Human parvovirus B19 as a causative agent for rheumatoid arthritis

Takahashi, Yuichi; Murai, Chihiro; Shibata, S; Munakata, Yasuhiko; Ishii, Tomonori; Ishii, Keiko; Saitoh, Takako; Sawai, Takashi; Sugamura, Kazuo; Sasaki, Takeshi

doi:10.1073/pnas.95.14.8227

Cited by 245 publications

(166 citation statements)

References 32 publications

(19 reference statements)

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“…Currently, a large body of evidence points toward the involvement of DNA viruses in the pathogenesis of RA. In the synovial tissue of RA patients, parvovirus B19, Epstein-Barr virus, and cytomegalovirus were found to be frequently present (3,4,7,(42)(43)(44)(45). Although not fully investigated, it is also very likely that RNA viruses occur in the synovial compartment.…”

Section: Discussionmentioning

confidence: 99%

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Roelofs¹,

Joosten²,

Abdollahi‐Roodsaz³

et al. 2005

Arthritis & Rheumatism

292

219

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Objective. To evaluate the expression of Toll-like receptors (TLRs) 3 and 7 in synovium and to study potential differences in the maturation and cytokine production mediated by TLR-2, TLR-3, TLR-4, and TLR-7/8 by dendritic cells (DCs) from rheumatoid arthritis (RA) patients and DCs from healthy controls.Methods. Synovial expression of TLR-3 and TLR-7 in RA was studied using immunohistochemistry. Monocyte-derived DCs from RA patients and healthy controls were cultured for 6 days and subsequently stimulated for 48 hours via TLR-mediated pathways (lipoteichoic acid, Pam 3 Cys, and fibroblast-stimulating lipopeptide 1 for TLR-2, poly[I-C] for TLR-3, lipopolysaccharide and extra domain A for TLR-4, and R848 for TLR-7/8). Phenotypic DC maturation was measured using flow cytometry. The secretion of tumor necrosis factor ␣ (TNF␣), interleukin-6 (IL-6), IL-10, and IL-12 was measured using the Bio-Plex system. Cell lines expressing TLR-2 and TLR-4 were used for the detection of TLR-2 and TLR-4 ligands in serum and synovial fluid from RA patients.Results. TLR-3 and TLR-7 were highly expressed in RA synovium. All TLR ligands elicited phenotypic DC maturation equally between DCs from RA patients and those from healthy controls. TLR-2-and TLR-4-mediated stimulation of DCs from RA patients resulted in markedly higher production of inflammatory mediators (TNF␣ and IL-6) compared with DCs from healthy controls. In contrast, upon stimulation of TLR-3 and TLR-7/8, the level of cytokine production was equal between DCs from RA patients and those from healthy controls. Remarkably, both TLR-3 and TLR-7/8 stimulation resulted in a skewed balance toward IL-12. Intriguingly, the combined stimulation of TLR-4 and TLR-3-7/8 resulted in a marked synergy with respect to the production of inflammatory mediators. As a proof of concept, TLR-4 ligands were increased in the serum and synovial fluid of RA patients.Conclusion. TLRs are involved in the regulation of DC activation and cytokine production. We hypothesize that various TLR ligands in the joint trigger multiple TLRs simultaneously, favoring the breakthrough of tolerance in RA.

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Section: Discussionmentioning

confidence: 99%

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Roelofs¹,

Joosten²,

Abdollahi‐Roodsaz³

et al. 2005

Arthritis & Rheumatism

292

219

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“…These symptomsinclude polyarthropathy, anemia, skin rash, and edema (4,5). Many reports have demonstrated a close association between parvovirus B 19 and rheumatoid arthritis (9). The association with systemic lupus erythem- …”

Section: Discussionmentioning

confidence: 99%

Acute Parvovirus B19 Infection Mimicking Chronic fatigue Syndrome

et al. 2003

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“…Furthermore, a strong geneenvironment interaction between HLA SE alleles and cigarette smoking is present in anti-CCP antibodypositive patients but not in anti-CCP antibody-negative patients (21,23). Infectious agents, both bacterial and viral, have also been proposed as potential environmental stimuli (24)(25)(26)(27), although to date, no single organism has survived as a compelling candidate for the etiology of the disease. Given that citrullinated proteins are target autoantigens in RA, the pathogen Porphyromonas gingivalis, which expresses the citrullinating enzyme peptidyl arginine deiminase (PAD) (28), could be an environmental trigger of RA in a manner similar to that proposed for smoking (21).…”

mentioning

confidence: 99%

Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase

Lundberg

Kinloch

Fisher

et al. 2008

Arthritis & Rheumatism

338

313

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Objective. To map the antibody response to human citrullinated ␣-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine crossreactivity with bacterial enolase.Methods. Serum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with citrullinated ␣-enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross-reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross-reactivity with bacterial enolase was investigated by immunoblotting.Results. An immunodominant peptide, citrullinated ␣-enolase peptide 1, was identified. Antibodies to this epitope were observed in 37-62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine-containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated ␣-enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r 2 ‫؍‬ 0.803, P < 0.0001). Affinitypurified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis enolase.Conclusion. We have identified an immunodominant epitope in citrullinated ␣-enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross-reactivity with bacterial enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.

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Human parvovirus B19 as a causative agent for rheumatoid arthritis

Abstract: Human parvovirus B19 (B19) DNA was detected in the synovial tissues in 30 of 39 patients with rheumatoid arthritis (RA), and infrequently in those with osteoarthritis and traumatic joints. On the other hand, the expression of the B19 antigen VP-1 was specific (

Cited by 245 publications

References 32 publications

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

The expression of toll‐like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll‐like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells

Acute Parvovirus B19 Infection Mimicking Chronic fatigue Syndrome

Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase

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