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1.
Tibor T. Glant Timea Ocsko Adrienn Markovics Zoltan Szekanecz Robert S. Katz Tibor A. Rauch Katalin Mikecz 《PloS one》2016,11(3)
Background
Rheumatoid arthritis (RA) is an autoimmune disease of the synovial joints. The autoimmune character of RA is underscored by prominent production of autoantibodies such as those against IgG (rheumatoid factor), and a broad array of joint tissue-specific and other endogenous citrullinated proteins. Anti-citrullinated protein antibodies (ACPA) can be detected in the sera and synovial fluids of RA patients and ACPA seropositivity is one of the diagnostic criteria of RA. Studies have demonstrated that RA T cells respond to citrullinated peptides (epitopes) of proteoglycan (PG) aggrecan, which is one of the most abundant macromolecules of articular cartilage. However, it is not known if the PG molecule is citrullinated in vivo in human cartilage, and if so, whether citrulline-containing neoepitopes of PG (CitPG) can contribute to autoimmunity in RA.Methods
CitPG was detected in human cartilage extracts using ACPA+ RA sera in dot blot and Western blot. Citrullination status of in vitro citrullinated recombinant G1 domain of human PG (rhG1) was confirmed by antibody-based and chemical methods, and potential sites of citrullination in rhG1 were explored by molecular modeling. CitPG-specific serum autoantibodies were quantified by enzyme-linked immunosorbent assays, and CitPG was localized in osteoarthritic (OA) and RA cartilage using immunohistochemistry.Findings
Sera from ACPA+ RA patients reacted with PG purified from normal human cartilage specimens. PG fragments (mainly those containing the G1 domain) from OA or RA cartilage extracts were recognized by ACPA+ sera but not by serum from ACPA- individuals. ACPA+ sera also reacted with in vitro citrullinated rhG1 and G3 domain-containing fragment(s) of PG. Molecular modeling suggested multiple sites of potential citrullination within the G1 domain. The immunohistochemical localization of CitPG was different in OA and RA cartilage.Conclusions
CitPG is a new member of citrullinated proteins identified in human joints. CitPG could be found in both normal and diseased cartilage specimens. Antibodies against CitPG may trigger or augment arthritis by forming immune complexes with this autoantigen in the joints of ACPA+ RA patients. 相似文献2.
Kinloch A Tatzer V Wait R Peston D Lundberg K Donatien P Moyes D Taylor PC Venables PJ 《Arthritis research & therapy》2005,7(6):R1421-R1429
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 alpha-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 alpha-enolase by immunoblotting of the purified antigens. Twenty-four sera from patients with RA (46%) reacted with citrullinated alpha-enolase, of which seven (13%) also recognised the non-citrullinated protein. Six samples from the controls (15%) reacted with both forms. Alpha-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 alpha-enolase as a candidate autoantigen that could drive the chronic inflammatory response in RA. 相似文献
3.
Andrew Kinloch Verena Tatzer Robin Wait David Peston Karin Lundberg Phillipe Donatien David Moyes Peter C Taylor Patrick J Venables 《Arthritis research & therapy》2005,7(6):R1421
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. 相似文献
4.
Joyce JBC van Beers Annemiek Willemze Judith Stammen-Vogelzangs Jan W Drijfhout René EM Toes Ger J M Pruijn 《Arthritis research & therapy》2012,14(1):R35-16
Introduction
Fibronectin is one of the most abundant proteins present in the inflamed joint. Here, we characterized the citrullination of fibronectin in the joints of rheumatoid arthritis (RA) patients and studied the prevalence, epitope specificity and human leukocyte antigen (HLA) association of autoantibodies against citrullinated fibronectin in RA.Methods
Citrullinated residues in fibronectin isolated from RA patient synovial fluid were identified by mass spectrometry. The corresponding citrullinated and non-citrullinated peptides were synthesized and used to analyze the presence of autoantibodies to these peptides in RA sera and sera from other diseases and healthy controls by ELISA. The data were compared with risk factors like shared epitope HLA alleles and smoking, and with clinical features.Results
Five citrullinated residues were identified in fibronectin from RA synovial fluid. RA sera reacted in a citrulline-dependent manner with two out of four citrullinated fibronectin peptides, one of which contains two adjacent citrulline residues, in contrast to non-RA sera, which were not reactive. The most frequently recognized peptide (FN-Cit1035,1036, LTVGLTXXGQPRQY, in which × represents citrulline) was primarily targeted by anti-CCP (cyclic citrullinated peptide) 2-positive RA patients. Anti-FN-Cit1035,1036 autoantibodies were detected in 50% of established anti-CCP2-positive RA patients and in 45% of such patients from a early arthritis clinic. These antibodies appeared to be predominantly of the immunoglobulin G (IgG) isotype and to be associated with HLA shared epitope alleles (odds ratio = 2.11).Conclusions
Fibronectin in the inflamed synovia of RA patients can be citrullinated at least at five positions. Together with the flanking amino acids, three of these citrullinated residues comprise two epitopes recognized by RA autoantibodies. Anti-citrullinated fibronectin peptide antibodies are associated with HLA shared epitope alleles. 相似文献5.
