Patrick J. Venables
University of Oxford
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Arthritis & Rheumatism | 2010
Natalia Wegner; Robin Wait; Aneta Sroka; Sigrun Eick; Ky-Anh Nguyen; Karin Lundberg; A. J. Kinloch; Shauna Culshaw; Jan Potempa; Patrick J. Venables
OBJECTIVEnTo investigate protein citrullination by the periodontal pathogen Porphyromonas gingivalis as a potential mechanism for breaking tolerance to citrullinated proteins in rheumatoid arthritis (RA).nnnMETHODSnThe expression of endogenous citrullinated proteins was analyzed by immunoblotting of cell extracts from P gingivalis and 10 other oral bacteria. P gingivalis-knockout strains lacking the bacterial peptidylarginine deiminases (PADs) or gingipains were created to assess the role of these enzymes in citrullination. Citrullination of human fibrinogen and α-enolase by P gingivalis was studied by incubating live wild-type and knockout strains with the proteins and analyzing the products by immunoblotting and mass spectrometry.nnnRESULTSnEndogenous protein citrullination was abundant in P gingivalis but lacking in the other oral bacteria. Deletion of the bacterial PAD gene resulted in complete abrogation of protein citrullination. Inactivation of arginine gingipains, but not lysine gingipains, led to decreased citrullination. Incubation of wild-type P gingivalis with fibrinogen or α-enolase caused degradation of the proteins and citrullination of the resulting peptides at carboxy-terminal arginine residues, which were identified by mass spectrometry.nnnCONCLUSIONnOur findings demonstrate that among the oral bacterial pathogens tested, P gingivalis is unique in its ability to citrullinate proteins. We further show that P gingivalis rapidly generates citrullinated host peptides by proteolytic cleavage at Arg-X peptide bonds by arginine gingipains, followed by citrullination of carboxy-terminal arginines by bacterial PAD. Our results suggest a novel model where P gingivalis-mediated citrullination of bacterial and host proteins provides a molecular mechanism for generating antigens that drive the autoimmune response in RA.
Immunological Reviews | 2010
Natalia Wegner; Karin Lundberg; A. J. Kinloch; Benjamin A Fisher; Vivianne Malmström; Marc Feldmann; Patrick J. Venables
Summary:u2002 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 α‐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 α‐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.
Arthritis Research & Therapy | 2005
A. J. Kinloch; Verena Tatzer; Robin Wait; David Peston; Karin Lundberg; Phillipe Donatien; David Moyes; Peter C. Taylor; Patrick J. Venables
Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis (RA), but little is understood about their citrullinated target antigens. We have detected a candidate citrullinated protein by immunoblotting lysates of monocytic and granulocytic HL-60 cells treated with peptidylarginine deiminase. In an initial screen of serum samples from four patients with RA and one control, a protein of molecular mass 47 kDa from monocytic HL-60s reacted with sera from the patients, but not with the serum from the control. Only the citrullinated form of the protein was recognised. The antigen was identified by tandem mass spectrometry as α-enolase, and the positions of nine citrulline residues in the sequence were determined. Serum samples from 52 patients with RA and 40 healthy controls were tested for presence of antibodies against citrullinated and non-citrullinated α-enolase by immunoblotting of the purified antigens. Twenty-four sera from patients with RA (46%) reacted with citrullinated α-enolase, of which seven (13%) also recognised the non-citrullinated protein. Six samples from the controls (15%) reacted with both forms. α-Enolase was detected in the RA joint, where it co-localised with citrullinated proteins. The presence of antibody together with expression of antigen within the joint implicates citrullinated α-enolase as a candidate autoantigen that could drive the chronic inflammatory response in RA.
Nature Genetics | 2009
Hiba Mahdi; Benjamin A Fisher; Henrik Källberg; Darren Plant; Vivianne Malmström; Johan Rönnelid; Peter Charles; Bo Ding; Lars Alfredsson; Leonid Padyukov; Deborah Symmons; Patrick J. Venables; Lars Klareskog; Karin Lundberg
Gene-environment associations are important in rheumatoid arthritis (RA) susceptibility, with an association existing between smoking, HLA- DRB1 shared epitope alleles, PTPN22 and antibodies to cyclic citrullinated peptides(CCP). Here, we test the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated α-enolase, accounts for an important portion of these associations. In 1,497 individuals from three RA cohorts, antibodies to the immunodominant citrullinated α-enolase CEP-1 epitope were detected in 43–63% of the anti-CCP–positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22 and smoking showed the strongest association with the anti-CEP-1–positive subset (odds ratio (OR) of 37, compared to an OR of 2 for the corresponding anti-CEP-1–negative, anti-CCP–positive subset). We conclude that citrullinated α-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of RA.
Arthritis & Rheumatism | 2008
Karin Lundberg; A. J. Kinloch; Benjamin A Fisher; Natalia Wegner; Robin Wait; Peter Charles; Ted R. Mikuls; Patrick J. Venables
OBJECTIVEnTo map the antibody response to human citrullinated alpha-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross-reactivity with bacterial enolase.nnnMETHODSnSerum 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 alpha-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.nnnRESULTSnAn immunodominant peptide, citrullinated alpha-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 alpha-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.nnnCONCLUSIONnWe have identified an immunodominant epitope in citrullinated alpha-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.
