Immune recognition of citrullinated proteoglycan aggrecan epitopes in mice with proteoglycan-induced arthritis and in patients with rheumatoid arthritis

Adrienn Markovics, Tímea Ocskó, Robert S. Katz, E. Búzás, Tibor T. Glant, Katalin Mikecz

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints. Anti-citrullinated protein antibodies (ACPA) are frequently found in RA. Previous studies identified a citrullinated epitope in cartilage proteoglycan (PG) aggrecan that elicited pro-inflammatory cytokine production by RA T cells. We recently reported the presence of ACPA-reactive (citrullinated) PG in RA cartilage. Herein, we sought to identify additional citrullinated epitopes in human PG that are recognized by T cells or antibodies from RA patients. Methods: We used mice with PG-induced arthritis (PGIA) as a screening tool to select citrulline (Cit)- containing PG peptides that were more immunogenic than the arginine (R)-containing counterparts. The selected peptide pairs were tested for induction of pro-inflammatory T-cell cytokine production in RA and healthy control peripheral blood mononuclear cell (PBMC) cultures using ELISA and flow cytometry. Anti-Cit and anti-R peptide antibodies were detected by ELISA. Results: Splenocytes from mice with PGIA exhibited greater T-cell cytokine secretion in response to the Cit than the R version of PG peptide 49 (P49) and anti-P49 antibodies were found in PGIA serum. PBMC from ACPA+ and ACPA- RA patients, but not from healthy controls, responded to Cit49 with robust cytokine production. High levels of anti-Cit49 antibodies were found in the plasma of a subset of ACPA+ RA patients. Another PG peptide (Cit13) similar to the previously described T-cell epitope induced greater cytokine responses than R13 by control (but not RA) PBMC, however, anti-Cit13 antibodies were rarely detected in human plasma. Conclusions: We identified a novel citrullinated PG epitope (Cit49) that is highly immunogenic in mice with PGIA and in RA patients. We also describe T-cell and antibody reactivity with Cit49 in ACPA+ RA. As citrullinated PG might be present in RA articular cartilage, Cit PG epitopeinduced T-cell activation or antibody deposition may occur in the joints of RA patients.

Original languageEnglish
Article numbere0160284
JournalPLoS One
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

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Aggrecans
rheumatoid arthritis
proteoglycans
arthritis
Proteoglycans
epitopes
Arthritis
Epitopes
Rheumatoid Arthritis
T-cells
antibodies
Antibodies
mice
Citrulline
T-lymphocytes
citrulline
Cytokines
peptides
Cartilage
Peptides

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Immune recognition of citrullinated proteoglycan aggrecan epitopes in mice with proteoglycan-induced arthritis and in patients with rheumatoid arthritis. / Markovics, Adrienn; Ocskó, Tímea; Katz, Robert S.; Búzás, E.; Glant, Tibor T.; Mikecz, Katalin.

In: PLoS One, Vol. 11, No. 7, e0160284, 01.07.2016.

Research output: Contribution to journalArticle

Markovics, Adrienn ; Ocskó, Tímea ; Katz, Robert S. ; Búzás, E. ; Glant, Tibor T. ; Mikecz, Katalin. / Immune recognition of citrullinated proteoglycan aggrecan epitopes in mice with proteoglycan-induced arthritis and in patients with rheumatoid arthritis. In: PLoS One. 2016 ; Vol. 11, No. 7.
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title = "Immune recognition of citrullinated proteoglycan aggrecan epitopes in mice with proteoglycan-induced arthritis and in patients with rheumatoid arthritis",
abstract = "Background: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints. Anti-citrullinated protein antibodies (ACPA) are frequently found in RA. Previous studies identified a citrullinated epitope in cartilage proteoglycan (PG) aggrecan that elicited pro-inflammatory cytokine production by RA T cells. We recently reported the presence of ACPA-reactive (citrullinated) PG in RA cartilage. Herein, we sought to identify additional citrullinated epitopes in human PG that are recognized by T cells or antibodies from RA patients. Methods: We used mice with PG-induced arthritis (PGIA) as a screening tool to select citrulline (Cit)- containing PG peptides that were more immunogenic than the arginine (R)-containing counterparts. The selected peptide pairs were tested for induction of pro-inflammatory T-cell cytokine production in RA and healthy control peripheral blood mononuclear cell (PBMC) cultures using ELISA and flow cytometry. Anti-Cit and anti-R peptide antibodies were detected by ELISA. Results: Splenocytes from mice with PGIA exhibited greater T-cell cytokine secretion in response to the Cit than the R version of PG peptide 49 (P49) and anti-P49 antibodies were found in PGIA serum. PBMC from ACPA+ and ACPA- RA patients, but not from healthy controls, responded to Cit49 with robust cytokine production. High levels of anti-Cit49 antibodies were found in the plasma of a subset of ACPA+ RA patients. Another PG peptide (Cit13) similar to the previously described T-cell epitope induced greater cytokine responses than R13 by control (but not RA) PBMC, however, anti-Cit13 antibodies were rarely detected in human plasma. Conclusions: We identified a novel citrullinated PG epitope (Cit49) that is highly immunogenic in mice with PGIA and in RA patients. We also describe T-cell and antibody reactivity with Cit49 in ACPA+ RA. As citrullinated PG might be present in RA articular cartilage, Cit PG epitopeinduced T-cell activation or antibody deposition may occur in the joints of RA patients.",
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T1 - Immune recognition of citrullinated proteoglycan aggrecan epitopes in mice with proteoglycan-induced arthritis and in patients with rheumatoid arthritis

