019-1026
  • Tidskriftsartikel (refereegranskat)abstract
    • The B10.RIII mouse strain (H-2r) develops chronic experimental autoimmune encephalomyelitis (EAE) upon immunization with the myelin basic protein 89–101 peptide. EAE was induced and studied in a backcross between B10.RIII and the EAE-resistant RIIIS/J strain (H-2r), and a complete genome scan with microsatellite markers was performed. Five loci were significantly linked to different traits and clinical subtypes of EAE on chromosomes 1, 5, 11, 15, and 16, three of the loci having sex specificity. The quantitative trait locus on chromosome 15 partly overlapped with the Eae2 locus, previously identified in crosses between the B10.RIII and RIIIS/J mouse strains. The loci on chromosomes 11 and 16 overlapped with Eae loci identified in other mouse crosses. By analyzing the backcross animals for lymphocyte phenotypes, the proportion of B and T cells in addition to the levels of CD4+CD8- and CD4-CD8+ T cells and the CD4+/CD8+ ratio in spleen were linked to different loci on chromosomes 1, 2, 3, 5, 6, 11, and 15. On chromosome 16, we found significant linkage to spleen cell proliferation. Several linkages overlapped with the quantitative trait loci for disease phenotypes. The identification of subphenotypes that are linked to the same loci as disease traits could be most useful in the search for candidate genes and biological pathways involved in the pathological process.
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6.
  • Kjellen, Peter, et al. (författare)
  • The H2-Ab gene influences the severity of experimental allergic encephalomyelitis induced by proteolipoprotein peptide 103-116
  • 2001
  • Ingår i: Journal of Neuroimmunology. - 1872-8421. ; 120:1-2, s. 25-33
  • Tidskriftsartikel (refereegranskat)abstract
    • Immunization of H2(p) and H2(q) congenic C3H mouse strains with the PLP 103-116 peptide elicited two distinct experimental allergic encephalomyelitis (EAE) disease courses. C3H.Q (H2(q)) mice developed an acute-phase disease with classical ascending paralytic signs whereas C3H.NB (H2(p)) developed a highly variable disease course with symptoms originating from CNS above the spinal chord. C3H.Q lacks functional H2-E molecules and share H2-Aalpha with C3H.NB. To examine if the differences found at positions 85, 86, 88, and 89 in the Abeta-chains account for disease susceptibility, H2(q) mice were made transgenic with the Ab(p) gene. The Ab(p)-transgenic mice on the C3H.Q background developed a more severe disease course, demonstrating the importance of class II. However, the onset was not affected and the disease showed a classical ascending paralysis similar to the C3H.Q suggesting that the observed brain symptoms were related to nonclass II genes. Inhibition studies performed on affinity purified MHC class II molecules indicated that the PLP 103-116 peptide bound to A(p) with slightly higher affinity than to A(q). Both A(q) and A(p) formed long-lived stable complexes (t(1/2)>24 h) with the PLP 103-116 peptide, but a higher amount of the peptide was loaded on to A(p) compared with A(q). An F2 gene segregation experiment, in which the low PLP 103-116 binding A(r) molecule and the high binding A(p) molecule could be compared for the influence on the disease susceptibility, indicated a role for both peptide binding affinity and non-MHC genes. Based on our results, we conclude that the H2-Ab gene controls severity of EAE but not necessarily the onset or type of disease course and that affinity of the disease-promoting peptide for the class II molecule is a critical pathogenic factor.
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7.
  • Liljander, Maria, et al. (författare)
  • Increased litter size and super-ovulation rate in congenic C57BL mice carrying a polymorphic fragment of NFR/N origin at the Fecq4 locus of chromosome 9.
  • 2009
  • Ingår i: Genetical Research. - 1469-5073. ; 91:4, s. 259-265
  • Tidskriftsartikel (refereegranskat)abstract
    • By analysing N2 mice from a cross between the inbred C57BL strain B10.Q and the NMRI-related NFR/N strain, we recently identified a quantitative trait locus (QTL) influencing litter size. This locus is now denoted Fecq4, and it is present on the murine chromosome 9. In the present paper, we describe how the Fecq4 fragment originating form the NFR/N mouse strain will affect B10.Q mice by means of breeding capacity, super-ovulation rate and embryonic development in vitro. Our results show that both the breeding capacity (number of pups produced/breeding cage during a 5 months period) and the mean litter size are significantly increased in B10.Q.NFR/N-Fecq4 congenic mice. Furthermore. B10.Q.NFR/N-Fecq4 congenic mice (both homozygous and heterozygous) did respond much better to super-ovulation than wild-type mice, resulting in a dramatically increased yield of fertilized 1-cell embryos. In addition, embryos containing the Fecq4 fragment were easy to cultivate in vitro, resulting in a higher yield of embryos reaching the blastocyst stage. We propose that B10.Q.NFR/N-Fecq4 congenic mice may be used to improve breeding or super-ovulation rate in different types of genetically modified mice (on C57BL background) that exhibit severe breeding problems. The Fecq4 fragment has been described in detail, and the possible role of polymorphic candidate genes near the linkage peak (58 Mb) has been discussed. Genes of the cytochrome P450 family (1, 11 and 19), such as Cyp19a1, are assumed to be particularly interesting, since they are known to exhibit female-associated reproductive phenotypes, affecting the ovulation rate, if mutated.
