| 1. |
- Gatto, Mariele, et al.
(författare)
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Early increase of circulating transitional B cells and autoantibodies to joint-related proteins in patients with metastatic melanoma developing checkpoint inhibitor-induced inflammatory arthritis.
- 2023
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 75:5, s. 856-863
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Tidskriftsartikel (refereegranskat)abstract
- To investigate potential associations between B cell-related immunological changes and development of inflammatory arthritis (IA) after treatment with immune checkpoint inhibitors (ICI).Patients who developed IA (ICI-IA) and patients who did not develop immune-related adverse events (non-irAE) after receiving ICI due to metastatic melanoma were consecutively recruited. Blood samples were collected at the time of ICI-IA occurrence and at different timepoints during treatment. Peripheral blood B cell subsets during ICI treatment were analyzed by flow cytometry. Rheumatoid factor, autoantibodies against citrullinated peptides and against joint-related proteins were measured.Proportions of CD19+ B cells were higher in patients with ICI-IA (n=7) vs. non-irAE (n=15; median (interquartile range, IQR), %: 11.7 (9.7-16.2) vs. 8.1 (5.7-11.0), p=0.03). The proportion and absolute numbers of transitional CD19+ CD10+ CD24hi CD38hi B cells were increased in patients with ICI-IA vs. non-irAE (median (IQR); %: 8.1 (4.9-12.1) vs. 3.6 (1.9-4.9); cells/μl: 10.7 (8.9-19.6) vs. 4.4 (2.3-6.6), p<0.01 for both), and higher levels of transitional B cells were associated with development of ICI-IA (OR 95% CI: 2.25 (1.03-4.9), p=0.04). Transitional B cells increased before the onset of overt ICI-IA and decreased from active to quiescent ICI-IA (p=0.02). Autoantibodies to collagen II epitopes were detected in up to 43% of ICI-IA patients compared to none of the non-irAE patients (p=0.02).Development of ICI-IA is accompanied by an increase in transitional B cells and by production of autoantibodies to joint-related proteins. Monitoring of B cell-driven abnormalities upon ICI treatment may help earlier recognition of ICI-IA. This article is protected by copyright. All rights reserved.
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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. |
- Li, Yanpeng, et al.
(författare)
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Cartilage-binding antibodies initiate joint inflammation and promote chronic erosive arthritis
- 2020
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Ingår i: Arthritis Research & Therapy. - : BMC. - 1478-6362. ; 22
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Tidskriftsartikel (refereegranskat)abstract
- Background: Antibodies binding to cartilage proteins are present in the blood and synovial fluid of early rheumatoid arthritis patients. In order to develop animal models mimicking the human disease, we have characterized the arthritogenic capacity of monoclonal antibodies directed towards different joint proteins in the cartilage.Methods: Purified antibodies specific to unmodified or citrullinated collagen type II (CII), collagen type XI (CXI), and cartilage oligomeric matrix protein (COMP) were produced as culture supernatant, affinity purified, pooled as antibody cocktails (Cab3 and Cab4), and injected intravenously into mice to induce arthritis. An adjuvant (lipopolysaccharide or mannan) was subsequently injected intraperitoneally on either day 5 or day 60 to enhance arthritis. Antibody binding and complement activation on the cartilage surface were analyzed by immunohistochemical methods. Bone erosions and joint deformations were analyzed by histological assessments, enzyme-linked immunosorbent assays, and micro-CT. Luminex was used to detect CII-triple helical epitope-specific antibody responses.Results: The new cartilage antibody cocktails induced an earlier and more severe disease than anti-CII antibody cocktail. Many of the mouse strains used developed severe arthritis with 3 antibodies, binding to collagen II, collagen XI, and cartilage oligomeric matrix protein (the Cab3 cocktail). Two new models of arthritis including Cab3-induced LPS-enhanced arthritis (lpsCAIA) and Cab3-induced mannan-enhanced arthritis (mCAIA) were established, causing severe bone erosions and bone loss, as well as epitope spreading of the B cell response. Cab4, with addition of an antibody to citrullinated collagen II, induced arthritis more efficiently in moderately susceptible C57BL/6 J mice.Conclusions: The new mouse model for RA induced with cartilage antibodies allows studies of chronic development of arthritis and epitope spreading of the autoimmune response and bone erosion.
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| 4. |
- Lindh, Ingrid, et al.
