| 1. |
- He, Yibo, et al.
(author)
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A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis.
- 2023
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)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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| 2. |
- Li, Taotao
(author)
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Functional studies of anti-gpi monoclonal antibodies and anti-citrullinated protein antibodies (ACPAS)
- 2023
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Doctoral thesis (other academic/artistic)abstract
- RA is an autoimmune disease that primarily impacts joints throughout the body. The disease can result in pain, stiffness, and reduced mobility. It is a chronic disease, meaning that it lasts a long time and can worsen over time if left untreated. As the disease progresses, it can lead to joint deformity and severe pain, which can significantly impact the patient's daily life. While there are treatments available to manage the symptoms of RA, there is currently no cure for the condition. Glucose-6-phosphate isomerase (GPI) is an enzyme that plays a key role in glycolysis, the metabolic pathway that breaks down glucose to produce energy. Establishment of two GPI-dependent arthritis mouse models (K/BxN and GPI protein-induced arthritis mouse models), successfully identifying GPI as one of the RA-associated autoantigens. In human RA, elevated levels of free GPI protein and anti-GPI autoantibodies were found in the sera and synovial fluid of RA patients. Despite extensive research on the pathogenicity of GPI in RA, many questions remain unanswered, including what are the major pathogenic B-cell epitopes of GPI? What is the prevalence of anti-GPI antibodies in RA patients? Are anti-GPI antibodies specific for RA disease? Cartilage Oligomeric Matrix Protein (COMP) is a glycoprotein that helps in the formation and maintenance of cartilage. It exists in the synovial fluid and serum of RA patients and the level of COMP have been found to be positively correlated with the severity of the disease. Studies have indicated that COMP might contribute to the breakdown of cartilage in RA by stimulating the production of inflammatory cytokines and activating enzymes known as matrix metalloproteinases. Anti-citrullinated protein antibodies (ACPAs) are autoantibodies that have highest specificity for RA. During the autoimmune stage of RA, which occurs years before clinical symptoms appear, the immune system already begins to produce ACPAs. Studies have shown that the production of ACPAs is highly associated with the HLA-DRB1*0401 allele, which is one of the highest genetic risk factor for RA. Some studies believed that HLADRB1* 0401 allele increases the likelihood of citrullinated peptides being presented to T cells, which can result in the production of ACPA by B cells. However, subsequent scientific research has disproved this hypothesis, indicating that HLA-DRB1*0401 does not exhibit a preference for presenting citrullinated peptides over non-citrullinated peptides. The current hypotheses and associated conclusions are either based solely on statistical analysis, so further experimental data must be obtained to test these hypotheses. In the first study, we identified the arthritogenic B cell epitopes of GPI in mice. We showed that this pathogenic GPI B cell epitope is exposed exclusively on structurally modified GPI on the cartilage surface. Identification of these specific B cells by tetramer technology showed that these cells were not negatively selected and present in naïve mice. These naturally autoreactive cells escaped tolerance mechanisms and could potentially play a pathogenic role in disease as shown by the association of the antibody response against this epitope with clinical disease parameters in human RA cohorts. In the second study, we investigated the pathogenic role of anti-COMP antibodies in murine arthritis models in conjunction with studies on the autoantibody response to COMP in human RA cohorts. In the third study, our findings demonstrate a link between the induction of ACPAs and the presence of HLA-DRB1*0401, as well as between the development of arthritis and this HLA allele. Interestingly, we found that the function of ACPAs is variable. ACPAs cross-reactive with cartilage can be pathogenic, whereas other promiscuous ACPAs can be protective or have no detectable impact on arthritis.
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| 3. |
- Romero-Castillo, Laura, et al.
(author)
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Human MHC Class II and Invariant Chain Knock-in Mice Mimic Rheumatoid Arthritis with Allele Restriction in Immune Response and Arthritis Association
- 2024
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In: Advanced Science. - 2198-3844.
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Journal article (peer-reviewed)abstract
- Transgenic mice expressing human major histocompatibility complex class II (MHCII) risk alleles are widely used in autoimmune disease research, but limitations arise due to non-physiologic expression. To address this, physiologically relevant mouse models are established via knock-in technology to explore the role of MHCII in diseases like rheumatoid arthritis. The gene sequences encoding the ectodomains are replaced with the human DRB1*04:01 and 04:02 alleles, DRA, and CD74 (invariant chain) in C57BL/6N mice. The collagen type II (Col2a1) gene is modified to mimic human COL2. Importantly, DRB1*04:01 knock-in mice display physiologic expression of human MHCII also on thymic epithelial cells, in contrast to DRB1*04:01 transgenic mice. Humanization of the invariant chain enhances MHCII expression on thymic epithelial cells, increases mature B cell numbers in spleen, and improves antigen presentation. To validate its functionality, the collagen-induced arthritis (CIA) model is used, where DRB1*04:01 expression led to a higher susceptibility to arthritis, as compared with mice expressing DRB1*04:02. In addition, the humanized T cell epitope on COL2 allows autoreactive T cell-mediated arthritis development. In conclusion, the humanized knock-in mouse faithfully expresses MHCII, confirming the DRB1*04:01 alleles role in rheumatoid arthritis and being also useful for studying MHCII-associated diseases.
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| 4. |
- Shi, Chen, et al.
(author)
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The Potential of Low Molecular Weight Heparin to Mitigate Cytokine Storm in Severe COVID-19 Patients : A Retrospective Cohort Study
- 2020
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In: Clinical and Translational Science. - : WILEY. - 1752-8054 .- 1752-8062. ; 13:6, s. 1087-1095
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Journal article (peer-reviewed)abstract
- On March 11, 2020, the World Health Organization declared its assessment of coronavirus disease 2019 (COVID-19) as a global pandemic. However, specific anti-severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) drugs are still under development, and patients are managed by multiple complementary treatments. We performed a retrospective analysis to compare and evaluate the effect of low molecular weight heparin (LMWH) treatment on disease progression. For this purpose, the clinical records and laboratory indicators were extracted from electronic medical records of 42 patients with COVID-19 (21 of whom were treated with LMWH, and 21 without LMWH) hospitalized (Union Hospital of Huazhong University of Science and Technology) from February 1 to March 15, 2020. Changes in the percentage of lymphocytes before and after LMWH treatment were significantly different from those in the control group (P = 0.011). Likewise, changes in the levels of D-dimer and fibrinogen degradation products in the LMWH group before and after treatment were significantly different from those in the control group (P = 0.035). Remarkably, IL-6 levels were significantly reduced after LMWH treatment (P = 0.006), indicating that, besides other beneficial properties, LMWH may exert an anti-inflammatory effect and attenuate in part the "cytokine storm" induced by the virus. Our results support the use of LMWH as a potential therapeutic drug for the treatment of COVID-19, paving the way for a subsequent well-controlled clinical study.
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| 5. |
- Urbonaviciute, Vilma, et al.
(author)
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Therapy targeting antigen-specific T cells by a peptide-based tolerizing vaccine against autoimmune arthritis
- 2023
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In: 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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Journal article (peer-reviewed)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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