Role of the galactosyl moiety of collagen glycopeptides for T-Cell stimulation in a model for rheumatoid arthritis

Holm, Bente; Baquer, Syed Mohamed; Holm, Lotta; Holmdahl, Rikard; Kihlberg, Jan

doi:10.1016/s0968-0896(03)00407-3

Cited by 15 publications

(8 citation statements)

References 24 publications

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“…Meanwhile, the lysine at position 270 will be shifted toward the center (P8) on DR4, as compared with its peripheral placement (P11) on A q . The K 264 residue clearly constitutes a critical TCR contact point for A q -restricted CII-specific T cells (44,45). However, the importance of the K 264 residue as a DR4-restricted TCR contact or class II MHC anchor point has been questioned, whereas K 270 should be exposed toward the TCR (2,4,46,47).…”

Section: Discussionmentioning

confidence: 99%

Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis

Batsalova¹,

Dzhambazov²,

Mehlen³

et al. 2010

Arthritis & Rheumatism

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Section: Discussionmentioning

confidence: 99%

Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis

Batsalova¹,

Dzhambazov²,

Mehlen³

et al. 2010

Arthritis & Rheumatism

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“…Deglycosylation of CII was performed by treatment with trifluoromethanesulfonic acid:anisol (2:1) for 3 hours on ice, followed by 1 hour of incubation at room temperature, as described elsewhere (16). The glycosylated peptide (GIAG-FKGEQGPKGET; where K represents GalHyL 264 ) corresponding to epitope CII 259-273 containing GalHyL 264 was synthesized using ␤-D-galactopyranosyl-5-hydroxy-L-lysine, as described previously (25). The nonglycosylated peptide pCII 259-273 was purchased from GenScript (Piscataway, NJ), and identity was confirmed by mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

The impact of glycosylation on HLA–DR1–restricted T cell recognition of type II collagen in a mouse model

Delwig

Altmann

Isaacs

et al. 2006

Arthritis & Rheumatism

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Objective. Type II collagen (CII) is a candidate autoantigen implicated in the pathogenesis of rheumatoid arthritis (RA). Posttranslational glycosylation of CII could alter intracellular antigen processing, leading to the development of autoimmune T cell responses. To address this possibility, we studied the intracellular processing of CII for presentation of the arthritogenic glycosylated epitope CII 259-273 to CD4 T cells in macrophages from HLA-DR1-transgenic mice.Methods. HLA-DR1-transgenic mice were generated on a class II major histocompatibility complexdeficient background, and T cell hybridomas specific for the glycosylated and nonglycosylated epitope CII [259][260][261][262][263][264][265][266][267][268][269][270][271][272][273] were developed. Subcellular fractionation of macrophages was used to localize CII degradation to particular compartments and to identify the catalytic subtype of proteinases involved.Results. We showed that the glycosylated CII 259-273epitope required more extensive processing than did the nonglycosylated form of the same epitope. Dense fractions containing lysosomes were primarily engaged in the processing of CII for antigen presentation, since these compartments contained 1) enzyme activity that generated antigenic CII fragments bearing the arthritogenic glycosylated epitope, 2) the antigenic CII fragments themselves, 3) CII peptide-receptive HLA-DR1 molecules, and 4) peptide/HLA-DR1 complexes that could directly activate T cell hybridomas. Degradation of CII by dense fractions occurred optimally at pH 4.5 and was abrogated by inhibitors of serine and cysteine proteinases. Conclusion. Processing of the arthritogenic glycosylated CII259-273 epitope, which is implicated in the induction of autoimmune arthritis, is more stringently regulated than is processing of the nonglycosylated form of the same epitope. Mechanisms of intracellular processing of the glycosylated epitope may constitute novel therapeutic targets for the treatment of RA.

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“…The glycosylated peptide (GIAGF KGEQGPKGET; K = GalHyL 264 ) corresponding to epitope CII 259–273 GalHyL 264 was synthesized using β-D-galactopyranosyl-5-hydroxy-L-lysine, as described previously [26]. The non-glycosylated peptide pCII 259–273 was purchased from GenScript Corp. (Piscataway, NJ, USA), and purity was confirmed by high-performance liquid chromatography.…”

Section: Methodsmentioning

confidence: 99%

Untitled

et al. 2006

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Professional antigen-presenting cells, such as dendritic cells, macrophages and B cells have been implicated in the pathogenesis of rheumatoid arthritis, constituting a possible target for antigen-specific immunotherapy. We addressed the possibility of blocking antigen presentation of the type II collagen (CII)-derived immunodominant arthritogenic epitope CII [259][260][261][262][263][264][265][266][267][268][269][270][271][272][273] to specific CD4 T cells by inhibition of antigen uptake in HLA-DR1-transgenic mice in vitro and in vivo. Electron microscopy, confocal microscopy, subcellular fractionation and antigen presentation assays were used to establish the mechanisms of uptake, intracellular localization and antigen presentation of CII by dendritic cells and macrophages. We show that CII accumulated in membrane fractions of intermediate density corresponding to late endosomes. Treatment of dendritic cells and macrophages with cytochalasin D or amiloride prevented the intracellular appearance of CII and blocked antigen presentation of CII 259-273 to HLA-DR1-restricted T cell hybridomas. The data suggest that CII was taken up by dendritic cells and macrophages predominantly via macropinocytosis. Administration of amiloride in vivo prevented activation of CII-specific polyclonal T cells in the draining popliteal lymph nodes. This study suggests that selective targeting of CII internalization in professional antigen-presenting cells prevents activation of autoimmune T cells, constituting a novel therapeutic strategy for the immunotherapy of rheumatoid arthritis.

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Role of the galactosyl moiety of collagen glycopeptides for T-Cell stimulation in a model for rheumatoid arthritis

Cited by 15 publications

References 24 publications

Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis

Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis

The impact of glycosylation on HLA–DR1–restricted T cell recognition of type II collagen in a mouse model

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