Fcγ receptor profile of monocytes and macrophages from rheumatoid arthritis patients and their response to immune complexes formed with autoantibodies to citrullinated proteins

Laurent, Lætitia; Clavel, C; Lemaire, Olivia; Anquetil, Florence; Cornillet, Martin; Zabraniecki, Laurent; Nogueira, Léonor; Fournie, B.; Serre, Guy; Sebbag, Mireille

doi:10.1136/ard.2010.142091

Cited by 95 publications

(66 citation statements)

References 51 publications

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“…As a consequence, ACPAs enhanced bone resorption in vitro and in vivo and elicited bone loss in vivo by increasing osteoclast differentiation. Interestingly, the mechanism by which ACPAs trigger bone loss involved TNF-α, the pivotal cytokine in the pathogenesis of RA: MCV-ACPAs induced production of TNF-α by osteoclast precursors, extending previous observations that ACPAs can directly affect cells of the monocyte/macrophage lineage (25)(26)(27)(28). For bone, TNF-α is highly important, as it not only facilitates the trafficking of osteoclast precursors from the bone marrow to the lymphoid organs, but also renders them more susceptible to further differentiation into osteoclasts by inducing the receptors of key differentiation factors for osteoclasts, such as MSCF and RANKL.…”

Section: Discussionsupporting

confidence: 52%

Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin

Harre

Georgess

Bang³

et al. 2012

J. Clin. Invest.

642

504

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Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and boneresorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-α from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bone.

show abstract

Section: Discussionsupporting

confidence: 52%

Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin

Harre

Georgess

Bang³

et al. 2012

J. Clin. Invest.

642

504

View full text Add to dashboard Cite

show abstract

“…Interestingly, ACPA was also shown to activate osteoclastogenesis independently of FcgRs 29 . Monocytes from patients with RA and SLE displayed an increased expression of activating receptor FcgRIIIA/B 35,36 . Patients with RA carrying the FcgRIIIA158V allele, which has a higher affinity for the human IgG1 than another allele (FcgRIIIA158F), were associated with a more severe bone erosion 37 .…”

Section: Discussionmentioning

confidence: 99%

Immune complexes regulate bone metabolism through FcRγ signalling

et al. 2015

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Autoantibody production and immune complex (IC) formation are frequently observed in autoimmune diseases associated with bone loss. However, it has been poorly understood whether ICs regulate bone metabolism directly. Here we show that the level of osteoclastogenesis is determined by the strength of FcRg signalling, which is dependent on the relative expression of positive and negative FcgRs (FcgRI/III/IV and IIB, respectively) as well as the availability of their ligands, ICs. Under physiological conditions, unexpectedly, FcgRIII inhibits osteoclastogenesis by depriving other osteoclastogenic Ig-like receptors of FcRg. Fcgr2b À / À mice lose bone upon the onset of a hypergammaglobulinemia or the administration of IgG1 ICs, which act mainly through FcgRIII. The IgG2 IC activates osteoclastogenesis by binding to FcgRI and FcgRIV, which is induced under inflammatory conditions. These results demonstrate a link between the adaptive immunity and bone, suggesting a regulatory role for ICs in bone resorption in general, and not only in inflammatory diseases.

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“…RF is an immune complex per definition, and cross-linking of such immune complexes could represent a strong enhancer for activation of cells of the monocyte/macrophage lineage. Immune complexes can induce cytokine expression in monocytes and trigger an inflammatory response 24. Some of these cytokines, in particular, tumour necrosis factor (TNF)-α, are known as potent inducers of osteoclast differentiation and bone resorption.…”

Section: Discussionmentioning

confidence: 99%

Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA

et al. 2014

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Objective To determine whether there is an additive effect of anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) on the number and size of bone erosions in patients with rheumatoid arthritis (RA) Methods 242 patients with RA received highresolution peripheral quantitative CT (HR-pQCT) scans of the metacarpophalangeal joints. Demographic and disease-specific parameters including ACPA and RF levels were recorded from all patients. Erosion numbers and their size were assessed in 238 patients at 714 individual joints (MCP 2, 3 and 4) and 5712 sites (each 4 quadrants in metacarpal heads and phalangeal bases). The volume of erosions was calculated by a semiellipsoid formula. Results Of the 238 patients, 112 patients showed RF and ACPAs (ACPAs+RF+), 28 only RF (RF+), 29 only ACPAs (ACPA+) and 69 were antibody negative (NEG). Erosion number and size were highest in RF+ACPAs+ patient group with significant differences compared with NEG patients with respect to erosion number ( p=0.001) and to ACPA-negative patients with respect to erosion size ( p<0.001). Results maintained significance in a linear mixed model showing ACPAs+RF+ status and disease duration being associated with higher number ( p=0.017 and p=0.005, respectively), and larger size ( p=0.014 and p=0.013, respectively) of bone erosions. Furthermore, erosion size was influenced by the presence and titre of RF only in ACPA-positive patients with RA but not in ACPA-negative patients. Conclusions ACPAs and RF show an additive effect on erosion number and erosion size. Concomitant presence of ACPAs and RF is associated with higher erosive disease burden in patients with RA. Furthermore, RF influences erosion size only in ACPA-positive but not in ACPA-negative patients.

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Fcγ receptor profile of monocytes and macrophages from rheumatoid arthritis patients and their response to immune complexes formed with autoantibodies to citrullinated proteins

Abstract: ACPA-containing immune complexes induce TNFα secretion by blood and synovial fluid-derived macrophages from RA patients, fitting with their probable involvement in RA pathophysiology.

Cited by 95 publications

References 51 publications

Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin

Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin

Immune complexes regulate bone metabolism through FcRγ signalling

Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA

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