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- Fernandez Lahore, Gonzalo
(författare)
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Identifying genetic determinants of T cell-dependent autoimmunity using forward genetics
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid arthritis (RA) affects 0.5-1% of the population and is an important health and socioeconomic problem. RA has a high degree of heritability. Thus, extensive efforts have been made to better understand the genetic variability contributing to disease susceptibility. However, dissecting the genetic component of RA in humans has been difficult due to heterogeneity in the human population, multiple testing issues, and lack of accessibility to relevant tissues for proof-of-concept studies. Genetic studies in mouse model systems circumvent these problems, enhancing the possibility to identify disease regulating genetic variants. Here, we use a forward genetics approach in mice to identify and characterize genetic determinants of RA and related autoimmune diseases. First, we have mapped quantitative trait loci (QTL) regulating experimental arthritis using linkage analysis, and then isolated these QTL in congenic strains for in depth functional characterization. Using this approach, we make several important observations. In the first study, we find that promoter polymorphisms regulating expression of the vitamin D receptor affect T cell activation and T cell-driven collagen-induced arthritis. These findings are particularly interesting considering the long-standing association between serum vitamin D and several autoimmune diseases. In the second study, we discover a spontaneous insertion of a long terminal repeat which leads to a deficiency in the SH3GL1 gene (Endophilin A2), protecting mice in several arthritis models. We are first to identify the immunomodulatory properties of SH3GL1, which may prove to be a valuable therapeutic target. In the third study, we identify a polymorphic estrogen receptor binding site that regulates susceptibility to experimental arthritis and other autoimmune models by interfering with estrogen regulation of the T cell marker CD2. These results suggest an important role for CD2 and estrogen in shaping the sexually dimorphic immune response. Collectively, our findings make a significant contribution towards the understanding of RA genetics while demonstrating the value of animal models.
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| 2. |
- He, Yibo, et al.
(författare)
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A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis.
- 2023
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Although elevated levels of anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA), the in vivo functions of these antibodies remain unclear. Here, we have expressed monoclonal ACPAs derived from patients with RA, and analyzed their functions in mice, as well as their specificities. None of the ACPAs showed arthritogenicity nor induced pain-associated behavior in mice. However, one of the antibodies, clone E4, protected mice from antibody-induced arthritis. E4 showed a binding pattern restricted to skin, macrophages and dendritic cells in lymphoid tissue, and cartilage derived from mouse and human arthritic joints. Proteomic analysis confirmed that E4 strongly binds to macrophages and certainRA synovial fluid proteins such as α-enolase. The protective effect of E4 was epitope-specific and dependent on the interaction between E4-citrullinated α-enolase immune complexes with FCGR2B on macrophages, resulting in increased IL-10 secretion and reduced osteoclastogenesis. These findings suggest that a subset of ACPAs have therapeutic potential in RA.
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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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