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Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies.

Ge C, Xu B, Liang B, Lönnblom E, Lundström SL, Zubarev RA, Ayoglu B, Nilsson P, Skogh T, Kastbom A, Malmström V, Klareskog L, Toes REM, Rispens T, Dobritzsch D, Holmdahl R
Arthritis Rheumatol 71 210-221 (2019)
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Cited: 33 times
EuropePMC logo PMID: 30152126

Abstract

Objective

Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA.

Methods

Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients.

Results

Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients.

Reviews citing this publication (10)

  1. Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology. Volkov M, van Schie KA, van der Woude D. Immunol Rev 294 148-163 (2020)
  2. Anti-Citrullinated Protein Antibodies in Patients with Rheumatoid Arthritis: Biological Effects and Mechanisms of Immunopathogenesis. Wu CY, Yang HY, Lai JH. Int J Mol Sci 21 E4015 (2020)
  3. Impact of Posttranslational Modification in Pathogenesis of Rheumatoid Arthritis: Focusing on Citrullination, Carbamylation, and Acetylation. Kwon EJ, Ju JH. Int J Mol Sci 22 10576 (2021)
  4. From risk to chronicity: evolution of autoreactive B cell and antibody responses in rheumatoid arthritis. Scherer HU, van der Woude D, Toes REM. Nat Rev Rheumatol 18 371-383 (2022)
  5. Autoantibodies in Rheumatoid Arthritis: Historical Background and Novel Findings. Sokolova MV, Schett G, Steffen U. Clin Rev Allergy Immunol 63 138-151 (2022)
  6. Disease mechanisms in preclinical rheumatoid arthritis: A narrative review. Romão VC, Fonseca JE. Front Med (Lausanne) 9 689711 (2022)
  7. Biomaterial-based immunotherapeutic strategies for rheumatoid arthritis. Tu AB, Lewis JS. Drug Deliv Transl Res 11 2371-2393 (2021)
  8. Antibody Cross-Reactivity in Auto-Immune Diseases. Trier NH, Houen G. Int J Mol Sci 24 13609 (2023)
  9. Significance of Type II Collagen Posttranslational Modifications: From Autoantigenesis to Improved Diagnosis and Treatment of Rheumatoid Arthritis. Batsalova T, Dzhambazov B. Int J Mol Sci 24 9884 (2023)
  10. [Autoantibodies and the autoreactive immune response : There is more to ACPA than ACPA]. Scherer HU. Z Rheumatol 79 893-897 (2020)

Articles citing this publication (23)