(författare)
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Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice
- 2014
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Ingår i: Arthritis Research & Therapy. - London : BioMed Central (BMC). - 1478-6362 .- 1478-6354. ; 16:4
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Antibodies towards type II collagen (CII) are detected in patients with rheumatoid arthritis (RA) and in non-human primates and rodents with collagen induced arthritis (CIA). We have previously shown that antibodies specific for several CII-epitopes are pathogenic using monoclonal antibodies from arthritic mice, although the role of different anti-CII epitopes has not been investigated in detail in other species. We therefore performed an inter-species comparative study of the autoantibody response to CII in patients with RA versus monkeys and mice with CIA. METHODS: Analysis of the full epitope repertoire along the disease course of CIA was performed using a library of CII triple-helical peptides. The antibody responses to the major CII epitopes were analyzed in sera and synovial fluid from RA patients, and in sera from rhesus monkeys (Macaca mulatta), common marmosets (Callithrix jacchus) and mice. RESULTS: Many CII epitopes including the major C1, U1, and J1 were associated with established CIA and arginine residues played an important role in the anti-CII antibody interactions. The major epitopes were also recognized in RA patients, both in sera and even more pronounced in synovial fluid: 77% of the patients had antibodies to the U1 epitope. The anti-CII immune response was not restricted to the anti-citrulline protein antibodies (ACPA) positive RA group. CONCLUSION: CII conformational dependent antibody responses are common in RA and are likely to originate from rheumatoid joints but did not show a correlation with ACPA response. Importantly, the fine specificity of the anti-CII response is similar with CIA in monkeys and rodents where the recognized epitopes are conserved and have a major pathogenic role. Thus, anti-CII antibodies may both contribute to, as well as be the consequence of, local joint inflammation. © 2014 Lindh et al.; licensee BioMed Central Ltd.
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| 5. |
- Lönnblom, Erik
(författare)
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Antibodies as pathogenic factors and biomarkers in rheumatoid arthritis
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ever since the evolution of an adaptive immune system capable of creating immune receptors that may recognize self-antigens, we have been at risk of autoimmunity. There are over 100 different types of autoimmune diseases targeting almost every available tissue from head to toe, with joints and connective tissues being a common target. In addition to autoimmune diseases, infections and degenerative joint diseases can cause joint inflammation making differential diagnosis between them difficult. The most common autoimmune disease to afflict the joints is rheumatoid arthritis (RA), affecting nearly 1% of the world population, predominantly women. The etiology of RA is not known, although it involves interaction between multiple genes and environmental risk factors. It is characterized by chronic inflammation of the joints, which without successful treatment can lead to joint destruction. One of the hallmarks of RA is the presence of autoantibodies, often observed in serum several years before any symptoms of disease. The two classes of autoantibodies focused on today are rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPA), the latter being a highly specific biomarker for a large subset of RA-patients. The ACPA have greatly aided in diagnosing RA in many patients. Yet their function and origin are still not known. Nevertheless, a subset of patients still lacks a specific biomarker. All studies in this thesis have autoantibodies in arthritis as a common theme, and four of them use a bead-based multiplex platform established during the PhD-project. In Study I, we explored the hypothesized link between periodontitis induced by the oral pathogen P.gingivalis, and its effect on arthritis progression and the production of ACPA. This study revealed a citrulline specific antibody response against P.gingivalis peptidyl arginine deiminase derived peptide, although the link to the arthritis development could not be confirmed. In Study II, we synthesized a library of triple helical peptides (THP) as a tool to characterize antibodies against type II collagen (CII). The peptides were tested in two cohorts of RA patients, as well as on monoclonal antibodies (mAb), and in collagen induced arthritis. The THPs were subsequently used in Study III to elucidate the specificity and function of antibodies against type XI collagen (CXI), revealing a shared epitope between CXI and CII in mice, rats and humans with arthritis. In addition, the THPs were also used in Study IV to explore the cross-reactivity of a joint-reactive mouse ACPA, demonstrating a molecular mechanism of how an ACPA can trigger arthritis. For Study V, the specificity of several human ACPA were dissected with a bead based multiplex assay and compared to polyclonal responses in two RA cohorts. Crystal structures of the ACPA revealed for the first time the structural basis of how human ACPA bind citrulline residues on different peptides. The data presented in this thesis provide further evidence that the major determinant of the arthritogenicity of antibodies lies in their ability to cross-react to joint proteins. Dissecting these specificities may lead to the establishment of new clinical biomarkers.
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| 6. |
- Xu, Zhongwei, et al.
(författare)
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A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) involves several classes of pathogenic autoantibodies, some of which react with type-II collagen (COL2) in articular cartilage. We previously described a subset of COL2 antibodies targeting the F4 epitope (ERGLKGHRGFT) that could be regulatory. Here, using phage display, we developed recombinant antibodies against this epitope and examined the underlying mechanism of action. One of these antibodies, R69-4, protected against cartilage antibody- and collagen-induced arthritis in mice, but not autoimmune disease models independent of arthritogenic autoantibodies. R69-4 was further shown to cross-react with a large range of proteins within the inflamed synovial fluid, such as the complement protein C1q. Complexed R69-4 inhibited neutrophil FCGR3 signaling, thereby impairing downstream IL-1β secretion and neutrophil self-orchestrated recruitment. Likewise, human isotypes of R69-4 protected against arthritis with comparable efficiency. We conclude that R69-4 abrogates autoantibody-mediated arthritis mainly by hindering FCGR3 signaling, highlighting its potential clinical utility in acute RA.
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