Monika Hansson Linda Mathsson Thomas Schlederer Lena Israelsson Per Matsson Leonor Nogueira Per-Johan Jakobsson Karin Lundberg Vivianne Malmstr?m Guy Serre Rikard Holmdahl Mats Nystrand Lars Klareskog Johan R?nnelid 《Arthritis research & therapy》2012,14(5):R201
Introduction
Autoantibodies directed against citrullinated proteins/peptides (ACPAs) are highly specific and predictive for the development of rheumatoid arthritis (RA). Different subgroups of RA patients, which have different prognoses and may require different treatments, are characterized by different autoantibody profiles. The objective of this study was to develop a microarray for the detection of multiple RA-associated autoantibodies, initially focusing on responses against citrullinated epitopes on candidate autoantigens in RA.Methods
The microarray is based on Phadia''s ImmunoCAP ISAC system, with which reactivity to more than 100 antigens can be analyzed simultaneously, by using minute serum volumes (< 10 μl). Twelve citrullinated peptides, and the corresponding native arginine-containing control peptides, were immobilized in an arrayed fashion onto a chemically modified glass slide, allowing a three-dimensional layer with high binding capacity. The assay was optimized concerning serum dilution and glass surface, whereas each individual antigen was optimized concerning coupling chemistry, antigen concentration, and selection of spotting buffer. The performance of each peptide in the ImmunoCAP ISAC system was compared with the performance in enzyme-linked immunosorbent assays (ELISAs). Serum from 927 RA patients and 461 healthy controls from a matched case-control study were applied onto reaction sites on glass slides, followed by fluorescent-labeled anti-human immunoglobulin G (IgG) antibody. Fluorescence intensities were detected with a laser scanner, and the results analyzed by using image-analysis software.Results
Strong correlations between the ImmunoCAP ISAC system and ELISA results were found for individual citrullinated peptides (Spearman ρ typically between 0.75 and 0.90). Reactivity of RA sera with the peptides was seen mainly in the anticyclic citrullinated peptide 2 (CCP2)-positive subset, but some additional reactivity with single citrullinated peptides was seen in the anti-CCP2-negative subset. Adjusting for reactivity against arginine-containing control peptides did not uniformly change the diagnostic performance for antibodies against the individual citrullinated peptides.Conclusions
The multiplexed array, for detection of autoantibodies against multiple citrullinated epitopes on candidate RA autoantigens, will be of benefit in studies of RA pathogenesis, diagnosis, and potentially as a guide to individualized treatment. 相似文献6.
Amezcua-Guerra LM Springall R Marquez-Velasco R Gómez-García L Vargas A Bojalil R 《Arthritis research & therapy》2006,8(5):R144-5
'Rhupus' is a rare condition sharing features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). If rhupus is a distinctive entity, an overlap between RA and SLE or a subset of SLE is currently debated. This study was performed to explore the prevalence of antibodies against cyclic citrullinated peptides (anti-CCP antibodies) in rhupus. Patients meeting American College of Rheumatology criteria for RA, SLE, or both were included. Clinical and radiographic features were recorded and sera were searched for anti-CCP antibodies, rheumatoid factor, antinuclear antibodies, anti-extractable nuclear antigens, and antibodies against double-stranded DNA (anti-dsDNA antibodies). Seven patients for each group were included. Clinical and serological features for RA or SLE were similar between rhupus and RA patients, and between rhupus and SLE patients, respectively. Values for anti-CCP antibodies obtained were significantly (p < 0.05) higher in RA (6/7) and rhupus (4/7) than in SLE patients (0/7) and healthy subjects (0/7). Our data support the possibility that rhupus is an overlap between RA and SLE, because highly specific autoantibodies for RA (anti-CCP) and for SLE (anti-dsDNA and anti-Sm) are detected in coexistence. 相似文献
7.
