| 1. |
- Gelderman, Kyra, et al.
(författare)
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Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species
- 2007
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 117:10, s. 3020-3028
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Tidskriftsartikel (refereegranskat)abstract
- Reduced capacity to produce ROS increases the severity of T cell-dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance to the level of that of wild-type mice in a collagen-induced arthritis model but not in a T cell-independent anti-collagen antibody-induced arthritis model. T cell activation was downregulated and skewed toward Th2 in transgenic mice. In vitro, IL-2 production and T cell proliferation were suppressed by macrophage ROS, irrespective of T cell origin. IFN-gamma production, however, was independent of macrophage ROS but dependent on T cell origin. These effects were antigen dependent but not restricted to collagen type II. In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis.
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| 2. |
- Gelderman, Kyra, et al.
(författare)
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Rheumatoid arthritis: The role of reactive oxygen species in disease development and therapeutic strategies
- 2007
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Ingår i: Antioxidants & Redox Signaling. - : Mary Ann Liebert Inc. - 1557-7716 .- 1523-0864. ; 9:10, s. 1541-1567
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Forskningsöversikt (refereegranskat)abstract
- Autoimmune diseases such as rheumatoid arthritis (RA) are chronic diseases that cannot be prevented or cured. If the pathologic basis of such diseases would be known, it might be easier to develop new drugs interfering with critical pathways. Genetic analysis of animal models for autoimmune diseases can result in discovery of proteins and pathways that play a 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.
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| 3. |
- Pizzolla, Angela, et al.
(författare)
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CD68-expressing cells can prime T cells and initiate autoimmune arthritis in the absence of reactive oxygen species.
- 2011
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 41:2, s. 403-412
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Tidskriftsartikel (refereegranskat)abstract
- It is widely believed that DC, but not macrophages, prime naïve T cells in vivo. Here, we investigated the ability of CD68-expressing cells (commonly defined as macrophages) in priming autoreactive T cells and initiating collagen-induced arthritis (CIA) in the mouse. For this purpose, a transgenic mouse was developed (MBQ mouse) where macrophages exclusively expressed the MHC class II H2-A(q) (A(q) ) on an H2-A(p) (A(p) ) background. A(q) , but not A(p) expression mediates susceptibility to CIA through presentation of type II collagen (CII) to T cells. CIA severity is enhanced by a mutation in the Ncf1 gene, impairing reactive oxygen species (ROS) production by the phagocyte NADPH oxidase (NOX2) complex. Expression of functional Ncf1 on macrophages was previously shown to protect from severe CIA. To study the effect of ROS on macrophage-mediated priming of T cells, the Ncf1 mutation was introduced in the MBQ mouse. Upon CII immunization, Ncf1-mutated MBQ mice, but not Ncf1 wild-type MBQ mice nor Ncf1-mutated A(p) mice, activated autoreactive T cells and developed CIA. These findings demonstrate for the first time that macrophages can initiate arthritis and that the process is negatively regulated by ROS produced via the NOX2 complex.
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