Author
Natalia Wegner
Other affiliations: University of Oxford
Bio: Natalia Wegner is an academic researcher from Imperial College London. The author has contributed to research in topics: Porphyromonas gingivalis & Citrullination. The author has an hindex of 9, co-authored 13 publications receiving 2198 citations. Previous affiliations of Natalia Wegner include University of Oxford.
Topics: Porphyromonas gingivalis, Citrullination, Autoimmunity, Antigen, Enolase
Papers
More filters
••
TL;DR: It is shown that P gingivalis rapidly generates citrullinated host peptides by proteolytic cleavage at Arg-X peptide bonds by arginine gingipains, followed bycitrullination of carboxy-terminal arginines by bacterial PAD.
Abstract: Objectives
To investigate protein citrullination by the periodontal pathogen Porphyromonas gingivalis (P. gingivalis) as a potential mechanism for breaking tolerance to citrullinated proteins in rheumatoid arthritis (RA).
608 citations
••
TL;DR: Rheumatoid arthritis (RA) is now clearly a true autoimmune disease with accumulating evidence of pathogenic disease‐specific autoimmunity to citrullinated proteins, and both smoking and Porphyromonas gingivalis are attractive etiological agents for further investigation into the gene/environment/autoimmunities triad of RA.
Abstract: Rheumatoid arthritis (RA) is now clearly a true autoimmune disease with accumulating evidence of pathogenic disease-specific autoimmunity to citrullinated proteins. Citrullination, also termed deimination, is a modification of arginine side chains catalyzed by peptidylarginine deiminase (PAD) enzymes. This post-translational modification has the potential to alter the structure, antigenicity, and function of proteins. In RA, antibodies to cyclic citrullinated peptides are now well established for clinical diagnosis, though we argue that the identification of specific citrullinated antigens, as whole proteins, is necessary for exploring pathogenic mechanisms. Four citrullinated antigens, fibrinogen, vimentin, collagen type II, and alpha-enolase, are now well established, with others awaiting further characterization. All four proteins are expressed in the joint, and there is evidence that antibodies to citrullinated fibrinogen and collagen type II mediate inflammation by the formation of immune complexes, both in humans and animal models. Antibodies to citrullinated proteins are associated with HLA 'shared epitope' alleles, and autoimmunity to at least one antigenic sequence, the CEP-1 peptide from citrullinated alpha-enolase (KIHAcitEIFDScitGNPTVE), shows a specific association with HLA-DRB1*0401, *0404, 620W PTPN22, and smoking. Periodontitis, in which Porphyromonas gingivalis is a major pathogenic bacterium, has been linked to RA in epidemiological studies and also shares similar gene/environment associations. This is also the only bacterium identified that expresses endogenous citrullinated proteins and its own bacterial PAD enzyme, though the precise molecular mechanisms of bacterial citrullination have yet to be explored. Thus, both smoking and Porphyromonas gingivalis are attractive etiological agents for further investigation into the gene/environment/autoimmunity triad of RA.
444 citations
••
TL;DR: The 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.
Abstract: Objective
To map the antibody response to human citrullinated α-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross-reactivity 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 α-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 α-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 α-enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2 = 0.803, P < 0.0001). Affinity-purified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis enolase.
Conclusion
We have identified an immunodominant epitope in citrullinated α-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.
374 citations
••
TL;DR: The hypothesis of molecular mimicry in the etiology of RA is explored, with citrullinated enolase as the specific antigen involved.
Abstract: Antibodies to citrullinated enolase define a subset of rheumatoid arthritis (RA) associated with smoking and DR4 alleles. In this Perspectives article, the authors review epidemiological and genetic links between periodontitis (a disease in whichPorphyromonas gingivalis is a major pathogen) and RA and propose that that the association might be causal, due to molecular mimicry between epitopes on host and P. gingivaliscitrullinated enolases driving the autoimmune response. Autoimmunity in rheumatoid arthritis (RA) is characterized by an antibody response to citrullinated proteins. Two of the risk factors for RA—HLA-DRB1 shared epitope alleles and smoking—are also associated with periodontitis, which is largely, but not exclusively, caused by Porphyromonas gingivalis infection. Furthermore, RA and periodontitis have a similar pathophysiology, characterized by destructive inflammation. The citrullination of proteins by P. gingivalis and the subsequent generation of autoantigens that drive autoimmunity in RA represents a possible causative link between these two diseases. Antibodies directed towards the immunodominant epitope of human citrullinated α-enolase cross-react with a conserved sequence on citrullinated P. gingivalis enolase. On the basis of this cross-reactivity, in this Perspectives article we explore the hypothesis of molecular mimicry in the etiology of RA, with citrullinated enolase as the specific antigen involved.
314 citations
••
TL;DR: The results highlight the importance of synovial fluid for the expression of citrullinated autoantigens in inflammatory arthritis, and provide evidence that the alpha-enolase was citruLLinated in RA synvial fluid.
