T cell recognition of carbohydrates on type II collagen.

Michaëlsson, Erik; Malmström, Vivianne; Reis, Salette; Engström, Åke; Burkhardt, Harald; Holmdahl, Rikard

doi:10.1084/jem.180.2.745

Cited by 199 publications

(142 citation statements)

References 21 publications

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“…This results in smaller CII fragments being picked up by APC and presented by MHC class II. Previous studies from our laboratory showed that CII-specific T cells predominantly recognize glycosylation at position 264 in the CII260-270 epitope and that glycosylated CII is more arthritogenic than non-glycosylated CII is [3,11,13,20]. In addition, adoptive transfer of glycopeptidespecific T cells into CII-immunized DBA/1 mice increases the incidence and severity of arthritis as well as the production of CII-specific antibodies [21].…”

Section: Discussionmentioning

confidence: 84%

“…This T cell determinant contains lysine residues at position 264 and 270, which can become posttranslationally modified by hydroxylation and further galactosylated and glucosylated, creating many different epitopes containing hydroxyl, mono-and disaccharide groups in both RA and CIA. We have previously shown that autoreactive T cells predominantly recognize this epitope when it is posttranslationally modified at positions 264 and 270 by hydroxylation and further glycosylation [11][12][13]. The dominant T cell epitope is the side-chain of lysine at position 264 (K264) when the peptide is bound to A q , but when bound to DR4 the T cells recognize either position K264 or K270, although position 264 seems to be the more dominant of the two in this case.…”

Section: Introductionmentioning

confidence: 94%

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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

et al. 2005

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Type II collagen (CII) is a target for autoreactive T cells in both rheumatoid arthritis and the murine model collagen-induced arthritis. The determinant core of CII has been identified as CII260-270, and the alteration of this T cell epitope by posttranslational modifications is known to be critical for development of arthritis in mice. Using CIIspecific T cell hybridomas we have now shown that the immunodominant T cell epitope in the normal (healthy) human and rat joint cartilage is O-glycosylated at the critical T cell receptor recognition position 264 with a mono-or di-saccharide attached to a hydroxylysine. In contrast, in the arthritic human and rat joint cartilage there are both glycosylated and non-glycosylated CII forms. Glycosylated CII from normal cartilage could not be recognized by T cells reactive to peptides having only lysine or hydroxylysine at position 264, showing that antigen-presenting cells could not degrade the O-linked carbohydrate. Thus, the variable forms of the glycosylated epitope are determined by the structures present in cartilage, and these vary during the disease course. We conclude that the chondrocyte determines the structures presented to the immune system and that these structures are different in normal versus arthritic states.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 94%

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

et al. 2005

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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 structural basis of MHC control of collagen-induced arthritis; binding of the immunodominant type II collagen 256 – 270 glycopeptide to H-2Aq and H-2Ap molecules

et al. 1998

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The Aq major histocompatibility complex (MHC) class II molecule is associated with susceptibility to murine collagen-induced arthritis (CIA), whereas the closely related H-2Ap molecule is not. To understand the molecular basis for this difference, we have analyzed the ability of H-2Aq and H-2Ap molecules (referred to as Aq and Ap) to bind and present collagen type II (CII)-derived glycosylated and non-glycosylated peptides. T cell clones specific for the immunodominant CII 256-270 peptide and restricted to both Aq and Ap molecules were identified. When these clones were incubated with CII protein and either Aq- or Ap-expressing antigen-presenting cells (APC), only Aq-expressing APC were able to induce stimulation. With the use of A(beta) transgenic mice this could be shown to be solely dependent on the MHC class II molecule itself and to be independent of other MHC- or non-MHC genes. Peptide binding studies were performed using affinity-purified MHC class II molecules. The CII 256-270 peptide bound with lower affinity to the Ap molecule than to the Aq molecule. Using a set of alanine-substituted CII 256-270 peptides, MHC class II and T cell receptor (TCR) contacts were identified. Mainly the side chains of isoleucine 260 and phenylalanine 263 were used for binding both the Aq and Ap molecule, i.e. the peptide was orientated similarly in the binding clefts. The major TCR contact amino acids were lysine 264, which can be posttranslationally modified, and glutamic acid 266, which is the only amino acid in the heterologous peptide which differs from the mouse sequence. Glycosylation at positions 264 and 270 of the CII 256-270 peptide did not change the anchor positions used for binding to the Aq or Ap molecules. The autologous form of the peptide (with aspartic acid at position 266) bound with lower affinity to the Aq molecule as compared with the heterologous peptide. The variable affinity displayed by the immunodominant CII 256-270 peptide for different MHC class II molecules, the identification of MHC and TCR contacts and the significance of glycosylation of these have important implications for the understanding of the molecular basis for inherited MHC class II-associated susceptibility to CIA and in turn, for development of novel treatment strategies in this disease.

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T cell recognition of carbohydrates on type II collagen.

Cited by 199 publications

References 21 publications

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

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

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

The structural basis of MHC control of collagen-induced arthritis; binding of the immunodominant type II collagen 256 – 270 glycopeptide to H-2Aq and H-2Ap molecules

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