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8.
  • Liljander, Maria, et al. (författare)
  • Increased susceptibility to collagen-induced arthritis in female mice carrying congenic Cia40/Pregq2 fragments.
  • 2008
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 10:4
  • Tidskriftsartikel (refereegranskat)abstract
    • ABSTRACT: INTRODUCTION: Collagen-induced arthritis (CIA) in mice is a commonly used experimental model for rheumatoid arthritis (RA). We have previously identified a significant quantitative trait locus denoted Cia40 on chromosome 11 that affects CIA in older female mice. This locus colocalizes with another locus, denoted Pregq2, known to affect reproductive success. The present study was performed to evaluate the role of the Cia40 locus in congenic B10.Q mice and to identify possible polymorphic candidate genes, which may also be relevant in the context of RA. METHODS: Congenic B10.Q mice carrying an NFR/N fragment surrounding the Cia40/Pregq2 loci were created by 10 generations of backcrossing (N10). The congenic mice were investigated in the CIA model, and the incidence and severity of arthritis as well as the serum levels of anti-collagen II (CII) antibodies were recorded. RESULTS: Significant effects on onset, incidence, severity, and anti-CII antibody titers were observed in female mice carrying a heterozygous congenic Cia40/Pregq2 fragment of NFR/N origin, containing one or more polymorphic genes. Congenic male mice did not show increased incidence of CIA, but males carrying a heterozygous fragment showed a significant increase in severity in comparison with wildtype B10.Q males (littermates). CONCLUSION: The Cia40/Pregq2 locus at chromosome 11 contains one or more polymorphic genes of NFR/N origin that significantly influence both incidence and severity of CIA in heterozygous congenic mice of the B10.Q strain. The major polymorphic candidate genes for the effects on CIA are Cd79b, Abca8a, and Map2k6. The congenic fragment also contains polymorphic genes that affect reproductive behavior and reproductive success. The Sox9 gene, known to influence sex reversal, is a candidate gene for the reproductive phenotype.
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9.
  • Lindvall, Therese, et al. (författare)
  • An encephalomyelitis-specific locus on chromosome 16 in mouse controls disease development and expression of immune-regulatory genes
  • 2011
  • Ingår i: Journal of Neuroimmunology. - Amsterdam : Elsevier. - 0165-5728 .- 1872-8421. ; 235:1-2, s. 40-47
  • Tidskriftsartikel (refereegranskat)abstract
    • A locus on mouse chromosome 16 was found to control experimental autoimmune encephalomyelitis (EAE) in studies using congenic mice. Genes within the congenic region control encephalomyelitis but not arthritis, indicating the presence of genes in this region involved in central nervous system (CNS) specific mechanisms. Flow cytometry analyses of expression of two candidate genes within the linked locus, Cd200 and Btla, demonstrated a significantly lower expression of CD200 on CD4+ T cells and higher expression of BTLA on B cells from the congenic mice. These results suggest that genes within this mouse chromosome 16 locus specifically control EAE development possibly through immune-regulatory cell-surface molecules. © 2011 Elsevier B.V.
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10.
  • Lindvall, Therese, et al. (författare)
  • Dissection of a locus on mouse chromosome 5 reveals arthritis promoting and inhibitory genes
  • 2009
  • Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction In a cross between two mouse strains, the susceptible B10.RIII (H-2r) and resistant RIIIS/J (H-2r) strains, a locus on mouse chromosome 5 (Eae39) was previously shown to control experimental autoimmune encephalomyelitis (EAE). Recently, quantitative trait loci (QTL), linked to disease in different experimental arthritis models, were mapped to this region. The aim of the present study was to investigate whether genes within Eae39, in addition to EAE, control development of collagen-induced arthritis (CIA). Methods CIA, induced by immunisation with bovine type II collagen, was studied in Eae39 congenic and sub-interval congenic mice. Antibody titres were investigated with ELISA. Gene-typing was performed by microsatellite mapping and statistics was calculated by standard methods. Results Experiments of CIA in Eae39 congenic- and sub-interval congenic mice, carrying RIIIS/J genes on the B10. RIII genetic background, revealed three loci within Eae39 that control disease and anti-collagen antibody titres. Two of the loci promoted disease and the third locus was protected against CIA development. By further breeding of mice with small congenic fragments, we identified a 3.2 mega base pair (Mbp) interval that regulates disease. Conclusions Disease-promoting and disease-protecting genes within the Eae39 locus on mouse chromosome 5 control susceptibility to CIA. A disease-protecting locus in the telomeric part of Eae39 results in lower anti-collagen antibody responses. The study shows the importance of breeding sub-congenic mouse strains to reveal genetic effects on complex diseases.
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