title: A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid arthritis patients with a toll-like receptor 4-mediated disease.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland. ehatterer@novimmune.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Hatterer
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Limin
authors.initials: L
authors.lastname: Shang
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Simonet
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Herren
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Daubeuf
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Teixeira
authors.affiliation: University School of Medicine, Institute of infection, immunity and inflammation, 120 University Place, Glasgow, UK.
authors.forename: James
authors.initials: J
authors.lastname: Reilly
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.|Present Address: Glenmark Pharmaceuticals SA, 5 chemin de la Combeta, 2300, La-Chaux-de-Fonds, Switzerland.
authors.forename: Greg
authors.initials: G
authors.lastname: Elson
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Nelson
authors.affiliation: Geneva University Hospital, 26 avenue Beau-Sejour, 1211, Geneva, Switzerland.
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
authors.affiliation: Stanford University, 1000 Welch Rd Suite 203, Palo Alto, CA, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sokolove
authors.affiliation: University School of Medicine, Institute of infection, immunity and inflammation, 120 University Place, Glasgow, UK.
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Kosco-Vilbois
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Ferlin
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Monnet
authors.affiliation: , NovImmune SA, 14 chemin des Aulx, 1228, Plan les Ouates, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: De Min
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D013582:Synovial Fluid / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; C000619441:NI-0101; D010456:Peptides, Cyclic; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C487763:cyclic citrullinated peptide
keywords: ACPA; Cytokines; Monoclonal antibody; Rheumatoid arthritis; Synovial gluid; Toll-like receptor 4