Nature Reviews Rheumatology | 2010
Karin Lundberg; Natalia Wegner; Tülay Yucel-Lindberg; Patrick J. Venables
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.
Arthritis & Rheumatism | 2008
A. J. Kinloch; Karin Lundberg; Robin Wait; Natalia Wegner; Ngee Han Lim; A.J.W. Zendman; Tore Saxne; Vivianne Malmström; Patrick J. Venables
OBJECTIVEnTo examine synovial fluid as a site for generating citrullinated antigens, including the candidate autoantigen citrullinated alpha-enolase, in rheumatoid arthritis (RA).nnnMETHODSnSynovial 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.nnnRESULTSnCitrullinated 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/microl in RA samples, 4.3 ng/microl in SpA samples, and <0.9 ng/microl 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 16 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 1 OA sample.nnnCONCLUSIONnThese 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.
Arthritis & Rheumatism | 2010
Omri Snir; Mona Widhe; Monika Hermansson; Caroline von Spee; Johan Lindberg; Sanne Hensen; Karin Lundberg; Åke Engström; Patrick J. Venables; René E. M. Toes; Rikard Holmdahl; Lars Klareskog; Vivianne Malmström
OBJECTIVEnHigh titers of specific anti-citrullinated protein antibodies (ACPAs) are frequently present in the serum of rheumatoid arthritis (RA) patients, but their presence in synovial fluid is less well characterized. The purpose of this study was to compare the levels of antibody to 4 well-defined citrullinated candidate RA autoantigens in serum and synovial fluid and to determine whether antibodies to one citrullinated antigen are dominant over another. Furthermore, we studied their relationships with mutated citrullinated vimentin (MCV), a newly identified RA-specific serum assay, and the classic cyclic citrullinated peptide (CCP) in the synovial fluid of well-defined HLA-DR groups.nnnMETHODSnPaired serum and synovial fluid samples from 290 RA patients and serum samples from 100 age- and sex-matched healthy controls were analyzed for the presence of anti-MCV and anti-CCP antibodies and for reactivity to citrullinated fibrinogen, alpha-enolase, type II collagen, and vimentin. A total of 219 of the 290 patients were genotyped for the HLA-DR shared epitope alleles.nnnRESULTSnSignificantly higher proportions of antibodies against all RA-associated citrullinated antigens were found in synovial fluid as compared with serum. This was also true for the MCV and CCP responses but not for non-RA-associated anti-tetanus toxoid antibodies. As expected, we found a high correlation between citrullinated vimentin and MCV responses. All synovial fluid ACPAs were predominantly associated with HLA-DRB1*04 alleles and were confined to the CCP+/MCV+ subset of patients.nnnCONCLUSIONnMCV and CCP positivity represent a similar subset of RA patients, whereas ACPAs with different fine specificities fall into subgroups of anti-CCP+/anti-MCV+ patients. The levels of all specific ACPAs were elevated in synovial fluid, suggesting that there is local antibody production and/or retention of ACPAs at the site of inflammation governed by RA-predisposing genes.
Annals of the Rheumatic Diseases | 2009
Omri Snir; Mona Widhe; C. von Spee; Johan Lindberg; L. Padyukov; Karin Lundberg; Åke Engström; Patrick J. Venables; Joakim Lundeberg; Rikard Holmdahl; Lars Klareskog; Vivianne Malmström
Background: Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis (RA), and associate with HLA-DRB1 shared epitope (SE) alleles. Objective: To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles. Methods: Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, α-enolase peptide-1 and the C1-epitope of type II collagen (C1III). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed. Results: 72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients’ sera and in 41% for both citrullinated α-enolase peptide-1 and citrullinated C1III. These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles. Conclusions: Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.
PLOS Pathogens | 2013
Katarzyna Maresz; Annelie Hellvard; Aneta Sroka; Karina Adamowicz; Ewa Bielecka; Joanna Koziel; Katarzyna Gawron; Danuta Mizgalska; Katarzyna Marcińska; Małgorzata Benedyk; Krzysztof Pyrc; Anne-Marie Quirke; Roland Jonsson; Saba Alzabin; Patrick J. Venables; Ky-Anh Nguyen; Piotr Mydel; Jan Potempa
Rheumatoid arthritis and periodontitis are two prevalent chronic inflammatory diseases in humans and are associated with each other both clinically and epidemiologically. Recent findings suggest a causative link between periodontal infection and rheumatoid arthritis via bacteria-dependent induction of a pathogenic autoimmune response to citrullinated epitopes. Here we showed that infection with viable periodontal pathogen Porphyromonas gingivalis strain W83 exacerbated collagen-induced arthritis (CIA) in a mouse model, as manifested by earlier onset, accelerated progression and enhanced severity of the disease, including significantly increased bone and cartilage destruction. The ability of P. gingivalis to augment CIA was dependent on the expression of a unique P. gingivalis peptidylarginine deiminase (PPAD), which converts arginine residues in proteins to citrulline. Infection with wild type P. gingivalis was responsible for significantly increased levels of autoantibodies to collagen type II and citrullinated epitopes as a PPAD-null mutant did not elicit similar host response. High level of citrullinated proteins was also detected at the site of infection with wild-type P. gingivalis. Together, these results suggest bacterial PAD as the mechanistic link between P. gingivalis periodontal infection and rheumatoid arthritis.