OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are characteristic of rheumatoid arthritis (RA). However, their presence years before the onset of clinical RA is perplexing. Although multiple putative citrullinated antigens have been identified, no studies have demonstrated the specific capacity of these antigens to initiate inflammatory arthritis. This study was undertaken to recapitulate the transition from preclinical to clinical RA and to demonstrate the capacity of local citrullination to facilitate this transition. METHODS: We performed proteomic analysis of activated human neutrophils to identify citrullinated proteins, including those targeted as part of the RA immune response. Using enzyme-linked immunosorbent assay, we compared RA and osteoarthritis synovial fluid for levels of citrullinated histone H2B and its immune complex. Using macrophage activation assays, we assessed the effect of histone citrullination on immunostimulatory capacity and evaluated the stimulatory capacity of native and citrullinated H2B immune complexes. Finally, we assessed the potential for anti-citrullinated H2B antibodies to mediate arthritis in vivo. RESULTS: We identified robust targeting of neutrophil-derived citrullinated histones by the ACPA immune response. More than 90% of the RA patients had anti-citrullinated H2B antibodies. Histone citrullination increased innate immunostimulatory capacity, and immune complexes containing citrullinated histones activated macrophage cytokine production and propagated neutrophil activation. Finally, we demonstrated that immunization with H2B was arthritogenic, but only in the setting of underlying articular inflammation. CONCLUSION: Our findings indicate that citrullinated histones, specifically citrullinated H2B, are an antigenic target of the ACPA immune response. Furthermore, local generation of citrullinated antigen during low-grade articular inflammation provides a mechanistic model for the conversion from preclinical autoimmunity to inflammatory arthritis. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are characteristic of rheumatoid arthritis (RA). However, their presence years before the onset of clinical RA is perplexing. Although multiple putative citrullinated antigens have been identified, no studies have demonstrated the specific capacity of these antigens to initiate inflammatory arthritis. This study was undertaken to recapitulate the transition from preclinical to clinical RA and to demonstrate the capacity of local citrullination to facilitate this transition. METHODS: We performed proteomic analysis of activated human neutrophils to identify citrullinated proteins, including those targeted as part of the RA immune response. Using enzyme-linked immunosorbent assay, we compared RA and osteoarthritis synovial fluid for levels of citrullinated histone H2B and its immune complex. Using macrophage activation assays, we assessed the effect of histone citrullination on immunostimulatory capacity and evaluated the stimulatory capacity of native and citrullinatedH2B immune complexes. Finally, we assessed the potential for anti-citrullinatedH2B antibodies to mediate arthritis in vivo. RESULTS: We identified robust targeting of neutrophil-derived citrullinated histones by the ACPA immune response. More than 90% of the RA patients had anti-citrullinatedH2B antibodies. Histone citrullination increased innate immunostimulatory capacity, and immune complexes containing citrullinated histones activated macrophage cytokine production and propagated neutrophil activation. Finally, we demonstrated that immunization with H2B was arthritogenic, but only in the setting of underlying articular inflammation. CONCLUSION: Our findings indicate that citrullinated histones, specifically citrullinatedH2B, are an antigenic target of the ACPA immune response. Furthermore, local generation of citrullinated antigen during low-grade articular inflammation provides a mechanistic model for the conversion from preclinical autoimmunity to inflammatory arthritis. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
