Kristin Bauer

University of Rostock, Rostock, Mecklenburg-Vorpommern, Germany

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Publications (7)37.92 Total impact

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    ABSTRACT: Autoimmune diseases such as rheumatoid arthritis (RA) are chronic diseases that cannot be prevented or cured If the pathologic basis of such disease would be known, it might be easier to develop new drugs interfering with critical pathway. Genetic analysis of animal models for autoimmune diseases can result in discovery of proteins and pathways that play key function in pathogenesis, which may provide rationales for new therapeutic strategies. Currently, only the MHC class II is clearly associated with human RA and animal models for RA. However, recent data from rats and mice with a polymorphism in Ncf1, a member of the NADPH oxidase complex, indicate a role for oxidative burst in protection from arthritis. Oxidative burst-activating substances can treat and prevent arthritis in rats, as efficiently as clinically applied drugs, suggesting a novel pathway to a therapeutic target in human RA. Here, the authors discuss the role of oxygen radicals in regulating the immune system and autoimmune disease. It is proposed that reactive oxygen species set the threshold for T cell activation and thereby regulate chronic autoimmune inflammatory diseases like RA. In the light of this new hypothesis, new possibilities for preventive and therapeutic treatment of chronic inflammatory diseases are discussed.
    Antioxidants and Redox Signaling 11/2007; 9(10):1541-67. · 7.19 Impact Factor
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    ABSTRACT: The view on reactive oxygen species (ROS) in inflammation is currently shifting from being considered damaging toward having a more complex role in regulating inflammatory reactions. We recently demonstrated a role of ROS in regulation of animal models for the autoimmune disease rheumatoid arthritis. Low levels of ROS production, due to a mutation in the Ncf1 gene coding for the Ncf1 (alias p47(phox)) subunit of the NADPH oxidase complex, was shown to be associated with increased autoimmunity and arthritis severity in both rats and mice. To further investigate the role of ROS in autoimmunity, we studied transgenic mice expressing collagen type II (CII) with a mutation (D266E) in the immunodominant epitope that mimics the rat and human CII (i.e., mutated mouse collagen or MMC). This mutation results in a stronger binding of the epitope to the MHC class II molecule and leads to more pronounced tolerance and resistance to arthritis induced with rat CII. When the Ncf1 mutation was bred into these mice, tolerance was broken, resulting in enhanced T cell autoreactivity, high titers of anti-CII Abs, and development of severe arthritis. These findings highlight the importance of a sufficient ROS production in maintenance of tolerance to self-Ags, a central mechanism in autoimmune diseases such as rheumatoid arthritis. This is important as we, for the first time, can follow the effect of ROS on molecular mechanisms where T cells are responsible for either protection or promotion of arthritis depending on the level of oxygen species produced.
    The Journal of Immunology 09/2007; 179(3):1431-7. · 5.52 Impact Factor
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    ABSTRACT: Advanced intercross line (AIL) is a powerful tool for high-resolution mapping of quantitative trait loci (QTLs). Several AILs have been generated to refine QTLs since the method was proposed about a decade ago. However, no AIL has been used for identifying novel QTLs. Here we used an AIL to test this possibility. We genotyped 308 (DBA/1 x FVB/N) F(11/12) AIL mice with 109 informative markers covering four chromosomes, with an average intermarker distance of 5.5 Mb. Several normally distributed quantitative traits involved in the immune response during the course of collagen-induced arthritis (CIA), such as anti-collagen II antibodies, T-cell subset proportions and reactive oxygen species (ROS) production were taken as phenotypes. Four QTLs, namely Ciaa1, Lctlp1, Lctlp2 and Rosq1, controlling anti-collagen II IgG2a levels, lymph nodes CD8(+) T cell proportion and ROS production were identified with support intervals of 15, 14, 8 and 8 Mb, respectively. Alleles of Lctlp1 and Lctlp2 suppressing CD8(+) T cell proportion as well as the Rosq1 allele enhancing ROS production were correlated with higher CIA severity scores. Taken together, we successfully used an AIL to identify novel QTLs controlling immune responses during CIA with relatively small support intervals.
    Genes and Immunity 07/2007; 8(4):296-301. · 3.68 Impact Factor
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    ABSTRACT: Quantitative traits such as complex diseases are controlled by many small-effect genes that are difficult to identify. Here we present a novel strategy to identify the candidate genes for small-effect quantitative trait loci (QTL) in collagen induced arthritis (CIA) using global genome and transcriptome approaches. First, we performed genome linkage analysis in F2 progeny of the CIA susceptible and resistant strains to search for small-effect QTL. Second, we detected gene expression patterns of both strains during CIA. The candidate genes were identified using three criteria: they are located in a genomic region linked to CIA; they are disease-specific differentially expressed during CIA; and they are strain-specific differentially expressed regarding the two parental strains. Eight small-effect QTL controlling CIA severity were identified. Of 22,000 screened genes, 117 were both strain-specific and disease-specific differentially expressed during CIA. Of these 117 genes, 21 were located inside the support intervals of the 8 small-effect QTL and thus were considered as candidate genes.
