IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies

Laurent, Lætitia; Anquetil, Florence; Clavel, C; Ndongo-Thiam, Ndiémé; Offer, Géraldine; Miossec, Pierre; Pasquali, Jean‐Louis; Sebbag, Mireille; Serre, Guy

doi:10.1136/annrheumdis-2013-204543

Cited by 105 publications

(88 citation statements)

References 52 publications

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“…Although beyond the scope of the current study, assessing the global proinflammatory potential of the IgM RF fine specificities coexisting in single patients may unravel interindividual differences for which it would be interesting to investigate the existence of an association with RA severity. With the monoclonal IgM RF HUL, we had previously demonstrated that TNF-a secretion by macrophages did not occur when interaction with IgG did not take place (33). However, a direct interplay of the IgM RF with a receptor that could strengthen the interaction of cells with IgM RF-containing IC had not been excluded.…”

Section: Discussionmentioning

confidence: 99%

“…This amplified the macrophage cytokine secretion and skewed it in favor of proinflammatory cytokines, leading to an increased capacity to prompt IL-6 secretion by RA synoviocytes (33). Although interaction sites on human IgGs for FcgRs are primarily situated in their lower hinge region, residues in the Cg2 domain are also involved in the interaction (43).…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation by ACPA-IC formed in the absence or presence of RF was performed essentially as previously described (33). Briefly, 96-well plates were coated with C-FBG (0.5 mg/well) and IC were generated by incubation with ACPA + IgG (2.5 mg/ml) supplemented or not with an IgM or IgA RF fraction at the indicated RF mass concentration.…”

Section: Macrophage Stimulationmentioning

confidence: 99%

“…To inhibit FcaRI occupancy, peptide M was incubated for 1 h with either the passively adsorbed IgA or the preformed IgA RF-containing ACPA-IC prior to washing and macrophage addition. For all stimulations, after 6 h culture, supernatants were harvested and stored at 230˚C until measurement of cytokine concentrations in simplex or multiplex assays, as previously described (33).…”

Section: Macrophage Stimulationmentioning

confidence: 99%

“…Taken together, these data strongly argue that, therein, such IC could constitute a (privileged) target of RF. We have previously demonstrated the ability of several monoclonal IgMs with RF activity from patients with mixed cryoglobulinemia to skew the ACPA-IC-induced proinflammatory cytokine response of macrophages toward more inflammation (33). However, notably given the possible influence on this effect of the fine epitope specificity of RF clones, and, conceivably, of their potentially variable posttranslational modifications, it was necessary to assess whether IgM RF from RA patients also exhibited this property.…”

mentioning

confidence: 99%

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IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

Anquetil

Clavel

Offer

et al. 2015

The Journal of Immunology

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108

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Rheumatoid factors (RF) and the disease-specific anti–citrullinated protein autoantibodies (ACPA) coexist in the joints of rheumatoid arthritis (RA) patients where they probably contribute to synovitis. We investigated the influence of IgM and IgA RF on the FcR- and complement-dependent effects of ACPA immune complexes (ACPA-IC). When stimulated by ACPA-IC formed in the presence of IgM RF or IgA RF fractions purified from RA serum pools, M-CSF–generated macrophages skewed their cytokine response toward inflammation, with increases in the TNF-α/IL-10 ratio and in IL-6 and IL-8 secretion, and decreases in the IL-1Ra/IL-1β ratio. In the IgM RF-mediated amplification of the inflammatory response of macrophages, the participation of an IgM receptor was excluded, notably by showing that they did not express any established receptor for IgM. Rather, this amplification depended on the IgM RF-mediated recruitment of more IgG into the ACPA-IC. However, the macrophages expressed FcαRI and blocking its interaction with IgA inhibited the IgA RF-mediated amplification of TNF-α secretion induced by ACPA-IC, showing its major implication in the effects of RF of the IgA class. LPS further amplified the TNF-α response of macrophages to RF-containing ACPA-IC. Lastly, the presence of IgM or IgA RF increased the capacity of ACPA-IC to activate the complement cascade. Therefore, specifically using autoantibodies from RA patients, the strong FcR-mediated or complement-dependent pathogenic potential of IC including both ACPA and IgM or IgA RF was established. Simultaneous FcR triggering by these RF-containing ACPA-IC and TLR4 ligation possibly makes a major contribution to RA synovitis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Macrophage Stimulationmentioning

confidence: 99%

Section: Macrophage Stimulationmentioning

confidence: 99%

mentioning

confidence: 99%

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IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