Abstract: Objective. To examine synovial fluid as a site for generating citrullinated antigens, including the candidate autoantigen citrullinated alpha-enolase, in rheumatoid arthritis (RA). Methods. Synovial fluid was obtained from 20 patients with RA, 20 patients with spondylarthritides (SpA), and 20 patients with osteoarthritis (OA). Samples were resolved using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by staining with Coomassie blue and immunoblotting for citrullinated proteins, alpha-enolase, and the deiminating enzymes peptidylarginine deiminase type 2 (PAD-2) and PAD-4. Proteins from an RA synovial fluid sample were separated by 2-dimensional electrophoresis, and each protein was identified by immunoblotting and mass spectrometry. Antibodies to citrullinated alpha-enolase peptide 1 (CEP-1) and cyclic citrullinated peptide 2 were measured by enzyme-linked immunosorbent assay. Results. Citrullinated polypeptides were detected in the synovial fluid from patients with RA and patients with SpA, but not in OA samples. Alpha-enolase was detected in all of the samples, with mean levels of 6.4 ng/mu l in RA samples, 4.3 ng/mu l in SpA samples, and <0.9 ng/mu l in OA samples. Two-dimensional electrophoresis provided evidence that the alpha-enolase was citrullinated in RA synovial fluid. The citrullinating enzyme PAD-4 was detected in samples from all 3 disease groups. PAD-2 was detected in 18 of the RA samples, in 1.6 of the SpA samples, and in none of the OA samples. Antibodies to CEP-1 were found in 12 of the RA samples (60%), in none of the SpA samples, and in I OA sample. Conclusion. These results highlight the importance of synovial fluid for the expression of citrullinated autoantigens in inflammatory arthritis. Whereas the expression of citrullinated proteins is a product of inflammation, the antibody response remains specific for RA.
248 citations
Cited by
More filters
••
TL;DR: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
Abstract: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
3,975 citations
•
[...]
05 Nov 2009
TL;DR: 结节病易误诊,据王洪武等~([1])收集国内18篇关于此第一印象中拟诊 结核5例,为此应引起临床对本 病诊
Abstract: 结节病易误诊,据王洪武等~([1])收集国内18篇关于此病误诊的文献,误诊率高达63.2%,当然有误诊就会有误治,如孙永昌等~([2])报道26例结节病在影像学检查诊断的第一印象中拟诊结核5例,其中就有2例完成规范的抗结核治疗,为此应引起临床对本病诊治的重视。
1,821 citations
••
TL;DR: The mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites are discussed.
Abstract: Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health. Recent studies have provided insights into the emergence and persistence of dysbiotic oral microbial communities that can mediate inflammatory pathology at local as well as distant sites. This Review discusses the mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites.
1,621 citations
••
TL;DR: Critical assessment of the available literature that supports the keystone-pathogen hypothesis holds that certain low-abundance microbial pathogens can orchestrate inflammatory disease by remodelling a normally benign microbiota into a dysbiotic one.
Abstract: Recent studies have highlighted the importance of the human microbiome in health and disease. However, for the most part the mechanisms by which the microbiome mediates disease, or protection from it, remain poorly understood. The keystone-pathogen hypothesis holds that certain low-abundance microbial pathogens can orchestrate inflammatory disease by remodelling a normally benign microbiota into a dysbiotic one. In this Opinion article, we critically assess the available literature that supports this hypothesis, which may provide a novel conceptual basis for the development of targeted diagnostics and treatments for complex dysbiotic diseases.
1,199 citations
••
TL;DR: A treat-to-target strategy aimed at reducing disease activity by at least 50% within 3 months and achieving remission or low disease activity within 6 months, with sequential drug treatment if needed, can prevent RA-related disability.
Abstract: Importance Rheumatoid arthritis (RA) occurs in about 5 per 1000 people and can lead to severe joint damage and disability. Significant progress has been made over the past 2 decades regarding understanding of disease pathophysiology, optimal outcome measures, and effective treatment strategies, including the recognition of the importance of diagnosing and treating RA early. Observations Early diagnosis and treatment of RA can avert or substantially slow progression of joint damage in up to 90% of patients, thereby preventing irreversible disability. The development of novel instruments to measure disease activity and identify the presence or absence of remission have facilitated new treatment strategies to arrest RA before joints are damaged irreversibly. Outcomes have been improved by recognizing the benefits of early diagnosis and early therapy with disease-modifying antirheumatic drugs (DMARDs). The treatment target is remission or a state of at least low disease activity, which should be attained within 6 months. Methotrexate is first-line therapy and should be prescribed at an optimal dose of 25 mg weekly and in combination with glucocorticoids; 40% to 50% of patients reach remission or at least low disease activity with this regimen. If this treatment fails, sequential application of targeted therapies, such as biologic agents (eg, tumor necrosis factor [TNF] inhibitors) or Janus kinase inhibitors in combination with methotrexate, have allowed up to 75% of these patients to reach the treatment target over time. New therapies have been developed in response to new pathogenetic findings. The costs of some therapies are considerable, but these costs are decreasing with the advent of biosimilar drugs (drugs essentially identical to the original biologic drugs but usually available at lower cost). Conclusions and relevance Scientific advances have improved therapies that prevent progression of irreversible joint damage in up to 90% of patients with RA. Early treatment with methotrexate plus glucocorticoids and subsequently with other DMARDs, such as inhibitors of TNF, IL-6, or Janus kinases, improves outcomes and prevents RA-related disability. A treat-to-target strategy aimed at reducing disease activity by at least 50% within 3 months and achieving remission or low disease activity within 6 months, with sequential drug treatment if needed, can prevent RA-related disability.
1,042 citations