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- Ge, C. R., et al.
(författare)
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Antibodies to Cartilage Oligomeric Matrix Protein Are Pathogenic in Mice and May Be Clinically Relevant in Rheumatoid Arthritis
- 2022
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205.
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Tidskriftsartikel (refereegranskat)abstract
- Objective Cartilage oligomeric matrix protein (COMP) is an autoantigen in rheumatoid arthritis (RA) and experimental models of arthritis. This study was undertaken to investigate the structure, function, and relevance of anti-COMP antibodies. Methods We investigated the pathogenicity of monoclonal anti-COMP antibodies in mice using passive transfer experiments, and we explored the interaction of anti-COMP antibodies with cartilage using immunohistochemical staining. The interaction of the monoclonal antibody 15A11 in complex with its specific COMP epitope P6 was determined by x-ray crystallography. An enzyme-linked immunosorbent assay and a surface plasma resonance technique were used to study the modulation of calcium ion binding to 15A11. The clinical relevance and value of serum IgG specific to the COMP P6 epitope and its citrullinated variants were evaluated in a large Swedish cohort of RA patients. Results The murine monoclonal anti-COMP antibody 15A11 induced arthritis in naive mice. The crystal structure of the 15A11-P6 complex explained how the antibody could bind to COMP, which can be modulated by calcium ions. Moreover, serum IgG specific to the COMP P6 peptide and its citrullinated variants was detectable at significantly higher levels in RA patients compared to healthy controls and correlated with a higher disease activity score. Conclusion Our findings provide the structural basis for binding a pathogenic anti-COMP antibody to cartilage. The recognized epitope can be citrullinated, and levels of antibodies to this epitope are elevated in RA patients and correlate with higher disease activity, implicating a pathogenic role of anti-COMP antibodies in a subset of RA patients.
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- Ge, Changrong P, et al.
(författare)
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Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
- 2017
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Ingår i: JCI INSIGHT. - : AMER SOC CLINICAL INVESTIGATION INC. - 2379-3708. ; 2:13
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Tidskriftsartikel (refereegranskat)abstract
- Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif "RG-TG" within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.
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- Hagert, C., et al.
(författare)
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Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells : A Novel Experimental Model of Rheumatoid Arthritis
- 2018
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Ingår i: Arthritis & Rheumatology. - Hoboken : Wiley. - 2326-5191 .- 2326-5205 .- 1529-0131. ; 70:8, s. 1343-1353
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To develop a new chronic rheumatoid arthritis model that is driven by the innate immune system. METHODS: Injection of a cocktail of 4 monoclonal antibodies against type II collagen, followed on days 5 and 60 by intraperitoneal injections of mannan (from Saccharomyces cerevisiae), was used to induce development of chronic arthritis in B10.Q mice. The role of the innate immune system as compared to the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains. RESULTS: A new model of chronic relapsing arthritis was characterized in B10.Q mice, in which a persistently active, chronic disease was found. This relapsing disease was driven by macrophages lacking the ability to mount a reactive oxygen species response against pathogens, and was associated with the classical/alternative pathway, but not the lectin pathway, of complement activation. The disease was independent of Fcgamma receptor type III, and also independent of the activity of adaptive immune cells (B and T cells), indicating that the innate immune system, involving complement activation, could be the sole driver of chronicity. CONCLUSION: Chronic active arthritis can be driven innately by macrophages without the involvement of T and B cells in the adaptive immune system.
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- Hagert, C, et al.