Anquetil

Clavel

Offer

et al. 2015

The Journal of Immunology

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108

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IgG Subclass Specificity Discriminates Restricted IgM Rheumatoid Factor Responses From More Mature Anti–Citrullinated Protein Antibody–Associated or Isotype‐Switched IgA Responses

Falkenburg

Schaardenburg

Heer

et al. 2015

Arthritis & Rheumatology

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Objective To investigate the presence and patterns of specific IgG subclass recognition by IgM rheumatoid factor (IgM‐RF) and IgA‐RF with a newly developed enzyme‐linked immunosorbent assay (ELISA), which can discriminate between polyspecific and restricted RF responses. Methods Polyspecific and restricted RF responses were determined with our ELISA, which uses individually coated recombinant IgG subclasses instead of polyclonal IgG as target antibodies. Fine specificity was determined using target antibodies with single amino acid mutations in the Fc region. Results In a screening panel of 93 sera that were previously found to be IgM‐RF positive in a conventional RF assay, we were able to discriminate between sera with polyspecific IgM‐RF responses (i.e., RF responses directed against all 4 IgG subclasses) and those with restricted IgM‐RF responses, with low or absent relative reactivity against IgG2, IgG3, or IgG4. We found the largest variation for anti‐IgG3 reactivity. Samples without detectable anti‐IgG4 reactivity formed an independent group from the other restricted RF responses and the polyspecific RF responses. The specificity of these anti‐IgG4–negative sera could be pinpointed to single amino acid differences between IgG1 and IgG4. Polyspecific RF responses more often showed signs of RF response maturation, with more isotype switching to IgA‐RF, as compared to restricted RF responses. In a cohort of IgM‐RF+ and/or anti–citrullinated protein antibody (ACPA)–positive arthralgia patients, we found restricted RF responses in 35% (49 of 140) of RF+/ACPA– patients, while RF+/ACPA+ patients, who have a much higher risk of developing rheumatoid arthritis, virtually always (123 of 128 [96%]) showed a polyspecific RF response. Conclusion IgG subclass–specific RF distinguishes between immature restricted RF responses and potentially more pathogenic, ACPA‐associated polyspecific responses.

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Identification of IRX1 as a Risk Locus for Rheumatoid Factor Positivity in Rheumatoid Arthritis in a Genome‐Wide Association Study

Juliá¹,

Blanco

Fernández‐Gutiérrez

et al. 2016

Arthritis & Rheumatology

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Objective. Rheumatoid factor (RF) is a wellestablished diagnostic and prognostic biomarker in rheumatoid arthritis (RA). However,~20% of RA patients are negative for this anti-IgG antibody. To date, only variation at the HLA-DRB1 gene has been associated with the presence of RF. This study was undertaken to identify additional genetic variants associated with RF positivity.Methods. A genome-wide association study (GWAS) for RF positivity was performed using an Illumina Quad610 genotyping platform. A total of 937 RF-positive and 323 RF-negative RA patients were genotyped for >550,000 single-nucleotide polymorphisms (SNPs). Association testing was performed using an allelic chi-square test implemented in Plink software. An independent cohort of 472 RF-positive and 190 RF-negative RA patients was used to validate the most significant findings.Results. In the discovery stage, a SNP in the IRX1 locus on chromosome 5p15.3 (SNP rs1502644) showed a genome-wide significant association with RF positivity (P 5 4.13 3 10 28 , odds ratio [OR] 0.37 [95% confidence interval (95% CI) 0.26-0.53]). In the validation stage, the association of IRX1 with RF was replicated in an independent group of RA patients (P 5 0.034, OR 0.58 [95% CI 0.35-0.97] and combined P 5 1.14 3 10 28 , OR 0.43 [95% CI 0.32-0.58]).Conclusion. To our knowledge, this is the first GWAS of RF positivity in RA. Variation at the IRX1 locus on chromosome 5p15.3 is associated with the presence of RF. Our findings indicate that IRX1 and HLA-DRB1 are the strongest genetic factors for RF production in RA.

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IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies

Cited by 105 publications

References 52 publications

IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

IgG Subclass Specificity Discriminates Restricted IgM Rheumatoid Factor Responses From More Mature Anti–Citrullinated Protein Antibody–Associated or Isotype‐Switched IgA Responses

Identification of IRX1 as a Risk Locus for Rheumatoid Factor Positivity in Rheumatoid Arthritis in a Genome‐Wide Association Study

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