| 1. |
- Luo, Huqiao
(författare)
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Unveiling the protective mechanisms of NOX2-derived ROS against autoimmune diseases
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), pose a significant burden on society, affecting a considerable portion of the global population. Both SLE and RA are known to have a strong genetic component, with shared genetic predispositions such as neutrophil cytosolic factor 1 (NCF1), which encodes for a subunit of NADPH oxidase 2 (NOX2) complex. Genetic variants of NCF1 that result in low production of NOX2-derived reactive oxygen species (ROS) have been identified as a significant risk factor for patients with SLE or RA, as well as animal models of these diseases. This finding has challenged the traditional paradigm that ROS are proinflammatory and cause tissue destruction in autoimmune diseases. In line with this, deficiency in another NOX2 subunit, NCF4, has also been linked to RA. However, the regulatory role of NCF1 and NCF4 in SLE and RA remains unclear. Here, we investigated the protective mechanisms of these subunits using mice carrying Ncf1 defects or Ncf4 mutation in lupus and arthritis models. In the first study, we found that mouse Ncf1m1j mutation and human NCF1R90H polymorphism exacerbated disease in lupus models by enhancing the development, accumulation, and function of plasmacytoid dendritic cells (pDCs) as the driver of the type I interferon system. Restoration of NCF1-dependent ROS specifically in pDCs protected against lupus. These findings explained the causative effect of dysfunctional NCF1 in lupus and highlighted the protective role of pDC-derived ROS, providing insights for potential therapeutic strategies in patients with relevant genetic defects. In the second study, we revealed that the Ncf1m1j mutation contributed to the development of collagen-induced arthritis (CIA) driven by autoreactive T cells. This was due to a decrease in the expression of autoimmune regulator in medullary thymic epithelial cells and B cells, resulting in the release of potentially autoreactive T cells. These results suggested a regulatory role of NCF1 in T cell tolerance and protection against autoimmunity. In the third study, we discovered that the Ncf4R58A mutation, which results in decreased production of NOX2-derived intracellular ROS, exacerbated CIA by promoting the formation and migration of plasma cells. This led to elevated levels of pathogenic autoantibodies and joint inflammation, ultimately resulting in severe disease. Our findings contribute to a better understanding of the crucial involvement of intrinsically produced NOX2-derived ROS in controlling the autoimmune responses. Overall, our findings shed light on the mechanisms by which NOX2-derived ROS play a regulatory role in autoimmune diseases.
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| 3. |
- Urbonaviciute, Vilma, et al.
(författare)
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Therapy targeting antigen-specific T cells by a peptide-based tolerizing vaccine against autoimmune arthritis
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Stockholm : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:25
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Tidskriftsartikel (refereegranskat)abstract
- A longstanding goal has been to find an antigen-specific preventive therapy, i.e., a vaccine, for autoimmune diseases. It has been difficult to find safe ways to steer the targeting of natural regulatory antigen. Here, we show that the administration of exog-enous mouse major histocompatibility complex class II protein bounding a unique galactosylated collagen type II (COL2) peptide (Aq-galCOL2) directly interacts with the antigen-specific TCR through a positively charged tag. This leads to expanding a VISTA-positive nonconventional regulatory T cells, resulting in a potent dominant suppressive effect and protection against arthritis in mice. The therapeutic effect is dom-inant and tissue specific as the suppression can be transferred with regulatory T cells, which downregulate various autoimmune arthritis models including antibody-induced arthritis. Thus, the tolerogenic approach described here may be a promising dominant antigen-specific therapy for rheumatoid arthritis, and in principle, for autoimmune diseases in general.
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