Alejandro Balsa Arancha Cabezón Gisela Orozco Tatiana Cobo Eugenia Miranda-Carus Miguel Ángel López-Nevot José Luis Vicario Emilio Martín-Mola Javier Martín Dora Pascual-Salcedo 《Arthritis research & therapy》2010,12(2):R62
Introduction
The purpose of this study was to investigate the association between HLA-DRB1 alleles with susceptibility to rheumatoid arthritis (RA) and production of antibodies against citrullinated proteins (ACPA) and rheumatoid factor (RF). 相似文献8.
Antibodies against intact type II collagen (CII) are a feature of rheumatoid arthritis (RA) but have limited diagnostic value.
Here we assess whether either of the two major cyanogen bromide fragments of CII, namely CB10 or CB11, are more sensitive
substrates for the detection of antibodies in RA. Cleavage of bovine CII with cyanogen bromide yielded CB10 and CB11; these
were purified by column chromatography for use in an enzyme-linked immunosorbent assay. Serum antibodies were measured in
patients with RA, psoriatic arthritis (PsA), osteoarthritis (OA) and blood donors. Results were compared with those using
intact CII. Antibodies against CB10 were found in as many as 88% of 96 patients with long-standing RA, but only 12% of 33
patients with PsA, 6% of 34 patients with OA and 3% of 93 control sera. Lower frequencies for these diseases were obtained
on testing for antibodies against CB11: 50%, 6%, 21% and 2%, respectively. The sensitivity of detection in RA of antibodies
against CB10 compared with antibodies against intact CII (88% versus 24%) was not at the expense of specificity, which remained
high at 94%. The much higher frequency of antibodies against CB10 in RA than in other rheumatic diseases or control sera indicates
that CB10 is clearly a more sensitive substrate than the intact collagen molecule and, combined with other assays (rheumatoid
factor, anti-cyclic citrullinated peptide [anti-CCP]), might comprise a panel with a highly reliable predictive value. Moreover,
our findings should encourage renewed interest in the role of collagen autoimmunity in the pathogenesis of RA. 相似文献
9.
Antibodies directed to citrullinated proteins (e.g. anti-CCP [cyclic citrullinated peptide] antibodies) are highly specific
for rheumatoid arthritis (RA). These antibodies are produced at the site of inflammation in RA, and therefore citrullinated
antigens are also expected to be present in the inflamed synovium. We discuss literature showing that the presence of citrullinated
proteins in the synovium is not specific for RA. The RA-specific antibodies are therefore most likely the result of an abnormal
immune response that specifically occurs in RA patients. It was recently shown that presence of anti-CCP antibodies precedes
the onset of clinical symptoms of RA by years. It thus appears that it may take years for initial events that cause the generation
of anti-CCP antibodies to develop into full-blown disease. 相似文献
10.
Antibodies directed to citrullinated proteins (anti-cyclic citrullinated peptide) are highly specific for rheumatoid arthritis
(RA). Recent data suggest that the antibodies may be involved in the disease process of RA and that several RA-associated
genetic factors might be functionally linked to RA via modulation of the production of anti-cyclic citrullinated peptide antibodies
or citrullinated antigens. 相似文献
11.
Antibodies directed to citrullinated proteins (anti-cyclic citrullinated peptide) are highly specific for rheumatoid arthritis (RA). Recent data suggest that the antibodies may be involved in the disease process of RA and that several RA-associated genetic factors might be functionally linked to RA via modulation of the production of anti-cyclic citrullinated peptide antibodies or citrullinated antigens. 相似文献
12.
Franziska Renger Holger Bang Eugen Feist Gert Fredenhagen Alexander Natusch Marina Backhaus Gerd-R Burmester Karl Egerer 《Arthritis research & therapy》2010,12(3):R120
Introduction
Autoantibodies against mutated and citrullinated vimentin (MCV) represent a novel diagnostic marker for rheumatoid arthritis (RA). Recently, an increased sensitivity for anti-MCV compared to autoantibodies against cyclic citrullinated peptides (anti-CCP2) was shown in cohorts of patients with early RA and established disease. 相似文献13.
Anti-citrullinated collagen type I antibody is a target of autoimmunity in rheumatoid arthritis 总被引:6,自引:0,他引:6
Suzuki A Yamada R Ohtake-Yamanaka M Okazaki Y Sawada T Yamamoto K 《Biochemical and biophysical research communications》2005,333(2):418-426
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, but its autoimmune mechanisms are not clearly understood. Recently, anti-citrullinated peptide antibodies have been specifically observed in sera of RA patients. Furthermore, we identified RA-susceptible variant in a gene encoding citrullinating enzyme, peptidylarginine deiminase type 4 (PADI4). Therefore, we hypothesized that proteins which are modified in RA synovium by PADI4 act as autoantigens. Subsequently, we obtained human collagen type I (huCI) as one of the autoantigens using a RA synoviocyte cDNA library by immunoscreening. We also investigated that the levels of anti-citrullinated huCI were significantly higher in RA patient sera than in normal control sera with high specificity (99%) and positively correlated with the levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies. We concluded that huCI is a novel substrate protein of PADIs and that citrullinated huCI is a candidate autoantigen of RA. 相似文献
14.