    Arthritis research & therapy 02/2007; 9(1):R3. · 4.27 Impact Factor
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    ABSTRACT: The generation of advanced intercross lines (AIL) is a powerful approach for high-resolution fine mapping of quantitative trait loci (QTLs), because they accumulate much more recombination events compared with conventional F2 intercross and N2 backcross. However, the application of this approach is severely hampered by the requirements of excessive resources to maintain such crosses, i.e., in terms of animal care, space, and time. Therefore, in this study, we produced an AIL to fine map collagen-induced arthritis (CIA) QTLs using comparatively limited resources. We used only 308 (DBA/1 x FVB/N)F11/12 AIL mice to refine QTLs controlling the severity and onset of arthritis as well as the Ab response and T cell subset in CIA, namely Cia2, Cia27, and Trmq3. These QTLs were originally identified in (DBA/1 x FVB/N)F2 progeny. The confidence intervals of the three QTLs were refined from 40, 43, and 48 Mb to 12, 4.1, and 12 Mb, respectively. The data were complemented by the use of another QTL fine-mapping approach, haplotype analysis, to further refine Cia2 into a 2-Mb genomic region. To aid in the search for candidate genes for the QTLs, genome-wide expression profiling was performed to identify strain-specific differentially expressed genes within the confidence intervals. Of the 1396 strain-specific differentially expressed genes, 3, 3, and 12 genes were within the support intervals of the Cia2, Cia27, and Trmq3, respectively. In addition, this study revealed that Cia27 and Trmq3 controlling anti-CII IgG2a Ab and CD4:CD8 T cell ratio, respectively, also regulated CIA clinical phenotypes.
    The Journal of Immunology 12/2006; 177(10):7042-9. · 5.52 Impact Factor
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    ABSTRACT: Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8+ T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8+ T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp-/-, and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp+/+, 64%; DBA/1J-pfp-/-, 54%), a slightly delayed onset (onset of disease: DBA/1J-pfp+/+, 53 +/- 3.6; DBA/1J-pfp-/-, 59 +/- 4.9 (mean +/- SEM), and milder form of the disease (maximum disease score: DBA/1J-pfp+/+, 7.3 +/- 1.1; DBA/1J-pfp-/-, 3.4 +/- 1.4 (mean +/- SEM); P < 0.05). Concomitantly, peripheral T cell proliferation in response to the specific antigen bovine collagen II was increased in pfp-/- mice compared with pfp+/+ mice, arguing for an impaired killing of autoreactive T cells caused by pfp deficiency. Thus, pfp-mediated cytotoxicity is involved in the initiation of tissue damage in arthritis, but pfp-independent cytotoxic death pathways might also contribute to CIA.
    Arthritis research & therapy 01/2005; 7(4):R877-84. · 4.27 Impact Factor
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    ABSTRACT: Collagen-induced arthritis (CIA) in the mouse is one of the most widely used autoimmune experimental models, with many features similar to rheumatoid arthritis. This study sought to identify potential genetic regulatory mechanisms of CIA in major histocompatibility complex-matched (H2-q) F(2) hybrid mice. We used 126 polymorphic markers to perform simple sequence-length polymorphism analysis on 290 F(2) hybrids of arthritis-susceptible (DBA/1J) and arthritis-resistant (FVB/N) inbred mouse strains. The major clinical traits (disease severity and onset) were assessed, and serum antibodies specific to type II collagen (CII) were determined by enzyme-linked immunosorbent assay in 270 F(2) mice. Lymph nodes from 94 F(2) mice were used to test the ratio of CD4 to CD8 by fluorescence-activated cell sorter analysis, and cell proliferation was determined by XTT test. Two quantitative trait loci (QTLs) identified in previous studies were confirmed; these were severity-controlling Cia2 and onset-controlling Cia4 on chromosome 2. Moreover, we identified 5 new QTLs, 1 for CII-specific IgG2a antibodies on chromosome 5, 2 controlling the CII-specific IgG1 antibody response on chromosomes 10 and 13, 1 for the CD4:CD8 ratio on chromosome 2, and 1 for cell proliferation (measured by XTT test) on chromosome 16. Complement component C5 was identified as the probable main candidate gene for the QTLs Cia2 and Cia4. F(2) mice carrying a 2-basepair deletion of C5, the FVB/N allele, had low incidence and less severe disease as compared with those carrying the DBA/1J allele. This genome scan provides additional evidence confirming the role of C5 as a probable candidate gene for Cia2 and Cia4 loci, and identifies new QTLs controlling new traits in autoimmune arthritis.
    Arthritis & Rheumatology 12/2004; 50(11):3721-8. · 7.48 Impact Factor