IntroductionAntibodies 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.MethodsAnalysis 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.ResultsMany 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.ConclusionCII 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.
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 triplehelical 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.
Epitope-specific antibody responses recognized by germline-encoded structures are of significant relevance for the development of autoantibody-mediated autoimmune diseases.
The calcium-dependent enzyme tissue transglutaminase (tTG) is associated with diverse biological functions, such as induction of apoptosis, modeling of the extracellular matrix, receptor-mediated endocytosis, cell growth and differentiation, cell adhesion and signal transduction. Also, it may deamidate glutamine residues to glutamic acid and catalyze cross-linking of proteins. In this study, we have investigated the impact of tTG for posttranslational modifications and cross-linking of the immunodominant T-cell epitope CII260-270 and their effects on the collagen-induced arthritis, an animal model for rheumatoid arthritis. By using mass spectrometry analysis and hybridoma assays, we have demonstrated that tTG could perform both types of modifications (deamidation and cross-link formation) on the immunodominant T-cell epitope CII259-273. Replacement of the glutamine at position 267 with glutamic acid leads to a decreased binding affinity to MHC II. T cells recognized both non-modfied (Q 267 ) and modified (E 267 ) CII259-273-peptides. We also show that administration of tTG leads to increased incidence, severity and histopathological manifestations of collagen-induced arthritis in mice. Moreover, we conclude that both processes, deamidation and cross-linking, are involved in the tTG-catalyzed reactions, and in vivo administration of tTG enhances arthritis severity and joint destruction in mice.Key words: Collagen-induced arthritis . CII-peptide . Posttranslational modifications .T cells . Tissue transglutaminase IntroductionPosttranslational modifications of proteins are being recognized as increasingly important for the initiation and pathogenesis of autoimmune diseases. Such modifications could lead to breaking of the immunological tolerance to self proteins by creation of new epitopes within the target antigen. Rheumatoid arthritis (RA) is an autoimmune disease involving an inflammatory attack on peripheral cartilaginous joints characterized by leukocyte infiltration, secretion of inflammatory cytokines and auto-Ab, and subsequent cartilage destruction, irreversible bone erosion and joint deformation. Major candidate autoantigens in RA that are locally expressed in the joint are type II collagen (CII), fibrin, and proteoglycans. CII is of particular interest, since T-and B-cell autoimmune responses to this protein leads to collagen-induced arthritis (CIA) in mice [1], rats [2] and primates [3,4], which shares many phenotypic features with RA. The shared immunodominant T-cell epitope in CIA and RA has been identified as . Amino acids of this immunodominant core can be posttranslationally modified either by enzymatic processes or spontaneously. It is well established that during aging, inflammation, trauma or other pathologic processes, the frequency of posttranslational modifications, such as glycosylation, glycation, citrullination, oxidation, deamidation/transamidation or 2412phosphorylation, is increased [10,11]. The role of glycosylated immunodominant CII260-270-peptide for development of autoimmune arthri...
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