Vossenaar ER Després N Lapointe E van der Heijden A Lora M Senshu T van Venrooij WJ Ménard HA 《Arthritis research & therapy》2004,6(2):R142-R150
Antibodies directed to the Sa antigen are highly specific for rheumatoid arthritis (RA) and can be detected in approximately
40% of RA sera. The antigen, a doublet of protein bands of about 50 kDa, is present in placenta and in RA synovial tissue.
Although it has been stated that the Sa antigen is citrullinated vimentin, experimental proof for this claim has never been
published. In this study, we investigated the precise nature of the antigen. Peptide sequences that were obtained from highly
purified Sa antigen were unique to vimentin. Recombinant vimentin, however, was not recognized by anti-Sa reference sera.
In vivo, vimentin is subjected to various post-translational modifications, including citrullination. Since antibodies to citrullinated
proteins are known to be highly specific for RA, we investigated whether Sa is citrullinated and found that Sa indeed is citrullinated
vimentin. Anti-Sa antibodies thus belong to the family of anticitrullinated protein/peptide antibodies. The presence of the
Sa antigen in RA synovial tissue, and the recent observation that vimentin is citrullinated in dying human macrophages, make
citrullinated vimentin an interesting candidate autoantigen in RA and may provide new insights into the potential role of
citrullinated synovial antigens and the antibodies directed to them in the pathophysiology of RA. 相似文献
15.
Vander Cruyssen B Cantaert T Nogueira L Clavel C De Rycke L Dendoven A Sebag M Deforce D Vincent C Elewaut D Serre G De Keyser F 《Arthritis research & therapy》2006,8(4):R122-7
We studied the diagnostic performance of the anti-human citrullinated fibrinogen antibody (AhFibA) ELISA for rheumatoid arthritis (RA) in a consecutive cohort (population 1) and evaluated the agreement between the AhFibA ELISA and four other assays for anti-citrullinated protein/peptide antibodies (ACPAs) as well as rheumatoid factor in patients with longstanding RA (population 2). Population 1 consisted of 1024 patients with rheumatic symptoms; serum samples from these patients were sent to our laboratory for ACPA testing within the context of a diagnostic investigation for RA. Ninety-two of these patients were classified as having RA according to the American College of Rheumatology criteria and 463 were classified as non-RA patients. Population 2 consisted of 180 patients with longstanding RA and was used to assess agreement and correlations between five ACPA assays: anti-cyclic citrullinated peptide (CCP)1 and anti-CCP2 antibodies were detected using a commercially available ELISA, AhFibA using ELISA, and anti-PepA and anti-PepB antibodies using line immunoassay. Applying previously proposed cut-offs for AhFibA, we obtained a sensitivity of 60.9% and a specificity of 98.7% in population 1. Receiver operating characteristic curve analysis could not detect a significant difference in diagnostic performance between the AhFibA ELISA and anti-CCP2 assay. Performing a hierarchical nearest neighborhood cluster analysis of the five different ACPA assays in population 2, we identified two clusters: a cluster of anti-pepA, anti-pepB and anti-CCP1, and a cluster of AhFibA and anti-CCP2. In conclusion, we found that AhFibA and anti-CCP2 antibodies had similar diagnostic performance. However, disagreement between ACPA tests may occur. 相似文献
16.
Pascale Nicaise Roland Sabine Grootenboer Mignot Alessandra Bruns Margarita Hurtado Elisabeth Palazzo Gilles Hayem Philippe Dieudé Olivier Meyer Sylvie Chollet Martin 《Arthritis research & therapy》2008,10(6):R142
Introduction
Antibodies against cyclic citrullinated peptides (CCPs) are useful for diagnosing rheumatoid arthritis (RA). Antibodies to mutated citrullinated vimentin (MCV) were described recently in RA. The aims of this study were to evaluate the usefulness of anti-MCV for diagnosing RA in anti-CCP-negative patients and to monitor anti-MCV titres during infliximab therapy for RA. 相似文献17.
