Impaired activation-induced cell death promotes spontaneous arthritis in antigen (cartilage proteoglycan)-specific T cell receptor-transgenic mice

F. Boldizsár, Katalin Kis-Toth, Oktavia Tarjanyi, Katalin Olasz, Akos Hegyi, Katalin Mikecz, Tibor T. Glant

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Objective. To investigate whether genetic preponderance of a T cell receptor (TCR) recognizing an arthritogenic peptide of human cartilage proteoglycan (PG) is sufficient for development of arthritis. Methods. We performed a longitudinal study using BALB/c mice expressing a TCR that recognizes the arthritogenic ATEGRVRVNSAYQDK peptide of human cartilage PG. PG-specific TCR - transgenic (PG-TCR - Tg) mice were inspected weekly for peripheral arthritis until 12 months of age. Peripheral joints were examined histologically, and T cell responses, T cell activation markers, serum cytokines, and autoantibodies were measured. Apoptosis and signaling studies were performed in vitro on T cells from aged PG-TCR - Tg mice. Results. Spontaneous arthritis developed as early as 5-6 months of age, and the incidence increased to 40-50% by 12 months of age. Progressive inflammation began with cartilage and bone erosions in the interphalangeal joints, and later expanded to the proximal joints of the front and hind paws. Spontaneous arthritis was associated with a high proportion of activated CD4+ T cells, enhanced interferon-γ and interleukin-17 (IL-17) production, and elevated levels of serum autoantibodies. PG-TCR-Tg mice lacking IL-4 developed arthritis earlier and at a higher incidence than IL-4 - sufficient mice. Antigen-specific activation - induced cell death was diminished in vitro in CD4+ T cells of PG-TCR - Tg mice with spontaneous arthritis, especially in those lacking IL-4. Conclusion. The presence of CD4+ T cells expressing a TCR specific for an arthritogenic PG epitope is sufficient to trigger spontaneous autoimmune inflammation in the joints of BALB/c mice. IL-4 appears to be a negative regulator of this disease, through attenuation of activation-induced cell death.

Original languageEnglish
Pages (from-to)2984-2994
Number of pages11
JournalArthritis and Rheumatism
Volume62
Issue number10
DOIs
Publication statusPublished - Oct 2010

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Proteoglycans
T-Cell Antigen Receptor
Transgenic Mice
Arthritis
Cartilage
Cell Death
Antigens
T-Lymphocytes
Interleukin-4
Joints
Autoantibodies
Inflammation
Peptides
Interleukin-17
Incidence
Interferons
Longitudinal Studies
Epitopes
Biomarkers
Apoptosis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Impaired activation-induced cell death promotes spontaneous arthritis in antigen (cartilage proteoglycan)-specific T cell receptor-transgenic mice. / Boldizsár, F.; Kis-Toth, Katalin; Tarjanyi, Oktavia; Olasz, Katalin; Hegyi, Akos; Mikecz, Katalin; Glant, Tibor T.

In: Arthritis and Rheumatism, Vol. 62, No. 10, 10.2010, p. 2984-2994.

Research output: Contribution to journalArticle

Boldizsár, F. ; Kis-Toth, Katalin ; Tarjanyi, Oktavia ; Olasz, Katalin ; Hegyi, Akos ; Mikecz, Katalin ; Glant, Tibor T. / Impaired activation-induced cell death promotes spontaneous arthritis in antigen (cartilage proteoglycan)-specific T cell receptor-transgenic mice. In: Arthritis and Rheumatism. 2010 ; Vol. 62, No. 10. pp. 2984-2994.
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T1 - Impaired activation-induced cell death promotes spontaneous arthritis in antigen (cartilage proteoglycan)-specific T cell receptor-transgenic mice

AU - Boldizsár, F.

AU - Kis-Toth, Katalin

AU - Tarjanyi, Oktavia

AU - Olasz, Katalin

AU - Hegyi, Akos

AU - Mikecz, Katalin

AU - Glant, Tibor T.

PY - 2010/10

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N2 - Objective. To investigate whether genetic preponderance of a T cell receptor (TCR) recognizing an arthritogenic peptide of human cartilage proteoglycan (PG) is sufficient for development of arthritis. Methods. We performed a longitudinal study using BALB/c mice expressing a TCR that recognizes the arthritogenic ATEGRVRVNSAYQDK peptide of human cartilage PG. PG-specific TCR - transgenic (PG-TCR - Tg) mice were inspected weekly for peripheral arthritis until 12 months of age. Peripheral joints were examined histologically, and T cell responses, T cell activation markers, serum cytokines, and autoantibodies were measured. Apoptosis and signaling studies were performed in vitro on T cells from aged PG-TCR - Tg mice. Results. Spontaneous arthritis developed as early as 5-6 months of age, and the incidence increased to 40-50% by 12 months of age. Progressive inflammation began with cartilage and bone erosions in the interphalangeal joints, and later expanded to the proximal joints of the front and hind paws. Spontaneous arthritis was associated with a high proportion of activated CD4+ T cells, enhanced interferon-γ and interleukin-17 (IL-17) production, and elevated levels of serum autoantibodies. PG-TCR-Tg mice lacking IL-4 developed arthritis earlier and at a higher incidence than IL-4 - sufficient mice. Antigen-specific activation - induced cell death was diminished in vitro in CD4+ T cells of PG-TCR - Tg mice with spontaneous arthritis, especially in those lacking IL-4. Conclusion. The presence of CD4+ T cells expressing a TCR specific for an arthritogenic PG epitope is sufficient to trigger spontaneous autoimmune inflammation in the joints of BALB/c mice. IL-4 appears to be a negative regulator of this disease, through attenuation of activation-induced cell death.

AB - Objective. To investigate whether genetic preponderance of a T cell receptor (TCR) recognizing an arthritogenic peptide of human cartilage proteoglycan (PG) is sufficient for development of arthritis. Methods. We performed a longitudinal study using BALB/c mice expressing a TCR that recognizes the arthritogenic ATEGRVRVNSAYQDK peptide of human cartilage PG. PG-specific TCR - transgenic (PG-TCR - Tg) mice were inspected weekly for peripheral arthritis until 12 months of age. Peripheral joints were examined histologically, and T cell responses, T cell activation markers, serum cytokines, and autoantibodies were measured. Apoptosis and signaling studies were performed in vitro on T cells from aged PG-TCR - Tg mice. Results. Spontaneous arthritis developed as early as 5-6 months of age, and the incidence increased to 40-50% by 12 months of age. Progressive inflammation began with cartilage and bone erosions in the interphalangeal joints, and later expanded to the proximal joints of the front and hind paws. Spontaneous arthritis was associated with a high proportion of activated CD4+ T cells, enhanced interferon-γ and interleukin-17 (IL-17) production, and elevated levels of serum autoantibodies. PG-TCR-Tg mice lacking IL-4 developed arthritis earlier and at a higher incidence than IL-4 - sufficient mice. Antigen-specific activation - induced cell death was diminished in vitro in CD4+ T cells of PG-TCR - Tg mice with spontaneous arthritis, especially in those lacking IL-4. Conclusion. The presence of CD4+ T cells expressing a TCR specific for an arthritogenic PG epitope is sufficient to trigger spontaneous autoimmune inflammation in the joints of BALB/c mice. IL-4 appears to be a negative regulator of this disease, through attenuation of activation-induced cell death.

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