(författare)
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Rapid spread of mannan to the immune system, skin and joints within 6 hours after local exposure
- 2019
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Ingår i: Clinical and experimental immunology. - : Oxford University Press (OUP). - 1365-2249 .- 0009-9104. ; 196:3, s. 383-391
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis (Ps), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are common diseases dependent on environmental factors that activate the immune system in unknown ways. Mannan is a group of polysaccharides common in the environment; they are potentially pathogenic, because at least some of them induce Ps-, PsA- and RA-like inflammation in mice. Here, we used positron emission tomography/computed tomography to examine in-vivo transport and spread of mannan labelled with fluorine-18 [18F]. The results showed that mannan was transported to joints (knee) and bone marrow (tibia) of mice within 6 h after intraperitoneal injection. The time it took to transport mannan, and its presence in blood, indicated cellular transport of mannan within the circulatory system. In addition, mannan was filtered mainly through the spleen and liver. [18F]fluoromannan was excreted via kidneys, small intestine and, to some extent, the mouth. In conclusion, mannan reaches joints rapidly after injection, which may explain why mannan-induced inflammatory disease is targeted to these tissues.
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- Herren, Daniel B., et al.
(författare)
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Diagnostic and treatment recommendations for recurrent or persistent symptoms after trapeziectomy: a Delphi study
- 2024
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Ingår i: Journal of Hand Surgery, European Volume. - : SAGE PUBLICATIONS LTD. - 1753-1934 .- 2043-6289.
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this Delphi study was to provide a diagnostic and treatment algorithm for patients with persistent or recurrent symptoms after trapeziometacarpal joint resection arthroplasty. Three Delphi rounds were conducted in which surveys were sent to 182 experienced hand surgeons worldwide. Responses were received from 140 participants. A consensus threshold was set at 67% agreement. Diagnostic tools and treatment approaches for six common revision scenarios achieved consensus. Radiographs are appropriate as primary (97%) and CT scans as secondary (76%) diagnostic tools. For scaphometacarpal impingement, 67% of respondents agreed that revision interposition is appropriate, with 93% recommending autologous tendon for the interposition. Additional suspension was considered appropriate by 68% of the participants. The diagnostic and treatment algorithm can help the surgeon to identify the reason for persistent symptoms after trapeziometacarpal joint resection arthroplasty and to choose an appropriate treatment strategy.Level of evidence: V
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- Rein, Susanne, et al.
(författare)
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Alteration of ligamento-muscular reflex patterns after cutaneous and periarticular desensitization of the basal thumb joint : An electromyographic study
- 2023
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Ingår i: Journal of Hand Surgery-American Volume. - : Elsevier BV. - 0363-5023 .- 1531-6564. ; 48:6
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Stimulation of the dorsoradial ligament (DRL) of the first carpometacarpal joint (CMC-1) has shown a ligamento-muscular reflex pathway between the DRL and CMC-1 stabilizing muscles in healthy volunteers. However, it remains unclear how this ligamento-muscular reflex pattern is altered after anesthetizing sensory skin receptors and administering a further periarticular block around the CMC-1 joint, which may influence the dynamic aspects of joint stability.METHODS: Ligamento-muscular reflexes were obtained from the extensor pollicis longus, abductor pollicis longus, abductor pollicis brevis, and the first dorsal interosseous muscles in 10 healthy participants after establishing superficial anesthesia of the skin around the CMC-1. The DRL was stimulated with a fine wire electrode while EMG activities were recorded during isometric tip, key, and palmar pinch. The measurements were repeated after an additional periarticular CMC-1 block using 5 ml of 1% lidocaine. Average EMG values were analyzed to compare the prestimulus and poststimulus activity.RESULTS: Statistically significant changes in poststimulus EMG activity were observed in all 4 muscles and all 3 tested thumb positions. A markedly reduced activity in all 4 muscles was observed in the palmar position, followed by the tip and key pinch positions. Almost no reactions were observed in the first 20 ms poststimulus for all muscles in all positions.CONCLUSIONS: Superficial skin anesthesia and an additional periarticular CMC-1 block anesthesia resulted in a reduced ligamento-muscular reflex pattern in all 4 muscles.CLINICAL RELEVANCE: Ligamento-muscular reflexes play an important role in dynamic CMC-1 joint stability. The elimination of early reactions, those considered joint-protective reflexes, is a potential risk factor for developing osteoarthritis or injury because it results in an inability to adequately protect and stabilize the joint in sudden movements.
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