The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans

Dzhambazov, Balik; Holmdahl, Meirav; Yamada, Hisakata; Lu, Shemin; Vestberg, Mikael; Holm, Bente; Johnell, Olof; Kihlberg, Jan; Holmdahl, Rikard

doi:10.1002/eji.200425637

Cited by 75 publications

(87 citation statements)

References 28 publications

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“…We have shown that the genetic introduction of pNO 2 (21)(22)(23). For example, citrullination and glycosylation are posttranslational modifications reported to be involved in T cell-dependent autoimmune diseases (21)(22)(23)(24)(25).…”

Section: Resultsmentioning

confidence: 99%

Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids

Grünewald¹,

Hunt²,

Dong

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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For more than 2 centuries active immunotherapy has been at the forefront of efforts to prevent infectious disease [Waldmann TA (2003) Nat Med 9:269 -277]. However, the decreased ability of the immune system to mount a robust immune response to selfantigens has made it more difficult to generate therapeutic vaccines against cancer or chronic degenerative diseases. Recently, we showed that the site-specific incorporation of an immunogenic unnatural amino acid into an autologous protein offers a simple and effective approach to overcome self-tolerance. Here, we characterize the nature and durability of the polyclonal IgG antibody response and begin to establish the generality of p-nitrophenylalanine (pNO 2Phe)-induced loss of self-tolerance. Mutation of several surface residues of murine tumor necrosis factor-␣ (mTNF-␣) independently to pNO2Phe leads to a T cell-dependent polyclonal and sustainable anti-mTNF-␣ IgG autoantibody response that lasts for at least 40 weeks. The antibodies bind multiple epitopes on mTNF-␣ and protect mice from severe endotoxemia induced by lipopolysaccharide (LPS) challenge. Immunization of mice with a pNO 2Phe 43 mutant of murine retinol-binding protein (RBP4) also elicited a high titer IgG antibody response, which was cross-reactive with wild-type mRBP4. These findings suggest that this may be a relatively general approach to generate effective immunotherapeutics against cancer-associated or other weakly immunogenic antigens.retinol-binding protein ͉ tumor necrosis factor ͉ vaccination ͉ p-nitrophenylalanine ͉ genetic code

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Section: Resultsmentioning

confidence: 99%

Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids

Grünewald¹,

Hunt²,

Dong

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…We know from studies in CIA that the nature of such endogenous proteins could be quite complex because the T cell recognition in this case is dependent on various forms of glycosylation of type II collagen (40). In addition, this glycosylation is dependent on the status of chondrocytes in the joints that could vary depending on inflammatory conditions (41). In the present experiments, we could show that the T cell-induced inflammatory cascade in the joints is dependent on cytokines such as IFN-␥ and TNF-␣, which are believed to be secreted by T cells and macrophages.…”

Section: Discussionmentioning

confidence: 99%

Pristane, a Non-Antigenic Adjuvant, Induces MHC Class II-Restricted, Arthritogenic T Cells in the Rat

Holmberg

Tuncel

Yamada

et al. 2006

The Journal of Immunology

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Pristane-induced arthritis (PIA) in rats, a model for rheumatoid arthritis (RA), is a T cell-dependent disease. However, pristane itself is a lipid and unable to form a stable complex with a MHC class II molecule. Therefore, the specificity and function of the T cells in PIA are as unclear as in rheumatoid arthritis. In this study, we show that activated CD4+ αβT cells, which target peripheral joints, transfer PIA. The pristane-primed T cells are of oligo or polyclonal origin as determined by their arthritogenicity after stimulation with several mitogenic anti-TCRVβ and anti-TCRVα mAbs. Arthritogenic cells secreted IFN-γ and TNF-α (but not IL-4) when stimulated with Con A in vitro, and pretreatments of recipient rats with either anti-IFN-γ or a recombinant TNF-α receptor before transfer ameliorated arthritis development. Most importantly, we show that these T cells are MHC class II restricted, because treatment with Abs against either DQ or DR molecules ameliorates arthritis development. The MHC class II restriction was confirmed by transferring donor T cells to irradiated recipients that were syngenic, semiallogenic, or allogenic to MHC class II molecules, in which only syngenic and semiallogenic recipients developed arthritis. These data suggest that the in vivo administration of a non-antigenic adjuvant, like pristane, activates CD4+ αβT cells that are MHC class II restricted and arthritogenic.

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“…We have previously shown the importance of galactosylation at position K 264 of CII259-273 for the immune recognition [12][13][14][15][16][17] and that CII in the healthy individuals is completely glycosylated at this position [16]. In line with these findings, an additional modification at position Q 267 by deamidation makes the study of the immune response more complex.…”

Section: Discussionmentioning

confidence: 55%

“…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 phosphorylation, is increased [10,11]. The role of glycosylated immunodominant CII260-270-peptide for development of autoimmune arthritis has been previously described [12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

Dzhambazov

Lindh

Engström³

et al. 2009

Eur J Immunol

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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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The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans

Cited by 75 publications

References 28 publications

Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids

Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids

Pristane, a Non-Antigenic Adjuvant, Induces MHC Class II-Restricted, Arthritogenic T Cells in the Rat

Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

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