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- Hultqvist, Malin
(författare)
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The Role of Reactive Oxygen Species in Animal Models of Autoimmunity
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Reactive oxygen species (ROS) produced by the phagocyte NADPH oxidase complex are important in the killing of invading pathogens. Lately, a role of ROS has been suggested in regulation of the immune system. This was further highlighted when the Ncf1 gene, encoding a subunit of the NADPH oxidase complex, was found to regulate arthritis severity in rats. Interestingly, the fact that increased arthritis susceptibility was mediated by a lowered ROS production diverged from the general dogma that ROS in general promotes inflammation. The studies included in this thesis aimed to further investigate and characterize the influence of Ncf1 and ROS in autoimmune diseases such as arthritis and encephalomyelitis. By using animal models of the human Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS), we could confirm the importance of decreased ROS production in development of autoimmunity. This was validated by identification of a mouse Ncf1 mutation that also decreased ROS production and resulted in enhanced arthritis. In addition, we found that T cell reactivity was altered in animals with impaired ROS production, presumably through interaction with antigen presenting cells. We found that the redox level on T cell membranes was the determinant for arthritogenicity. Interestingly, we could also reverse the genetic effect by administrate NADPH oxidase activating oils into rats, thereby preventing and ameliorating disease. This is promising as these findings provide a novel pathway to target therapeutically in complex inflammatory diseases. In summary, this thesis describes a pathway in the pathology of arthritis and encephalomyelitis that reveals a new way to treat autoimmunity.
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| 2. |
- Johannesson, Martina, et al.
(författare)
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Genetics of autoimmune diseases: a multistep process.
- 2006
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Ingår i: Current Concepts in Autoimmunity and Chronic Inflammation (Current Topics in Microbiology and Immunology). - : Springer Berlin Heidelberg. - 0070-217X. - 9783540297130 ; :305
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Abstract in UndeterminedIt has so far been difficult to identify genes behind polygenic autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and type I diabetes (T1D). With proper animal models, some of the complexity behind these diseases can be reduced. The use of linkage analysis and positional cloning of genes in animal models for RA resulted in the identification of one of the genes regulating severity of arthritis in rats and mice, the Ncf1 gene. The Ncf1 gene encodes for the Ncf1 protein that is involved in production of free oxygen radicals through the NADPH oxidase complex, which opens up a new pathway for therapeutic treatment of inflammatory diseases. in most cases, however, a quantitative trait locus (QTL) is the sum effect of several genes within and outside the QTL, which make positional cloning difficult. Here we will discuss the possibilities and difficulties of gene identification in animal models of autoimmune disorders.
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