共查询到20条相似文献,搜索用时 31 毫秒
1.
Henri A Ménard Elvy Lapointe Moulay D Rochdi Zhi J Zhou 《Arthritis research & therapy》2000,2(6):429-4
The Sa system is a recently described immune system that has a specificity and positive predictive value of nearly 100% for rheumatoid arthritis (RA) in Asia, Europe and the Americas. Its sensitivity of 30-40% suggests that it identifies a subset of RA patients. Anti-Sa antibodies are present from disease onset and are predictive of disease severity. The immune reactants are plentiful in the target tissue: antigen is present in the synovium, IgG antibody in the fluid. Immunologically, Sa is a hapten-carrier antigen in which vimentin is the carrier and citrulline is the hapten. The citrullination of vimentin is closely related to apoptosis, and citrullinated vimentin is extremely sensitive to digestion by the ubiquitous calpains. Nevertheless, Sa is found in only a few cell lines. Calpastatin, the natural specific inhibitor of calpains, is also a RA-associated, albeit non-specific, autoimmune system. Is it possible that calpain-related apoptotic pathways could be prominent in cells containing Sa? The task is to reconcile the specificity of Sa/citrullinated proteins in a multifactorial and polygenic disease such as RA. 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.
Matsuo K Xiang Y Nakamura H Masuko K Yudoh K Noyori K Nishioka K Saito T Kato T 《Arthritis research & therapy》2006,8(6):R175-13
Recently, autoantibodies to some citrullinated autoantigens have been reported to be specific for rheumatoid arthritis (RA). However, an entire profile of and autoimmunity of the citrullinated proteins have been poorly understood. To understand the profile, we examined citrullinated autoantigens by a proteomic approach and further investigated the significance of citrullination in antigenicity of one of the autoantigens. Specifically, we detected citrullinated autoantigens in synovial tissue of a patient with RA by two-dimensional electrophoresis and Western blotting by using pooled sera from five patients with RA and anti-citrulline antibodies. After identifying the detected autoantigens by mass spectrometry, we investigated the contribution of citrullination to autoantigenicity by using a recombinant protein with or without citrullination on one of the identified novel citrullinated autoantigens. As a result, we found 51 citrullinated protein spots. Thirty (58.8%) of these spots were autoantigenic. We identified 13 out of the 30 detected citrullinated autoantigenic proteins. They contained three fibrinogen derivatives and several novel citrullinated autoantigens (for example, asporin and F-actin capping protein alpha-1 subunit [CapZalpha-1]). We further analyzed the contribution of citrullination to autoantigenicity in one of the detected citrullinated autoantigens, CapZalpha-1. As a result, frequencies of autoantibodies to non-citrullinated CapZalpha-1 were 36.7% in the RA group tested, 10.7% in the osteoarthritis (OA) group, and 6.5% in healthy donors. On the other hand, those to citrullinated CapZalpha-1 were 53.3% in the RA group, 7.1% in the OA group, and 6.5% in the healthy donors. This shows that autoantigenicity of citrullinated or non-citrullinated CapZalpha-1 is relevant to RA. The antibody titers to the citrullinated CapZalpha-1 were significantly higher than those to the non-citrullinated CapZalpha-1 in 36.7% of patients; however, the other patients showed almost equal antibody titers to both citrullinated and non-citrullinated CapZalpha-1. Therefore, the autoantibodies would target citrulline-related and/or citrulline-unrelated epitope(s) of CapZalpha-1. In conclusion, we report a profile of citrullinated autoantigens for the first time. Even though citrullination is closely related to autoantigenicity, citrullination would not always produce autoantigenicity in RA. Citrullinated and non-citrullinated autoantigens/autoepitopes would have different pathological roles in RA. 相似文献
5.
Kutty Selva Nandakumar 《Cell and tissue research》2010,339(1):213-220
Antibodies against cartilage proteins are highly prevalent in the sera and synovial fluids of rheumatoid arthritis (RA) patients
and also precede disease induction in various spontaneous and induced animal models of arthritis. These antibodies play an
important role in the induction and perpetuation of the clinical disease. Antibodies binding to cartilage protein(s), especially
the major articular cartilage protein, collagen type II (CII) can induce, in naive mice, an acute form of arthritis that can
substantially destroy the cartilage and bone architecture. More importantly, these anti-CII antibodies can also directly cause
the destruction of the target tissue preceding and independently of disease development and in the absence of any other pathogenic
inflammatory factors or the action of immune cells. Alternatively, antibodies to citrullinated protein antigens and rheumatoid
factor are well-validated prognostic and diagnostic markers of severe erosive RA, although their arthritogenic potential is
questioned. Recently, we have found that the monoclonal antibodies to citrulline-modified cartilage protein can bind cartilage
and synovial tissue and mediate arthritis in mice. Similarly, one of the pathogenic anti-CII monoclonal antibodies has rheumatoid-factor-like
activity, suggesting a disease-inducing role for these commonly prevalent antibodies in RA patients. Interestingly, recent
findings have also shown that the enzymatic cleavage or modification of pathogenic IgG antibodies protects the cartilage surface,
thereby opening up new therapeutic possibilities for protecting the cartilage from inflammatory damage. 相似文献
6.
Anti-Sa antibodies are detected in the serum of 20–47% of patients with rheumatoid arthritis. These antibodies have a high
degree of specificity for the disease, and appear to identify a subset of early rheumatoid arthritis patients destined to
have aggressive and destructive disease. It has recently been confirmed that anti-Sa antibodies are directed to citrullinated
vimentin, thus placing them in the anti-citrulline family of autoantibodies. The Sa antigen has previously been shown to be
present in synovium. This, along with the demonstration of citrullinated proteins in rheumatoid synovium, suggests that anti-Sa
antibodies may play a pathogenetic role in the initiation and/or persistence of rheumatoid synovitis. 相似文献
7.
