A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid arthritis patients with a toll-like receptor 4-mediated disease

Arthritis Research & Therapy, Oct 2016

Background Increased expression of toll-like receptor 4 (TLR4) and its endogenous ligands, is characteristic of rheumatoid arthritis (RA) synovitis. In this study, we evaluated how these TLR4 ligands may drive pathogenic processes and whether the fine profiling of anti-citrullinated protein antibodies (ACPA) based on their target specificity might provide a simple means to predict therapeutic benefit when neutralizing TLR4 in this disease. Methods The capacity of RA synovial fluids (RASF) to stimulate cytokine production in monocytes from patients with RA was analyzed by ELISA. The presence of TLR4 activators in RASF was determined by measuring the levels of ACPA, ACPA subtypes with reactivity to specific citrullinated peptides and other TLR4 ligands. Neutralization of TLR4 signaling was investigated using NI-0101, a therapeutic antibody that targets TLR4. Results RASF exhibited a heterogeneous capacity to induce production of proinflammatory cytokines by monocytes isolated from patients with RA. Such cytokine responses were significantly modified by TLR4 blockade achieved using NI-0101. The analysis of the content of RASF and matched sera demonstrated that ACPA fine specificities in patient samples predict cellular response to anti-TLR4 exposure in vitro. Conclusion TLR4 represents a possible therapeutic target in RA. Our study demonstrates that TLR4 inhibition in an ex vivo model of RA pathogenesis can significantly modulate cytokine release and does so in specific subgroups of RA patient-derived samples. It also suggests that ACPA fine profiling has the potential to identify RA patients with a predominantly TLR4-driven pathotype that could be used to predict preferential response to TLR4 antagonism.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://arthritis-research.com/content/pdf/s13075-016-1128-5.pdf

A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid arthritis patients with a toll-like receptor 4-mediated disease

Hatterer et al. Arthritis Research & Therapy A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid arthritis patients with a toll-like receptor 4-mediated disease Eric Hatterer 2 Limin Shang 2 Pierre Simonet 2 Suzanne Herren 2 Bruno Daubeuf 2 Stéphanie Teixeira 2 James Reilly 1 Greg Elson 2 3 Robert Nelson 2 Cem Gabay 0 Jeremy Sokolove 4 Iain B. McInnes 1 Marie Kosco-Vilbois 2 Walter Ferlin 2 Emmanuel Monnet 2 Cristina De Min 2 0 Geneva University Hospital , 26 avenue Beau-Sejour, 1211 Geneva , Switzerland 1 University School of Medicine, Institute of infection , immunity and inflammation, 120 University Place, Glasgow , UK 2 NovImmune SA , 14 chemin des Aulx, 1228 Plan les Ouates , Switzerland 3 Present Address: Glenmark Pharmaceuticals SA , 5 chemin de la Combeta, 2300 La-Chaux-de-Fonds , Switzerland 4 Stanford University , 1000 Welch Rd Suite 203, Palo Alto, CA , USA Background: Increased expression of toll-like receptor 4 (TLR4) and its endogenous ligands, is characteristic of rheumatoid arthritis (RA) synovitis. In this study, we evaluated how these TLR4 ligands may drive pathogenic processes and whether the fine profiling of anti-citrullinated protein antibodies (ACPA) based on their target specificity might provide a simple means to predict therapeutic benefit when neutralizing TLR4 in this disease. Methods: The capacity of RA synovial fluids (RASF) to stimulate cytokine production in monocytes from patients with RA was analyzed by ELISA. The presence of TLR4 activators in RASF was determined by measuring the levels of ACPA, ACPA subtypes with reactivity to specific citrullinated peptides and other TLR4 ligands. Neutralization of TLR4 signaling was investigated using NI-0101, a therapeutic antibody that targets TLR4. Results: RASF exhibited a heterogeneous capacity to induce production of proinflammatory cytokines by monocytes isolated from patients with RA. Such cytokine responses were significantly modified by TLR4 blockade achieved using NI-0101. The analysis of the content of RASF and matched sera demonstrated that ACPA fine specificities in patient samples predict cellular response to anti-TLR4 exposure in vitro. Conclusion: TLR4 represents a possible therapeutic target in RA. Our study demonstrates that TLR4 inhibition in an ex vivo model of RA pathogenesis can significantly modulate cytokine release and does so in specific subgroups of RA patient-derived samples. It also suggests that ACPA fine profiling has the potential to identify RA patients with a predominantly TLR4-driven pathotype that could be used to predict preferential response to TLR4 antagonism. Rheumatoid arthritis; Toll-like receptor 4; Synovial gluid; Cytokines; ACPA; Monoclonal antibody - Background Synovial inflammation is a hallmark of RA. While proinflammatory cytokines are considered to have a pivotal role in the pathogenesis of RA [1], the factors responsible for the initiation and perpetuation of the complex cytokine response are still not completely understood. Toll-like receptors (TLRs) play an important role in the * Correspondence: Eric Hatterer, Limin Shang and Pierre Simonet are co-first authors Emmanuel Monnet and Cristina De Min are co-senior authors 1NovImmune SA, 14 chemin des Aulx, 1228 Plan les Ouates, Switzerland Full list of author information is available at the end of the article initiation of innate immune responses and in the instruction of the adaptive arms of immunity. Both components of immune effector function are evident in RA pathogenesis and coincide with the tissue lesion. In particular, by their capacity to recognize the endogenous ligands released during tissue damage TLRs are attractive candidates for the mediation of chronicity in RA [2–6]. TLR4 is a receptor for immune complexes containing citrullinated proteins, in particular citrullinated fibrinogen (cFb-IC). Anti-cFb antibodies are present in over 50 % of patients with RA [7, 8]. Furthermore, anticitrullinated protein antibodies (ACPA) titers correspond © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. with more aggressive RA progression [9]. The presence of ACPA is one of the classification criteria for RA. For these reasons, the potential role of a subgroup of ACPA/ cit-peptide complexes with reactivity to TLR4 deserves to be investigated as a potential pathogenic pathway in RA. TLR4 deficiency or TLR4 pharmacological inhibition reduces disease p (...truncated)


This is a preview of a remote PDF: http://arthritis-research.com/content/pdf/s13075-016-1128-5.pdf

Eric Hatterer, Limin Shang, Pierre Simonet, Suzanne Herren, Bruno Daubeuf, Stéphanie Teixeira, James Reilly, Greg Elson, Robert Nelson, Cem Gabay, Jeremy Sokolove, Iain McInnes, Marie Kosco-Vilbois, Walter Ferlin, Emmanuel Monnet, Cristina De Min. A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid arthritis patients with a toll-like receptor 4-mediated disease, Arthritis Research & Therapy, 2016, pp. 224, 18, DOI: 10.1186/s13075-016-1128-5