Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis

Erika Darrah, Aeryon Kim, Xi Zhang, Tatiana Boronina, Robert N. Cole, Andrea Fava, Jon T. Giles, Clifton O. Bingham, Michael J. Chalmers, Patrick R. Griffin, Scheherazade Sadegh-Nasseri, Antony Rosen

Research output: Contribution to journalArticle

Abstract

Proteolysis of autoantigens can alter normal MHC class II antigen processing and has been implicated in the induction of autoimmune diseases. Many autoantigens are substrates for the protease granzyme B (GrB), but the mechanistic significance of this association is unknown. Peptidylarginine deiminase 4 (PAD4) is a frequent target of autoantibodies in patients with rheumatoid arthritis (RA) and a substrate for GrB. RA is strongly associated with specific MHC class II alleles, and elevated levels of GrB and PAD4 are found in the joints of RA patients, suggesting that GrB may alter the presentation of PAD4 by RA-associated class II alleles. In this study, complementary proteomic and immunologic approaches were utilized to define the effects of GrB cleavage on the structure, processing, and immunogenicity of PAD4. Hydrogen-deuterium exchange and a cell-free MHC class II antigen processing system revealed that proteolysis of PAD4 by GrB induced discrete structural changes in PAD4 that promoted enhanced presentation of several immunogenic peptides capable of stimulating PAD4-specific CD4+ T cells from patients with RA. This work demonstrates the existence of PAD4-specific T cells in patients with RA and supports a mechanistic role for GrB in enhancing the presentation of autoantigenic CD4+ T cell epitopes.

Original languageEnglish (US)
Pages (from-to)355-365
Number of pages11
JournalJournal of Proteome Research
Volume16
Issue number1
DOIs
StatePublished - Jan 6 2017

Fingerprint

Granzymes
Proteolysis
Epitopes
Rheumatoid Arthritis
Omsk Hemorrhagic Fever
Accessory Nerve
Histocompatibility Antigens Class II
Autoantigens
Antigen Presentation
Alleles
T-Lymphocytes
T-cells
Substrates
T-Lymphocyte Epitopes
Deuterium
Autoantibodies
Proteomics
Autoimmune Diseases
Hydrogen
Peptide Hydrolases

Keywords

  • antigen presentation
  • antigen processing
  • autoantigen
  • autoimmunity
  • epitope
  • hydrogen-deuterium exchange
  • mass spectrometry
  • peptidylarginine deiminase
  • rheumatoid arthritis
  • shared epitope

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry

Cite this

Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis. / Darrah, Erika; Kim, Aeryon; Zhang, Xi; Boronina, Tatiana; Cole, Robert N.; Fava, Andrea; Giles, Jon T.; Bingham, Clifton O.; Chalmers, Michael J.; Griffin, Patrick R.; Sadegh-Nasseri, Scheherazade; Rosen, Antony.

In: Journal of Proteome Research, Vol. 16, No. 1, 06.01.2017, p. 355-365.

Research output: Contribution to journalArticle

Darrah, Erika; Kim, Aeryon; Zhang, Xi; Boronina, Tatiana; Cole, Robert N.; Fava, Andrea; Giles, Jon T.; Bingham, Clifton O.; Chalmers, Michael J.; Griffin, Patrick R.; Sadegh-Nasseri, Scheherazade; Rosen, Antony / Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis.

In: Journal of Proteome Research, Vol. 16, No. 1, 06.01.2017, p. 355-365.

Research output: Contribution to journalArticle

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AB - Proteolysis of autoantigens can alter normal MHC class II antigen processing and has been implicated in the induction of autoimmune diseases. Many autoantigens are substrates for the protease granzyme B (GrB), but the mechanistic significance of this association is unknown. Peptidylarginine deiminase 4 (PAD4) is a frequent target of autoantibodies in patients with rheumatoid arthritis (RA) and a substrate for GrB. RA is strongly associated with specific MHC class II alleles, and elevated levels of GrB and PAD4 are found in the joints of RA patients, suggesting that GrB may alter the presentation of PAD4 by RA-associated class II alleles. In this study, complementary proteomic and immunologic approaches were utilized to define the effects of GrB cleavage on the structure, processing, and immunogenicity of PAD4. Hydrogen-deuterium exchange and a cell-free MHC class II antigen processing system revealed that proteolysis of PAD4 by GrB induced discrete structural changes in PAD4 that promoted enhanced presentation of several immunogenic peptides capable of stimulating PAD4-specific CD4+ T cells from patients with RA. This work demonstrates the existence of PAD4-specific T cells in patients with RA and supports a mechanistic role for GrB in enhancing the presentation of autoantigenic CD4+ T cell epitopes.

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