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

Eric Hatterer,Jeremy Sokolove,Suzanne Herren,Stéphanie Teixeira,Walter Ferlin,Robert Nelson,Bruno Daubeuf,Marie Kosco-Vilbois,Emmanuel Monnet,Limin Shang,Greg Elson,Cristina De Min,Iain B Mcinnes,Pierre Simonet,James Reilly,Cem Gabay

doi:10.1186/s13075-016-1128-5

Abstract

BackgroundIncreased 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.MethodsThe 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.ResultsRASF 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.ConclusionTLR4 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1128-5) contains supplementary material, which is available to authorized users.

Highlights

Increased expression of toll-like receptor 4 (TLR4) and its endogenous ligands, is characteristic of rheumatoid arthritis (RA) synovitis
Synovial fluids from patients with RA contain activators that stimulate disease-relevant cell types through the TLR4 pathway As RA synovial fluid (RASF) from some patients with RA contain endogenous TLR4 ligands, and as joint-infiltrating myeloid cells are a source of proinflammatory cytokines in RA, we first investigated whether the endogenous TLR4 ligands in RASF samples contribute to the inflammatory potential of RASF, by stimulating myeloid cells from RA donors
We demonstrated that RASFstimulated cytokine production in a subgroup of patients with RA was mediated through TLR4 activation

Summary

Introduction

Increased expression of toll-like receptor 4 (TLR4) and its endogenous ligands, is characteristic of rheumatoid arthritis (RA) synovitis. 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. Toll-like receptors (TLRs) play an important role in the TLR4 is a receptor for immune complexes containing citrullinated proteins, in particular citrullinated fibrinogen (cFb-IC). 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. It has been reported that myeloid cells from patients with RA demonstrate an exaggerated response to TLR4 agonism [14, 15]

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