| 1. |
- Bas, D. B., et al.
(författare)
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Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency
- 2012
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 64:12, s. 3886-3896
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivePain is one of the most debilitating symptoms reported by rheumatoid arthritis (RA) patients. While the collagen antibody–induced arthritis (CAIA) model is used for studying the effector phase of RA pathologic progression, it has not been evaluated as a model for studies of pain. Thus, this study was undertaken to examine pain-like behavior induced by anticollagen antibodies and to assess the effect of currently prescribed analgesics for RA. In addition, the involvement of spinal glia in antibody-induced pain was explored.MethodsCAIA was induced in mice by intravenous injection of a collagen antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Disease severity was assessed by visual and histologic examination. Pain-like behavior and the antinociceptive effect of diclofenac, buprenorphine, gabapentin, pentoxifylline, and JNK-interacting protein 1 were examined in mechanical stimulation experiments. Spinal astrocyte and microglia reactivity were investigated by real-time polymerase chain reaction and immunohistochemistry.ResultsFollowing the induction of CAIA, mice developed transient joint inflammation. In contrast, pain-like behavior was observed prior to, and outlasted, the visual signs of arthritis. Whereas gabapentin and buprenorphine attenuated mechanical hypersensitivity during both the inflammatory and postinflammatory phases of arthritis, diclofenac was antinociceptive only during the inflammatory phase. Spinal astrocytes and microglia displayed time-dependent signs of activation, and inhibition of glial activity reversed CAIA-induced mechanical hypersensitivity.ConclusionCAIA represents a multifaceted model for studies exploring the mechanisms of pain induced by inflammation in the articular joint. Our findings of a time-dependent prostaglandin and spinal glial contribution to antibody-induced pain highlight the importance of using appropriate disease models to assess joint-related pain.
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| 2. |
- Chemin, K, et al.
(författare)
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Reply
- 2016
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 68:8, s. 2053-2054
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Dobritzsch, Doreen, 1972-, et al.
(författare)
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Crystal structure of an arthritogenic anticollagen immune complex
- 2011
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 63:12, s. 3740-3748
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In rheumatoid arthritis, joint inflammation and cartilage destruction are mediated by autoantibodies directed to various self antigens. Type II collagen (CII)-specific antibodies are likely to play a role in this process and have been shown to induce experimental arthritis in susceptible animals. The purpose of this study was to reveal how arthritogenic autoantibodies recognize native CII in its triple-helical conformation. METHODS: Site-directed mutagenesis and crystallographic studies were performed to reveal crucial contact points between the CII antibody and the triple-helical CII peptide. RESULTS: The crystal structure of a pathogenic autoantibody bound to a major triple-helical epitope present on CII was determined, allowing a first and detailed description of the interactions within an arthritogenic complex that is frequently occurring in both mice and humans with autoimmune arthritis. The crystal structure emphasizes the role of arginine residues located in a commonly recognized motif on CII and reveals that germline-encoded elements are involved in the interaction with the epitope. CONCLUSION: The crystal structure of an arthritogenic antibody binding a triple-helical epitope on CII indicates a crucial role of germline-encoded and arginine residues as the target structures.
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| 4. |
- 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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| 8. |
- Kessel, C., et al.
(författare)
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A single functional group substitution in c5a breaks B cell and T cell tolerance and protects against experimental arthritis
- 2014
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 66:3, s. 610-621
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: A deficiency in C5 protects against arthritis development. However, there is currently no approach successfully translating these findings into arthritis therapy, as by targeting the key component, C5a. The aim of this study was to develop a vaccination strategy targeting C5a as therapy for patients with rheumatoid arthritis. METHODS: An anti-C5a vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (4NPA) into selected sites in the murine C5a molecule. C5a-4NPA variants were screened for their immunogenicity in mice on different arthritis-susceptible class II major histocompatibility complex (MHC) backgrounds. A candidate vaccine was tested for its impact on disease in a murine model of collagen-induced arthritis (CIA). Immunity toward endogenous C5a as well as type II collagen was monitored and characterized. RESULTS: Replacing a single tyrosine residue in position 35 (Y(35) ) with 4NPA allowed the generation of an anti-C5a vaccine, which partly protected mice against the development of CIA while strongly ameliorating the severity of clinical disease. Although differing in just 3 atoms from wild-type C5a (wtC5a), C5aY(35) 4NPA induced loss of T cell and B cell tolerance toward the endogenous protein in mice expressing class II MHC H-2(q) molecules. Despite differential B cell epitope recognition, antibodies induced by both wtC5a and C5aY(35) 4NPA neutralized C5a. Thus, anti-wtC5a IgG titers during arthritis priming were potentially of critical importance for disease protection, because high titers of C5a-neutralizing antibodies after disease onset were unable to reverse the course of arthritis. CONCLUSION: The results of this study suggest that the most effective anti-C5a treatment in arthritis can be accomplished using a preventive vaccination strategy, and that treatment using conventional biologic or small molecule strategies targeting the C5a/C5aR axis may miss the optimal window for therapeutic intervention during the subclinical priming phase of the disease.
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