Anti–citrullinated protein antibodies bind surface‐expressed citrullinated Grp78 on monocyte/macrophages and stimulate tumor necrosis factor α production

Lu, Ming‐Chi; Lai, Ning‐Sheng; Yu, Hui-Chun; Huang, Huey W.; Hsieh, Song-Chou; Yu, Chia‐Li

doi:10.1002/art.27386

Cited by 107 publications

(68 citation statements)

References 38 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: 77%

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

Harre

Georgess

Bang³

et al. 2012

J. Clin. Invest.

634

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.

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Section: Discussionsupporting

confidence: 77%

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

Harre

Georgess

Bang³

et al. 2012

J. Clin. Invest.

634

504

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“…This finding has made considerable impact, as it has opened up the way to relevant and novel insights into RA-diagnosis and etiopathology (1). For example, ACPA are now part of the new American College of Rheumatology/ European League Against Rheumatism criteria for RA (18), and have been implicated in RA-pathogenesis, both in animal models (19)(20)(21) and in ex vivo human studies (22)(23)(24)(25). Importantly, the description of ACPA has led to the realization that RA constitutes at least two clinical syndromes that share many clinical features, but differ with respect to genetic background, predisposing environmental factors and clinical progression/remission (3,4,(26)(27)(28).…”

Section: Resultsmentioning

confidence: 99%

Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage

Shi

Knevel

Suwannalai

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

477

577

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Autoimmune responses against posttranslationally modified antigens are a hallmark of several autoimmune diseases. For example, antibodies against citrullinated protein antigens (ACPA) have shown their relevance for the prognosis and diagnosis of rheumatoid arthritis (RA), and have been implicated in disease pathogenesis. It is conceivable that other autoantibody systems, recognizing other posttranslationally modified proteins, are also present in RA. Here, we describe the presence of an autoantibody system that discriminates between citrulline- and homocitrulline-containing antigens in the sera of RA-patients. IgG antibodies recognizing carbamylated (homocitrulline-containing) antigens were present in sera of over 45% of RA-patients. Likewise, anticarbamylated protein (anti-CarP) IgA antibodies were observed in 43% of RA-sera. ACPA and anti-CarP antibodies are distinct autoantibodies because, in selected double-positive patients, the anti-CarP antibody binding to carbamylated antigens could be inhibited by carbamylated antigens, but not by control or citrullinated antigens. Similarly, ACPA-binding to citrullinated antigens could only be inhibited by citrullinated antigens. In line with this observation, 16% of ACPA-negative RA-patients, as measured by a standard ACPA assay, harbored IgG anti-CarP antibodies, whereas 30% of these patients tested positive for IgA anti-CarP antibodies. The presence of anti-CarP antibodies was predictive for a more severe disease course in ACPA-negative patients as measured by radiological progression. Taken together, these data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens. These antibodies are predictive for a more severe clinical course in ACPA-negative RA-patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.

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“…RA patients frequently express anti-citrullinated protein antibodies (ACPAs); these are highly specifi c for RA, strongly associated with disease severity, and postulated to be pathogenic [ 23 ]. The ability of P. gingivalis to express PAD suggests that P. gingivalis infection could promote and/or exacerbate RA by facilitating autoantigen presentation and the subsequent expression of diseasespecifi c autoantibodies, ultimately leading to overexpression of proinfl ammatory and arthritogenic cytokines (e.g., TNF-α and interleukin-6 (IL-6)) in the synovium [ 24 ]. Consistent with these speculations, elevated P. gingivalis titers in RA patients are associated with increases in ACPA [ 25 ].…”

Section: Role Of Periodontitis and Subgingival Microbiome In Ra Pathomentioning

confidence: 99%

Periodontal Infections and Rheumatoid Arthritis

Bretz

Scher

Abramson

2016

A Clinician's Guide to Systemic Effects of Periodontal Diseases

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Anti–citrullinated protein antibodies bind surface‐expressed citrullinated Grp78 on monocyte/macrophages and stimulate tumor necrosis factor α production

Abstract: We clearly demonstrated that ACPAs enhance NF-kappaB activity and TNFalpha production in monocyte/macrophages via binding to surface-expressed citrullinated Grp78.

Cited by 107 publications

References 38 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

Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage

Periodontal Infections and Rheumatoid Arthritis

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