Authors: Fabrizio Semeraro; Concetta T Ammollo; James H Morrissey; George L Dale; Paul Friese; Naomi L Esmon; Charles T Esmon Journal: Blood Date: 2011-06-14 Impact factor: 22.113
Authors: Ramanjaneyulu Allam; Christina Rebecca Scherbaum; Murthy Narayana Darisipudi; Shrikant R Mulay; Holger Hägele; Julia Lichtnekert; Jan Henrik Hagemann; Khader Valli Rupanagudi; Mi Ryu; Claudia Schwarzenberger; Bernd Hohenstein; Christian Hugo; Bernd Uhl; Christoph A Reichel; Fritz Krombach; Marc Monestier; Helen Liapis; Kristin Moreth; Liliana Schaefer; Hans-Joachim Anders Journal: J Am Soc Nephrol Date: 2012-06-07 Impact factor: 10.121
Authors: Kristine A Kuhn; Liudmila Kulik; Beren Tomooka; Kristin J Braschler; William P Arend; William H Robinson; V Michael Holers Journal: J Clin Invest Date: 2006-04 Impact factor: 14.808
Authors: Jonathan A Hill; Scott Southwood; Alessandro Sette; Anthony M Jevnikar; David A Bell; Ewa Cairns Journal: J Immunol Date: 2003-07-15 Impact factor: 5.422
Authors: Chunyu Liu; Franak Batliwalla; Wentian Li; Annette Lee; Ronenn Roubenoff; Evan Beckman; Houman Khalili; Aarti Damle; Marlena Kern; Richard Furie; Josée Dupuis; Robert M Plenge; Marieke J H Coenen; Timothy W Behrens; John P Carulli; Peter K Gregersen Journal: Mol Med Date: 2008 Sep-Oct Impact factor: 6.354
Authors: Markus M J Nielen; Dirkjan van Schaardenburg; Henk W Reesink; Rob J van de Stadt; Irene E van der Horst-Bruinsma; Margret H M T de Koning; Moud R Habibuw; Jan P Vandenbroucke; Ben A C Dijkmans Journal: Arthritis Rheum Date: 2004-02
Authors: Dong Hyun Sohn; Jeremy Sokolove; Orr Sharpe; Jennifer C Erhart; Piyanka E Chandra; Lauren J Lahey; Tamsin M Lindstrom; Inyong Hwang; Katherine A Boyer; Thomas P Andriacchi; William H Robinson Journal: Arthritis Res Ther Date: 2012-01-08 Impact factor: 5.156
Authors: Yi Tian Ting; Jan Petersen; Sri H Ramarathinam; Stephen W Scally; Khai L Loh; Ranjeny Thomas; Anish Suri; Daniel G Baker; Anthony W Purcell; Hugh H Reid; Jamie Rossjohn Journal: J Biol Chem Date: 2018-01-09 Impact factor: 5.157
Authors: Anca I Catrina; Camilla I Svensson; Vivianne Malmström; Georg Schett; Lars Klareskog Journal: Nat Rev Rheumatol Date: 2016-12-15 Impact factor: 20.543
Authors: M Kristen Demoruelle; Kylie K Harrall; Linh Ho; Monica M Purmalek; Nickie L Seto; Heather M Rothfuss; Michael H Weisman; Joshua J Solomon; Aryeh Fischer; Yuko Okamoto; Lindsay B Kelmenson; Mark C Parish; Marie Feser; Chelsie Fleischer; Courtney Anderson; Michael Mahler; Jill M Norris; Mariana J Kaplan; Brian D Cherrington; V Michael Holers; Kevin D Deane Journal: Arthritis Rheumatol Date: 2017-05-02 Impact factor: 10.995
Authors: Serra E Elliott; Sarah Kongpachith; Nithya Lingampalli; Julia Z Adamska; Bryan J Cannon; Lisa K Blum; Michelle S Bloom; Matthew Henkel; Mandy J McGeachy; Larry W Moreland; William H Robinson Journal: Clin Immunol Date: 2020-02-05 Impact factor: 3.969
Authors: Serra E Elliott; Sarah Kongpachith; Nithya Lingampalli; Julia Z Adamska; Bryan J Cannon; Rong Mao; Lisa K Blum; William H Robinson Journal: Arthritis Rheumatol Date: 2018-10-20 Impact factor: 10.995
Authors: Maral Tajerian; Victor Hung; Hamda Khan; Lauren J Lahey; Yuan Sun; Frank Birklein; Heidrun H Krämer; William H Robinson; Wade S Kingery; J David Clark Journal: Exp Neurol Date: 2016-10-20 Impact factor: 5.330
Authors: Laura Geraldino-Pardilla; Jon T Giles; Jeremy Sokolove; Afshin Zartoshti; William H Robinson; Matthew Budoff; Robert Detrano; Sabahat Bokhari; Joan M Bathon Journal: Arthritis Care Res (Hoboken) Date: 2017-07-10 Impact factor: 4.794