Dataset Information

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

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.

SUBMITTER: Darrah E

PROVIDER: S-EPMC5218978 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Darrah Erika E Kim AeRyon A Zhang Xi X Boronina Tatiana T Cole Robert N RN Fava Andrea A Giles Jon T JT Bingham III Clifton O CO Chalmers Michael J MJ Griffin Patrick R PR Sadegh-Nasseri Scheherazade S Rosen Antony A

Journal of proteome research 20161020 1

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 ...[more]

PMID: 27700100

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Project description:ObjectiveTo determine if the baseline presence of autoantibodies to peptidylarginine deiminase 4 (PAD4) predicts therapeutic response to biologic and conventional disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) in whom methotrexate (MTX) monotherapy was unsuccessful.MethodsBaseline serum from 282 RA patients in whom MTX monotherapy was unsuccessful was screened for the presence of anti-PAD4 antibodies by immunoprecipitation. Clinical response to either triple DMARD (MTX, sulfasalazine, and hydroxychloroquine) or MTX/etanercept combination therapy was determined at 24 and 48 weeks post-treatment initiation. Disease activity was measured using the Disease Activity Score 28-joint assessment (DAS28), and erosive disease was quantified using the Sharp/van der Heijde scoring method. Generalized estimating equations (GEEs) were used to model the clinical responses to treatment in patients with and those without baseline anti-PAD4 antibodies.ResultsAnti-PAD4 antibody positivity was associated with male sex, a history of never smoking, and anti-citrullinated protein antibodies. At baseline, patients with anti-PAD4 antibodies had longer disease duration and significantly more radiographic joint damage than anti-PAD4-negative patients, but did not differ in disease activity according to the DAS28. In unadjusted analyses and multivariable GEE models, patients with anti-PAD4 antibodies exhibited greater improvements in DAS28 (adjusted P = 0.02 and P = 0.008, respectively) and less radiographic progression (adjusted P = 0.01 and P = 0.002, respectively) compared to anti-PAD antibody-negative patients, independent of treatment received.ConclusionAlthough anti-PAD4 antibodies were associated with worse baseline radiographic joint damage, suggesting a history of active or undiagnosed disease, treatment escalation therapy was more effective in reducing disease activity and slowing the progression of joint damage in this patient subset.

Project description:BackgroundGiven that autoantibodies to peptidylarginine deiminase 4 (PAD4) are associated with erosive disease in established rheumatoid arthritis (RA), this study was conducted to compare the clinical and prognostic use of anti-PAD4 antibodies in patients with early and established RA.MethodsSera from patients with early (duration <2 years; n = 422) or established (duration ≥2 years; n = 359) RA from two randomized clinical trials of tofacitinib ± methotrexate compared with adalimumab + MTX or MTX alone were evaluated for the presence of anti-PAD4 and anti-PAD3/4 antibodies at baseline and posttreatment time points. Summary statistics were calculated for demographic, clinical, and serological characteristics, and generalized estimating equations were used to model clinical outcomes by disease duration according to anti-PAD4 status.ResultsAnti-PAD4 antibodies were present in 22% and 40% of patients with early and established RA, respectively, stable following treatment, and associated with baseline joint damage only in established RA. In early RA, baseline anti-PAD4 antibodies were associated with a greater improvement in disease activity score 28-joint count using C-reactive protein levels after treatment compared with individuals with negative anti-PAD4 (P = 0.049). Tofacitinib ± MTX was more broadly efficacious than MTX alone at improving clinical outcomes in early and established RA, irrespective of anti-PAD4 status (P < 0.05 for all), whereas adalimumab + MTX exhibited differential benefits in achieving disease activity score remission in early RA (P = 0.036) and American College of Rheumatology 20 responses in established RA (P = 0.002).ConclusionDifferences in prevalence, clinical associations, and treatment-response outcomes according to anti-PAD4 antibody status in early and established RA suggests the existence of a therapeutic window to prevent the accumulation of irreversible joint damage in early patients with RA with anti-PAD4 antibodies.

Dataset Information

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

Publications

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

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