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J Proteome Res. 2017 Jan 6;16(1):355-365. doi: 10.1021/acs.jproteome.6b00617. Epub 2016 Oct 20.

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

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Division of Rheumatology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21224, United States.
Department of Pathology, Johns Hopkins University School of Medicine , Baltimore Maryland 21205, United States.
Department of Molecular Therapeutics, The Scripps Research Institute , Jupiter, Florida 33458, United States.
Department of Biological Chemistry, Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine , Baltimore Maryland 21205, United States.
Division of Rheumatology, Columbia University, College of Physicians and Surgeons , New York, New York 10027, United States.


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.


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

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