Bellatin MF Han M Fallena M Fan L Xia D Olsen N Branch V Karp D Stastny P 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(7):3542-3550
Autoantibodies against citrullinated protein Ags (ACPA) are associated with the development of rheumatoid arthritis (RA). This immune response against citrullinated protein Ags, which is thought to be facilitated by certain MHC HLA-DR alleles, is highly specific for this disease and has been speculated to be involved in the pathogenesis. We have previously studied cultures of B cells for the production of Abs against HLA Ags. The aim of the current study was to examine the role of B cells in the production of ACPA in patients with RA. Peripheral blood B cells from RA patients and healthy people were cultured with EL4-B5, a murine cell line expressing human CD40L, and with T cell factors to stimulate the in vitro production of Abs by B cells isolated from peripheral blood. ACPA were produced by cultured B cells from RA patients, as determined by reactivity to cyclic citrullinated peptide (CCP). The results showed that 22% of the healthy persons tested also had B cells that could produce ACPA. Patients with HLA-DR alleles carrying the RA-associated shared epitope appeared to have more B cells with autoimmune potential for CCP than those without such HLA alleles (odds ratio 8.1, p = 0.001). In healthy individuals, anti-CCP-producing B cells were also observed more frequently if the RA-associated MHC genes were present (odds ratio 8.0, p = 0.01). Analysis of B cells in cultures may shed light on the interaction of genetic and environmental factors in the development of RA. 相似文献
18.
目的:分析抗抗环瓜氨酸肽(CCP)、类风湿因子(RF)、抗角蛋白抗体(AKA)、抗链球菌溶血素"O"(ASO、)抗RA33抗体对类风湿关节炎诊断的临床价值。方法:选取2015年3月至2016年2月本院收治的79例类风湿关节炎患者视为观察组,另选取同期本院收治的85例非类风湿关节炎自身免疫疾病者视为对照组。比较类风湿关节炎和非类风湿关节炎患者抗CCP、RF、AKA、ASO、RA33阳性情况,对抗CCP、RF、AKA、ASO、RA33的特异度和敏感度予以分析。结果:两组患者的ASO阳性率比较无显著性差异(P0.05),观察组的抗CCP、RF、AKA、RA33阳性率显著高于对照组(P0.05)。抗CCP抗体诊断类风湿关节炎患者的敏感度为64.56%、特异度为92.94%;RF敏感度为60.46%、特异度为80.00%;AKA敏感度为51.90%、特异度为96.47%;ASO敏感度为10.13%、特异度为89.41%;抗RA33抗体敏感度为30.38%、特异度为95.29%。结论:抗CCP、RF、AKA、RA33对类风湿关节炎患者均具有较高的诊断价值,而ASO在类风湿关节炎患者中的诊断价值不明显。 相似文献
19.
Background
Previous studies indicate that natural bispecific antibodies can be readily produced in vivo when the body is simultaneously stimulated with 2 distinct antigens. Patients with rheumatoid arthritis (RA) usually exhibit persistent immune responses to various autoantigens, raising the possibility that natural bispecific antibodies against 2 distinct autoantigens might exist.Methodology/Principal Findings
We identified the presence of natural bispecific antibodies against cyclic citrullinated peptide (CCP) and immunoglobulin G (IgG) in RA patients'' sera by means of a double-antigen sandwich enzyme-linked immunosorbent assay (ELISA). The spontaneous emergence of bispecific antibodies was confirmed by mixing different proportions of 1 anti-CCP-positive serum and 1 rheumatoid factor (RF)-positive serum in vitro. Among the tested samples, positive correlations were found between the presence of bispecific antibodies and both IgG4 anti-CCP antibodies and IgG4 RF (r = 0.507, p<0.001 and r = 0.249, p = 0.044, respectively), suggesting that the IgG4 subclass is associated with this phenomenon. Furthermore, bispecific antibodies were selectively generated when several anti-CCP- and RF-positive sera were mixed pairwise, indicating that factors other than the monospecific antibody titers may also contribute to the production of the natural bispecific antibodies.Conclusions/Significance
We successfully identified the presence of natural bispecific antibodies. Our results suggest that these antibodies originate from anti-CCP and RF in the sera of RA patients. The natural occurrence of bispecific antibodies in human diseases may provide new insights for a better understanding of the diseases. Further investigations are needed to elucidate their precise generation mechanisms and explore their clinical significance in disease development and progression in a larger study population. 相似文献20.
Shoda H Fujio K Shibuya M Okamura T Sumitomo S Okamoto A Sawada T Yamamoto K 《Arthritis research & therapy》2011,13(6):R191-12