Hypothesis: The Humoral Immune Response to Oral Bacteria Provides a Stimulus for the Development of Rheumatoid Arthritis

Rosenstein, Elliot D.; Greenwald, Robert A.; Kushner, Laura J.; Weissmann, Gerald

doi:10.1007/s10753-004-6641-z

Cited by 316 publications

(309 citation statements)

References 72 publications

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“…However, there is also a striking genetic similarity between the 2 diseases in that both are associated with the HLA SE alleles (46,47). This, together with the fact that P gingivalis is the only bacterium known to synthesize its own PAD enzyme (28), lends support to another hypothesis: that P gingivalis may be the "septic stimulus" in RA, as proposed by Rosenstein et al (42). Therefore, individuals with periodontal infection may already be exposed to citrullinated antigens, including citrullinated bacterial enolase, generated by host PAD during the inflammatory response or by bacterial PAD produced as a virulence factor to evade host defense (28).…”

Section: Discussionmentioning

confidence: 82%

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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Section: Discussionmentioning

confidence: 82%

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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“…In this context, Rosenstein et al first hypothesized that the generation of citrullinated antigens by PPAD, the bacterial PAD enzyme derived from Porphyromonas gingivalis in periodontal tissue, could be a potential trigger for the initiation of ACPAs 45. In addition, the lungs have also been suggested to play a role in triggering the autoimmune response to citrullinated proteins 46.…”

Section: Discussionmentioning

confidence: 99%

Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid

Spengler

Lugonja

Ytterberg

et al. 2015

Arthritis & Rheumatology

182

172

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ObjectiveIn the majority of patients with rheumatoid arthritis (RA), antibodies specifically recognize citrullinated autoantigens that are generated by peptidylarginine deiminases (PADs). Neutrophils express high levels of PAD and accumulate in the synovial fluid (SF) of RA patients during disease flares. This study was undertaken to test the hypothesis that neutrophil cell death, induced by either NETosis (extrusion of genomic DNA–protein complexes known as neutrophil extracellular traps [NETs]) or necrosis, can contribute to production of autoantigens in the inflamed joint.MethodsExtracellular DNA was quantified in the SF of patients with RA, patients with osteoarthritis (OA), and patients with psoriatic arthritis (PsA). Release of PAD from neutrophils was investigated by Western blotting, mass spectrometry, immunofluorescence staining, and PAD activity assays. PAD2 and PAD4 protein expression, as well as PAD enzymatic activity, were assessed in the SF of patients with RA and those with OA.ResultsExtracellular DNA was detected at significantly higher levels in RA SF than in OA SF (P < 0.001) or PsA SF (P < 0.05), and its expression levels correlated with neutrophil concentrations and PAD activity in RA SF. Necrotic neutrophils released less soluble extracellular DNA compared to NETotic cells in vitro (P < 0.05). Higher PAD activity was detected in RA SF than in OA SF (P < 0.05). The citrullinated proteins PAD2 and PAD4 were found attached to NETs and also freely diffused in the supernatant. PAD enzymatic activity was detected in supernatants of neutrophils undergoing either NETosis or necrosis.ConclusionRelease of active PAD isoforms into the SF by neutrophil cell death is a plausible explanation for the generation of extracellular autoantigens in RA.

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“…Based on observations made in several populations, it has been hypothesized that the association between smoking and ACPAs may be attributable to increased expression of citrullinated antigens in the lungs of smokers (32)(33)(34). Alternatively, it has been proposed that the oral pathogen Porphyromonas gingivalis, which is capable of citrullinating endogenous antigens, may be involved in the initial breaking of immune tolerance (35). To address these hypotheses, a spectrum of environmental stimuli and their association with the fine specificity of ACPAs will need to be systematically examined in multiple populations, particularly genetically susceptible populations such as North American natives.…”

Section: Discussionmentioning

confidence: 99%

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

Ioan‐Facsinay¹,

Willemze²,

Robinson³

et al. 2008

Arthritis & Rheumatism

165

144

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Objective. Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives.Methods. The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease.Results. ACPA positivity was observed in 19% of the healthy relatives and ϳ91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs.Conclusion. The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies.Autoantibodies are characteristic of a large number of autoimmune diseases. Determining the pathogenicity of autoantibodies by showing their capacity to transfer disease, however, is complicated by ethical and practical difficulties. Therefore, only a small minority of autoantibodies, such as antiplatelet antibodies in idiopathic thrombocytopenia purpura or the antidesmoglein antibodies in pemphigus vulgaris, were convincingly shown to mediate a pathogenetic effect through placental transfer (1) or transfer into experimental animals (2), respectively.

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Hypothesis: The Humoral Immune Response to Oral Bacteria Provides a Stimulus for the Development of Rheumatoid Arthritis

Cited by 316 publications

References 72 publications

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

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

Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

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