Predominant cellular immune response to the cartilage autoantigenic G1 aggrecan in ankylosing spondylitis and rheumatoid arthritis

J. Zou, Y. Zhang, A. Thiel, M. Rudwaleit, S. L. Shi, A. Radbruch, R. Poole, J. Braun, J. Sieper

Research output: Contribution to journalArticle

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Abstract

Objectives. Based on their HLA association, both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) seem to be T-cell-driven diseases in which the autoantigens remain to be defined. One possible autoantigen is the G1 domain of aggrecan, the major cartilage proteoglycan. In BALB/c mice immunized with this protein, spondylitis and erosive polyarthritis have been reported. Immune reactivity to the G1 has been described in patients with RA and AS in an earlier study. Using novel and more sensitive techniques and relevant controls we sought to define the role of G1 as an autoantigen more precisely and to extend the specific analyses to the peptide level. Methods. Peripheral blood (PB) mononuclear cells (MNC) from 47 AS patients, 22 RA patients and 20 healthy normal controls were exposed in vitro for 6 h to the cartilage-derived autoantigens G1, human cartilage (HC) gp-39 and collagen II. Synovial fluid (SF) MNC from seven AS and four RA patients were similarly analysed. Furthermore, PB MNC of 15 AS and 10 RA patients were examined with overlapping 18-mer peptides covering the whole G1 protein to identify the immunodominant epitopes. T cells were stained by monoclonal antibodies directed against the surface markers CD4, CD69 and against the intracellular cytokines interferon-γ (IFNγ), tumour necrosis factor-α (TNFα), interleukin 4 (IL-4) and IL-10. The percentage of reactive T cells was quantified by flow cytometry. Results. After antigen-specific stimulation with the G1 protein, the CD4+ T cells of 30 AS patients (61.7%) and of 12 RA patients (54.5%) secreted significant amounts of IFNγ and TNFα, while, in contrast, only 10% of the normal controls showed a response (P <0.05). The synovial CD4+ T cells of five AS (71.5%) and of all four RA patients showed antigen-specific responses to the G1. In contrast, stimulation with HC gp-39 and collagen II showed no significant IFNγ and TNFα secretion of MNC in all groups. Several G1-derived T-cell epitopes were identified as immunodominant in PB MNC of AS and RA patients and were partly overlapping. Conclusions. These data show that a cellular immune response to G1 is present in most AS and RA patients. G1-immunodominant epitopes were identified. The relevance of this finding for the pathogenesis of AS and RA remains to be established.

Original languageEnglish (US)
Pages (from-to)846-855
Number of pages10
JournalRheumatology
Volume42
Issue number7
DOIs
StatePublished - Jul 1 2003
Externally publishedYes

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Aggrecans
Ankylosing Spondylitis
Cellular Immunity
Cartilage
Rheumatoid Arthritis
T-Lymphocytes
Autoantigens
Interferons
Immunodominant Epitopes
Blood Cells
Tumor Necrosis Factor-alpha
Collagen
Spondylitis
Antigens
Peptides
Proteins
T-Lymphocyte Epitopes
Synovial Fluid
Proteoglycans
Interleukin-4

Keywords

  • Aggrecan
  • Ankylosing spondylitis
  • G1 immunity
  • Rheumatoid arthritis
  • T-cell epitope

ASJC Scopus subject areas

  • Neuroscience(all)
  • Rheumatology

Cite this

Predominant cellular immune response to the cartilage autoantigenic G1 aggrecan in ankylosing spondylitis and rheumatoid arthritis. / Zou, J.; Zhang, Y.; Thiel, A.; Rudwaleit, M.; Shi, S. L.; Radbruch, A.; Poole, R.; Braun, J.; Sieper, J.

In: Rheumatology, Vol. 42, No. 7, 01.07.2003, p. 846-855.

Research output: Contribution to journalArticle

Zou, J, Zhang, Y, Thiel, A, Rudwaleit, M, Shi, SL, Radbruch, A, Poole, R, Braun, J & Sieper, J 2003, 'Predominant cellular immune response to the cartilage autoantigenic G1 aggrecan in ankylosing spondylitis and rheumatoid arthritis', Rheumatology, vol. 42, no. 7, pp. 846-855. https://doi.org/10.1093/rheumatology/keg230
Zou, J. ; Zhang, Y. ; Thiel, A. ; Rudwaleit, M. ; Shi, S. L. ; Radbruch, A. ; Poole, R. ; Braun, J. ; Sieper, J. / Predominant cellular immune response to the cartilage autoantigenic G1 aggrecan in ankylosing spondylitis and rheumatoid arthritis. In: Rheumatology. 2003 ; Vol. 42, No. 7. pp. 846-855.
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T1 - Predominant cellular immune response to the cartilage autoantigenic G1 aggrecan in ankylosing spondylitis and rheumatoid arthritis

AU - Zou, J.

AU - Zhang, Y.

AU - Thiel, A.

AU - Rudwaleit, M.

AU - Shi, S. L.

AU - Radbruch, A.

AU - Poole, R.

AU - Braun, J.

AU - Sieper, J.

PY - 2003/7/1

Y1 - 2003/7/1

N2 - Objectives. Based on their HLA association, both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) seem to be T-cell-driven diseases in which the autoantigens remain to be defined. One possible autoantigen is the G1 domain of aggrecan, the major cartilage proteoglycan. In BALB/c mice immunized with this protein, spondylitis and erosive polyarthritis have been reported. Immune reactivity to the G1 has been described in patients with RA and AS in an earlier study. Using novel and more sensitive techniques and relevant controls we sought to define the role of G1 as an autoantigen more precisely and to extend the specific analyses to the peptide level. Methods. Peripheral blood (PB) mononuclear cells (MNC) from 47 AS patients, 22 RA patients and 20 healthy normal controls were exposed in vitro for 6 h to the cartilage-derived autoantigens G1, human cartilage (HC) gp-39 and collagen II. Synovial fluid (SF) MNC from seven AS and four RA patients were similarly analysed. Furthermore, PB MNC of 15 AS and 10 RA patients were examined with overlapping 18-mer peptides covering the whole G1 protein to identify the immunodominant epitopes. T cells were stained by monoclonal antibodies directed against the surface markers CD4, CD69 and against the intracellular cytokines interferon-γ (IFNγ), tumour necrosis factor-α (TNFα), interleukin 4 (IL-4) and IL-10. The percentage of reactive T cells was quantified by flow cytometry. Results. After antigen-specific stimulation with the G1 protein, the CD4+ T cells of 30 AS patients (61.7%) and of 12 RA patients (54.5%) secreted significant amounts of IFNγ and TNFα, while, in contrast, only 10% of the normal controls showed a response (P <0.05). The synovial CD4+ T cells of five AS (71.5%) and of all four RA patients showed antigen-specific responses to the G1. In contrast, stimulation with HC gp-39 and collagen II showed no significant IFNγ and TNFα secretion of MNC in all groups. Several G1-derived T-cell epitopes were identified as immunodominant in PB MNC of AS and RA patients and were partly overlapping. Conclusions. These data show that a cellular immune response to G1 is present in most AS and RA patients. G1-immunodominant epitopes were identified. The relevance of this finding for the pathogenesis of AS and RA remains to be established.

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KW - Aggrecan

KW - Ankylosing spondylitis

KW - G1 immunity

KW - Rheumatoid arthritis

KW - T-cell epitope

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