  1. Presence of autoantibodies in "seronegative" rheumatoid arthritis associates with classical risk factors and high disease activity. Reed E, Hedström AK, Hansson M, Mathsson-Alm L, Brynedal B, Saevarsdottir S, Cornillet M, Jakobsson PJ, Holmdahl R, Skriner K, Serre G, Alfredsson L, Rönnelid J, Lundberg K. Arthritis Res Ther 22 170 (2020)
  2. Brain Citrullination Patterns and T Cell Reactivity of Cerebrospinal Fluid-Derived CD4+ T Cells in Multiple Sclerosis. Faigle W, Cruciani C, Wolski W, Roschitzki B, Puthenparampil M, Tomas-Ojer P, Sellés-Moreno C, Zeis T, Jelcic I, Schaeren-Wiemers N, Sospedra M, Martin R. Front Immunol 10 540 (2019)
  3. Antibody-induced pain-like behavior and bone erosion: links to subclinical inflammation, osteoclast activity, and acid-sensing ion channel 3-dependent sensitization. Jurczak A, Delay L, Barbier J, Simon N, Krock E, Sandor K, Agalave NM, Rudjito R, Wigerblad G, Rogóż K, Briat A, Miot-Noirault E, Martinez-Martinez A, Brömme D, Grönwall C, Malmström V, Klareskog L, Khoury S, Ferreira T, Labrum B, Deval E, Jiménez-Andrade JM, Marchand F, Svensson CI. Pain 163 1542-1559 (2022)
  4. N-Glycosylation Site Analysis of Citrullinated Antigen-Specific B-Cell Receptors Indicates Alternative Selection Pathways During Autoreactive B-Cell Development. Vergroesen RD, Slot LM, van Schaik BDC, Koning MT, Rispens T, van Kampen AHC, Toes REM, Scherer HU. Front Immunol 10 2092 (2019)
  5. Disordered Antigens and Epitope Overlap Between Anti-Citrullinated Protein Antibodies and Rheumatoid Factor in Rheumatoid Arthritis. Zheng Z, Mergaert AM, Fahmy LM, Bawadekar M, Holmes CL, Ong IM, Bridges AJ, Newton MA, Shelef MA. Arthritis Rheumatol 72 262-272 (2020)
  6. Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis: a prospective longitudinal inception cohort study. Boman A, Brink M, Lundquist A, Hansson M, Mathsson-Alm L, Rönnelid J, Berglin E, Holmdahl R, Skriner K, Serre G, Klareskog L, Rantapää-Dahlqvist S. RMD Open 5 e000946 (2019)
  7. Surface Ig variable domain glycosylation affects autoantigen binding and acts as threshold for human autoreactive B cell activation. Kissel T, Ge C, Hafkenscheid L, Kwekkeboom JC, Slot LM, Cavallari M, He Y, van Schie KA, Vergroesen RD, Kampstra ASB, Reijm S, Stoeken-Rijsbergen G, Koeleman C, Voortman LM, Heitman LH, Xu B, Pruijn GJM, Wuhrer M, Rispens T, Huizinga TWJ, Scherer HU, Reth M, Holmdahl R, Toes REM. Sci Adv 8 eabm1759 (2022)
  8. Co-immunization with hemagglutinin stem immunogens elicits cross-group neutralizing antibodies and broad protection against influenza A viruses. Moin SM, Boyington JC, Boyoglu-Barnum S, Gillespie RA, Cerutti G, Cheung CS, Cagigi A, Gallagher JR, Brand J, Prabhakaran M, Tsybovsky Y, Stephens T, Fisher BE, Creanga A, Ataca S, Rawi R, Corbett KS, Crank MC, Karlsson Hedestam GB, Gorman J, McDermott AB, Harris AK, Zhou T, Kwong PD, Shapiro L, Mascola JR, Graham BS, Kanekiyo M. Immunity 55 2405-2418.e7 (2022)
  9. Citrullination of a phage-displayed human peptidome library reveals the fine specificities of rheumatoid arthritis-associated autoantibodies. Román-Meléndez GD, Monaco DR, Montagne JM, Quizon RS, Konig MF, Astatke M, Darrah E, Larman HB. EBioMedicine 71 103506 (2021)
  10. Pathogenic Role of Circulating Citrullinated Antigens and Anti-Cyclic Monoclonal Citrullinated Peptide Antibodies in Rheumatoid Arthritis. Won P, Kim Y, Jung H, Rim YA, Sohn DH, Robinson WH, Moon SJ, Ju JH. Front Immunol 12 692242 (2021)
  11. Cross-reactivity of IgM anti-modified protein antibodies in rheumatoid arthritis despite limited mutational load. Reijm S, Kissel T, Stoeken-Rijsbergen G, Slot LM, Wortel CM, van Dooren HJ, Levarht NEW, Kampstra ASB, Derksen VFAM, Heer PO, Bang H, Drijfhout JW, Trouw LA, Huizinga TWJ, Rispens T, Scherer HU, Toes REM. Arthritis Res Ther 23 230 (2021)
  12. Comment New Relationships for Old Autoantibodies in Rheumatoid Arthritis. Shelef MA. Arthritis Rheumatol 71 1396-1399 (2019)
  13. A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis. He Y, Ge C, Moreno-Giró À, Xu B, Beusch CM, Sandor K, Su J, Cheng L, Lönnblom E, Lundqvist C, Slot LM, Tong D, Urbonaviciute V, Liang B, Li T, Lahore GF, Aoun M, Malmström V, Rispens T, Ernfors P, Svensson CI, Scherer HU, Toes REM, Gjertsson I, Ekwall O, Zubarev RA, Holmdahl R. Nat Commun 14 691 (2023)
  14. Antibodies to Cartilage Oligomeric Matrix Protein Are Pathogenic in Mice and May Be Clinically Relevant in Rheumatoid Arthritis. Ge C, Tong D, Lönnblom E, Liang B, Cai W, Fahlquist-Hagert C, Li T, Kastbom A, Gjertsson I, Dobritzsch D, Holmdahl R. Arthritis Rheumatol 74 961-971 (2022)
  15. Specificity of Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis. Trier NH, Holm BE, Hansen PR, Slot O, Locht H, Houen G. Antibodies (Basel) 8 E37 (2019)
  16. Loop Grafting between Similar Local Environments for Fc-Silent Antibodies. Lešnik S, Hodošček M, Podobnik B, Konc J. J Chem Inf Model 60 5475-5486 (2020)
  17. Rheumatoid arthritis sera antibodies to citrullinated collagen type II bind to joint cartilage. Li Q, Li Y, Liang B, Xu R, Xu B, Lönnblom E, Feng H, Bai J, Stawikowska R, Ge C, Lu A, Fields GB, Xiao L, Holmdahl R. Arthritis Res Ther 24 257 (2022)
  18. Identification of potential autoantigens in anti-CCP-positive and anti-CCP-negative rheumatoid arthritis using citrulline-specific protein arrays. Poulsen TBG, Damgaard D, Jørgensen MM, Senolt L, Blackburn JM, Nielsen CH, Stensballe A. Sci Rep 11 17300 (2021)
  19. [Strong inflammation is essential for expression of articular cartilage-specific citrullinated antigens]. Qin G, Lin X, Liang P, Li Y, Zhou C, Kutty SN, Rikard H. Nan Fang Yi Ke Da Xue Xue Bao 40 1081-1089 (2020)
  20. ACPA epitopes - what are we actually looking at? van de Stadt LA, Rispens T. Nat Rev Rheumatol 15 130-132 (2019)
  21. Anticitrullinated antibodies recognize rheumatoid arthritis associated T-cell epitopes modified by bacterial L-asparaginase. Batsalova T, Teneva I, Bardarov K, Moten D, Dzhambazov B. Cent Eur J Immunol 48 174-188 (2023)
  22. Autoreactive B cells in rheumatoid arthritis include mainly activated CXCR3+ memory B cells and plasmablasts. Reijm S, Kwekkeboom JC, Blomberg NJ, Suurmond J, van der Woude D, Toes RE, Scherer HU. JCI Insight 8 e172006 (2023)
  23. Correlation genotype-phenotype: MEFV gene mutations and Moroccan patients with rheumatoid arthritis. Missoum H, Adadi N, Alami M, Toufik H, Bouyahya A, Laarabi FZ, Bachir F, Maghraoui AE, Bakri Y. Pan Afr Med J 41 121 (2022)


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