Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4+ monozygotic twins discordant for rheumatoid arthritis

M. De Santis, A. Ceribelli, F. Cavaciocchi, E. Generali, M. Massarotti, N. Isailovic, C. Crotti, H. U. Scherer, C. Montecucco, C. Selmi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4 HLA-DR4)+ woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3+ woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)−17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261–273), the native B cell epitope (B359–369) or the R360 citrullinated B cell epitope (citB359–369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4+ twins, but not in the DR3+ RA. The collagen-specific activation of CD4+ T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4+ subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells.

Original languageEnglish (US)
Pages (from-to)309-319
Number of pages11
JournalClinical and Experimental Immunology
Volume185
Issue number3
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Fingerprint

Collagen Type II
Monozygotic Twins
HLA Antigens
T-Lymphocyte Epitopes
Epitopes
Rheumatoid Arthritis
B-Lymphocyte Epitopes
T-Lymphocytes
Interleukin-10
B-Lymphocytes
Collagen
Interleukin-17
Cytokines
Interleukin-4
Interleukin-6
Annexins
Adaptive Immunity
Interferons
Blood Cells
Leukocytes

Keywords

  • carbamylation
  • citrullination
  • rheumatoid arthritis
  • type II human collagen

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4+ monozygotic twins discordant for rheumatoid arthritis. / De Santis, M.; Ceribelli, A.; Cavaciocchi, F.; Generali, E.; Massarotti, M.; Isailovic, N.; Crotti, C.; Scherer, H. U.; Montecucco, C.; Selmi, C.

In: Clinical and Experimental Immunology, Vol. 185, No. 3, 01.09.2016, p. 309-319.

Research output: Contribution to journalArticle

De Santis, M, Ceribelli, A, Cavaciocchi, F, Generali, E, Massarotti, M, Isailovic, N, Crotti, C, Scherer, HU, Montecucco, C & Selmi, C 2016, 'Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4+ monozygotic twins discordant for rheumatoid arthritis', Clinical and Experimental Immunology, vol. 185, no. 3, pp. 309-319. https://doi.org/10.1111/cei.12825
De Santis, M. ; Ceribelli, A. ; Cavaciocchi, F. ; Generali, E. ; Massarotti, M. ; Isailovic, N. ; Crotti, C. ; Scherer, H. U. ; Montecucco, C. ; Selmi, C. / Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4+ monozygotic twins discordant for rheumatoid arthritis. In: Clinical and Experimental Immunology. 2016 ; Vol. 185, No. 3. pp. 309-319.
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abstract = "The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4− HLA-DR4)+ woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3+ woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)−17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261–273), the native B cell epitope (B359–369) or the R360 citrullinated B cell epitope (citB359–369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4+ twins, but not in the DR3+ RA. The collagen-specific activation of CD4+ T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4+ subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells.",
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AU - Cavaciocchi, F.

AU - Generali, E.

AU - Massarotti, M.

AU - Isailovic, N.

AU - Crotti, C.

AU - Scherer, H. U.

AU - Montecucco, C.

AU - Selmi, C.

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