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- Guérard, Simon
(författare)
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Investigation of T cell driven arthritis induced by mannan in ZAP70 mutated SKG mice
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmune diseases are particularly challenging to study in human due to their complex multifactorial nature. In rheumatoid arthritis (RA), self-reactivity directed against joints leads to pain, tissue destruction and eventually invalidity if left untreated. Although there have been great advances in therapies over the past decades, there is still no cure. In this context, animal models are essential to improve our understanding of RA, identify new therapeutic targets and also evaluate new drugs. Unfortunately, no single model can perfectly mimic the human pathology. Hence, using a combination of independent models is critical to validate findings. The SKG arthritis model is a novel murine model in which defective central tolerance, due to reduced TCR signaling from a mutation in ZAP70, leads to chronic T cell driven arthritis. The understanding of the SKG model has grown over the years, and its use in drug discovery is now also steadily increasing. In this thesis, the SKG model is carefully characterized regarding innate immunity activation by mannan (paper I), the influence of genetic backgrounds (paper II), and the role of collagen type II (CII) as a potential self-antigen (paper III). Finally, the SKG model is used to study the regulation of arthritis by reactive oxygen species (ROS) (paper IV). Stimulation of innate immunity is essential to activate T cells and trigger chronic arthritis in SKG mice. In specific pathogen free (SPF) animal facilities, this can be achieved by a single injection of mannan, a polysaccharide extracted from S. cerevisiae. Paper I focuses on innate activation and the acute skin and joints inflammation it triggers in non-SKG mice. This manuscript highlights the importance of IL-17, potentially originating from γδ T cells, giving significant insight in the early phase of SKG arthritis preceding αβT cells involvement. Prior to this thesis, the SKG model had only been described on the BALB/c genetic background. In paper II, the mutation was backcrossed over more than 10 generations on B10.Q and B6.Q genetic backgrounds. Arthritis susceptibility is unaffected by the genetic backgrounds investigated, allowing the use of the SKG model on these common strains. This finding opens many possibilities in terms of crosses with genetically modified strains. Using a series of CII-specific TCR transgenic strains, paper III investigates the role of CII self-reactivity in the SKG model. Although CII reactivity is spontaneously observed in arthritic SKG mice, further increasing CII self-reactivity does not affect arthritis. In fact, restricting T cells repertoire to CII reactivity abolishes susceptibility to arthritis. CII reactivity is therefore not essential in SKG arthritis, and is likely a consequence of joints destruction. Finally, paper IV uses the SKG model to dissect the mechanisms of immunoregulation by ROS in autoimmunity. Thymic selection and T cells activation are unaffected by ROS deficiency. Although concentrations of anti-CII antibodies are higher in ROS deficient mice, the sera itself is not pathogenic. Instead, it is ROS production in the periphery, in particular from macrophages, which mediates immunosuppression in SKG arthritis.
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- Khmaladze, Ia, et al.
(författare)
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Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washington, DC : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:35, s. E3669-E3678
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by gammadelta T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcgamma receptor III, mast cells, and histamine) and adaptive immune players (alphabeta T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-alpha secretion and stimulation of local gammadelta T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.
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