AU - Markovics, Adrienn

AU - Ocskó, Tímea

AU - Katz, Robert S.

AU - Búzás, E.

AU - Glant, Tibor T.

AU - Mikecz, Katalin

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Background: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints. Anti-citrullinated protein antibodies (ACPA) are frequently found in RA. Previous studies identified a citrullinated epitope in cartilage proteoglycan (PG) aggrecan that elicited pro-inflammatory cytokine production by RA T cells. We recently reported the presence of ACPA-reactive (citrullinated) PG in RA cartilage. Herein, we sought to identify additional citrullinated epitopes in human PG that are recognized by T cells or antibodies from RA patients. Methods: We used mice with PG-induced arthritis (PGIA) as a screening tool to select citrulline (Cit)- containing PG peptides that were more immunogenic than the arginine (R)-containing counterparts. The selected peptide pairs were tested for induction of pro-inflammatory T-cell cytokine production in RA and healthy control peripheral blood mononuclear cell (PBMC) cultures using ELISA and flow cytometry. Anti-Cit and anti-R peptide antibodies were detected by ELISA. Results: Splenocytes from mice with PGIA exhibited greater T-cell cytokine secretion in response to the Cit than the R version of PG peptide 49 (P49) and anti-P49 antibodies were found in PGIA serum. PBMC from ACPA+ and ACPA- RA patients, but not from healthy controls, responded to Cit49 with robust cytokine production. High levels of anti-Cit49 antibodies were found in the plasma of a subset of ACPA+ RA patients. Another PG peptide (Cit13) similar to the previously described T-cell epitope induced greater cytokine responses than R13 by control (but not RA) PBMC, however, anti-Cit13 antibodies were rarely detected in human plasma. Conclusions: We identified a novel citrullinated PG epitope (Cit49) that is highly immunogenic in mice with PGIA and in RA patients. We also describe T-cell and antibody reactivity with Cit49 in ACPA+ RA. As citrullinated PG might be present in RA articular cartilage, Cit PG epitopeinduced T-cell activation or antibody deposition may occur in the joints of RA patients.

AB - Background: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints. Anti-citrullinated protein antibodies (ACPA) are frequently found in RA. Previous studies identified a citrullinated epitope in cartilage proteoglycan (PG) aggrecan that elicited pro-inflammatory cytokine production by RA T cells. We recently reported the presence of ACPA-reactive (citrullinated) PG in RA cartilage. Herein, we sought to identify additional citrullinated epitopes in human PG that are recognized by T cells or antibodies from RA patients. Methods: We used mice with PG-induced arthritis (PGIA) as a screening tool to select citrulline (Cit)- containing PG peptides that were more immunogenic than the arginine (R)-containing counterparts. The selected peptide pairs were tested for induction of pro-inflammatory T-cell cytokine production in RA and healthy control peripheral blood mononuclear cell (PBMC) cultures using ELISA and flow cytometry. Anti-Cit and anti-R peptide antibodies were detected by ELISA. Results: Splenocytes from mice with PGIA exhibited greater T-cell cytokine secretion in response to the Cit than the R version of PG peptide 49 (P49) and anti-P49 antibodies were found in PGIA serum. PBMC from ACPA+ and ACPA- RA patients, but not from healthy controls, responded to Cit49 with robust cytokine production. High levels of anti-Cit49 antibodies were found in the plasma of a subset of ACPA+ RA patients. Another PG peptide (Cit13) similar to the previously described T-cell epitope induced greater cytokine responses than R13 by control (but not RA) PBMC, however, anti-Cit13 antibodies were rarely detected in human plasma. Conclusions: We identified a novel citrullinated PG epitope (Cit49) that is highly immunogenic in mice with PGIA and in RA patients. We also describe T-cell and antibody reactivity with Cit49 in ACPA+ RA. As citrullinated PG might be present in RA articular cartilage, Cit PG epitopeinduced T-cell activation or antibody deposition may occur in the joints of RA patients.

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