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

Lundberg, Karin; Kinloch, A. J.; Fisher, Benjamin A; Wegner, Natalia; Wait, Robin; Charles, Peter; Mikuls, Ted R.; Venables, P. J. W.

doi:10.1002/art.23936

Cited by 339 publications

(339 citation statements)

References 43 publications

(39 reference statements)

Supporting

Mentioning

313

Contrasting

Unclassified

Order By: Relevance

“…The results depicted in Table 4 show that although citrullinated fibrinogen and Sa were recognized by IgG ACPAs from more than half of the patients with RA, virtually none of the IgG ACPApositive sera from healthy relatives recognized these antigens. (The results described in Table 4 were obtained with a linear ␣-enolase peptide containing a small difference in sequence compared with the peptide used by Lundberg et al, whose report appears elsewhere in this issue [28]). Interestingly, most of the RA sera that reacted with citrullinated antigens recognized both citrullinated fibrinogen and Sa.…”

Section: Resultsmentioning

confidence: 93%

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

166

144

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 93%

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

166

144

View full text Add to dashboard Cite

show abstract

“…Linear citrullinated (Cit) peptides derived from the sequence of human proteins were as follows: PAD 211-30 (VCitVFQATCitGKLSSKCSVVLG) derived from PAD, vim 60-75 (VYATCitSSAVCitLCitSSVP) derived from vimentin, enol [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] (KIHACitEIFDSCitGNPTVE) derived from alpha-enolase, fibrin 617-31 (HSTKCitGHAKSCitPVCitG) derived from the alpha chain of fibrinogen, col-II 358-75 (GACitGLTGCitPGDAGPPGPP) from type II collagen and fillaggrin [SHQEST(Cit)G(Cit)SRGRSGRSG] derived from filaggrin. A non-citrullinated peptide, ctrlPAD (EPLGLQCTFINDFFTYHIRH) derived from PAD was used as control.…”

Section: Synthetic Peptidesmentioning

confidence: 99%

“…Specifically, the vimentin and fibrinogen epitopes are the most frequently recognized by sera from ACPA-positive patients with long-standing RA [17]. Lundberg et al identified an immunodominant epitope in citrullinated alpha-enolase, to which antibodies are specific for RA [18]. Because RA patients recognize diversely distinct citrullinated epitopes of the same parent protein, an approach based on citrullinated peptides rather than whole proteins has been used in an attempt to obtain optimal discrimination ability [19].…”

Section: Introductionmentioning

confidence: 99%

Fine specificity of anti-citrullinated peptide antibodies discloses a heterogeneous antibody population in rheumatoid arthritis

Goules

Tzioufas

2013

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryAnti-citrullinated peptide antibodies (ACPA) are highly specific for rheumatoid arthritis (RA). However, the predominant B cell epitopes have not yet been defined. The aim of this study was to examine the reactivity of ACPA against different peptides derived from citrullinated proteins and to investigate whether or not these antibodies constitute a homogeneous population. For this purpose, sera from patients with RA (n = 141), systemic lupus erythematosus (SLE) (n = 60), Sjögren's syndrome (SS) (n = 54) and healthy controls (n = 100) were tested for their reactivity against six citrullinated peptides derived from peptidyl arginine deiminase (PAD), vimentin (vim), alpha-enolase (enol), fibrin, type II collagen (col-II) and filaggrin, respectively. A non-citrullinated control peptide derived from PAD was used as control (ctrlPAD 621-40 ). Antibody reactivity against each individual peptide was evaluated by enzyme-linked immunosorbent assay (ELISA). Specificity and cross-reactivity of ACPA were tested by using two prototype sera with homologous and cross-inhibition assays. Specificity of ACPA from two prototype sera was confirmed by purification of anti-peptide antibodies and homologous-inhibition experiments. We found that sera from patients with RA reacted diversely with the six citrullinated peptides. More specifically, PAD 211-30 displayed 29·08% sensitivity, vim 60-75 29·08%, enol 5-21 37·59%, fibrin 617-31 31·21%, col-II 358-75 29·97% and filaggrin 306-24 28·37%, while control ctrlPAD 621-40 showed no reactivity. All reactive peptides were found to be highly specific for RA. A notable cross-reaction (>70%) was found mainly between filaggrin and the majority of anti-citrullinated peptide antibodies. We concluded that ACPA in RA constitute a heterogeneous population with limited cross-reactivity and without a predominant epitope.

show abstract

“…Furthermore, P. gingivalis enolase is cross-reactive with the immunodominant epitope of citrullinated ENO1 in RA patients. [13]…”

Section: Introductionmentioning

confidence: 99%

“…The affinity-purified antibodies to the citrullinated epitope of ENO1 also react with native ENO1 [13]. Antibodies to ENO1 have been reported in a variety of infectious and autoimmune diseases, including RA [14].…”

Section: Introductionmentioning

confidence: 99%

Treponema denticola enolase contributes to the production of antibodies against ENO1 but not to the progression of periodontitis

et al. 2018

View full text Add to dashboard Cite

Autoantibodies against alpha-enolase (ENO1) are often detected in various infectious and autoimmune diseases. Anti-ENO1 antibody titers were reported to be associated with the severity of periodontitis in patients with rheumatoid arthritis. Because the enolase of the periodontal pathogen Treponema denticola (TdEno) has the highest homology with ENO1 among the enolases of human-associated bacteria, we hypothesized that anti-ENO1 autoantibodies produced during the immune response to TdEno may contribute to the progression of periodontitis and tested it in human and mouse systems. In human subjects with healthy periodontium or chronic periodontitis, a strong positive correlation between the levels of anti-TdEno and anti-ENO1 antibodies was observed. In addition, the purified anti-TdEno antibodies recognized ENO1 as well as TdEno in a dot blot, confirming the cross-reactivity between TdEno and ENO1. However, anti-ENO1 antibody titers were not associated with the severity of periodontitis. To further investigate the role of TdEno in the production of anti-ENO1 antibodies and the progression of periodontitis, mice received an oral gavage of P. gingivalis alone, subcutaneous immunization with TdEno alone, or both P. gingivalis oral gavage and TdEno immunization. Immunization with TdEno induced not only anti-TdEno but also anti-mouse Eno1 (mEno1) antibodies and increased the expression of TNFα in the gingival tissues. However, alveolar bone loss was not increased by TdEno immunization. In conclusion, autoreactive anti-ENO1/mEno1 antibodies that are produced as byproducts during the antibody response to TdEno play a minimal role in the progression of periodontitis in the absence of rheumatoid arthritis.

show abstract

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

Cited by 339 publications

References 43 publications

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

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

Fine specificity of anti-citrullinated peptide antibodies discloses a heterogeneous antibody population in rheumatoid arthritis

Treponema denticola enolase contributes to the production of antibodies against ENO1 but not to the progression of periodontitis

Contact Info

Product

Resources

About