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
8.
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
9.
Kosuke Matsuo Yang Xiang Hiroshi Nakamura Kayo Masuko Kazuo Yudoh Koji Noyori Kusuki Nishioka Tomoyuki Saito Tomohiro Kato 《Arthritis research & therapy》2007,8(6):R175
Recently, autoantibodies to some citrullinated autoantigens have been reported to be specific for rheumatoid arthritis (RA).
However, an entire profile of and autoimmunity of the citrullinated proteins have been poorly understood. To understand the
profile, we examined citrullinated autoantigens by a proteomic approach and further investigated the significance of citrullination
in antigenicity of one of the autoantigens. Specifically, we detected citrullinated autoantigens in synovial tissue of a patient
with RA by two-dimensional electrophoresis and Western blotting by using pooled sera from five patients with RA and anti-citrulline
antibodies. After identifying the detected autoantigens by mass spectrometry, we investigated the contribution of citrullination
to autoantigenicity by using a recombinant protein with or without citrullination on one of the identified novel citrullinated
autoantigens. As a result, we found 51 citrullinated protein spots. Thirty (58.8%) of these spots were autoantigenic. We identified
13 out of the 30 detected citrullinated autoantigenic proteins. They contained three fibrinogen derivatives and several novel
citrullinated autoantigens (for example, asporin and F-actin capping protein α-1 subunit [CapZα-1]). We further analyzed the
contribution of citrullination to autoantigenicity in one of the detected citrullinated autoantigens, CapZα-1. As a result,
frequencies of autoantibodies to non-citrullinated CapZα-1 were 36.7% in the RA group tested, 10.7% in the osteoarthritis
(OA) group, and 6.5% in healthy donors. On the other hand, those to citrullinated CapZα-1 were 53.3% in the RA group, 7.1%
in the OA group, and 6.5% in the healthy donors. This shows that autoantigenicity of citrullinated or non-citrullinated CapZα-1
is relevant to RA. The antibody titers to the citrullinated CapZα-1 were significantly higher than those to the non-citrullinated
CapZα-1 in 36.7% of patients; however, the other patients showed almost equal antibody titers to both citrullinated and non-citrullinated
CapZα-1. Therefore, the autoantibodies would target citrulline-related and/or citrulline-unrelated epitope(s) of CapZα-1.
In conclusion, we report a profile of citrullinated autoantigens for the first time. Even though citrullination is closely
related to autoantigenicity, citrullination would not always produce autoantigenicity in RA. Citrullinated and non-citrullinated
autoantigens/autoepitopes would have different pathological roles in RA. 相似文献
10.
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11.
Reinout Raijmakers Joyce JBC van Beers Mahmoud El-Azzouny Natasja FC Visser Borut Bo?i? Ger JM Pruijn Albert JR Heck 《Arthritis research & therapy》2012,14(3):R114-10
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints and the presence of autoantibodies directed against proteins containing the non-standard arginine-derived amino acid citrulline. The protein fibrinogen, which has an essential role in blood clotting, is one of the most prominent citrullinated autoantigens in RA, particularly because it can be found in the inflamed tissue of affected joints. Here, we set out to analyze the presence of citrullinated endogenous peptides in the synovial fluid of RA and arthritic control patients.Methods
Endogenous peptides were isolated from the synovial fluid of RA patients and controls by filtration and solid phase extraction. The peptides were identified and quantified using high-resolution liquid chromatography-mass spectrometry.Results
Our data reveal that the synovial fluid of RA patients contains soluble endogenous peptides, derived from fibrinogen, containing significant amounts of citrulline residues and, in some cases, also phosphorylated serine. Several citrullinated peptides are found to be more abundantly present in the synovial fluid of RA patients compared to patients suffering from other inflammatory diseases affecting the joints.Conclusions
The increased presence of citrullinated peptides in RA patients points toward a possible specific role of these peptides in the immune response at the basis of the recognition of citrullinated peptides and proteins by RA patient autoantibodies. 相似文献12.
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
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.
Dejaco C Klotz W Larcher H Duftner C Schirmer M Herold M 《Arthritis research & therapy》2006,8(4):R119-6
Antibodies directed against citrullinated vimentin are members of the family of autoantibodies reactive with citrullinated proteins and are among the most specific serological markers for the diagnosis of rheumatoid arthritis (RA). This study was performed to test the diagnostic value of a newly developed enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies against a genetically modified citrullinated vimentin (anti-MCV) in comparison with a second-generation anti-cyclic citrullinated peptides (anti-CCP2) ELISA test system. Blinded sera from 631 patients (409 consecutive out-patients and 222 randomly selected stored sera) with RA (n = 164) and non-RA (osteoarthritis [n = 120], polymyalgia rheumatica/giant cell arteritis [n = 80], spondyloarthritis [n = 36], and other inflammatory rheumatic or non-inflammatory disease [n = 67]) were tested for the presence of anti-MCV and anti-CCP2 antibodies according to the manufacturers' instructions. The diagnostic performance of the anti-MCV was comparable with the anti-CCP2 assay for the diagnosis of RA according to the calculated area under the curve (0.824; 95% confidence interval (CI) 0.778-0.870 versus 0.818; 95% CI 0.767-0.869) as analysed by receiving operating characteristic curve. When categorised with a cutoff value of 20.0 U/ml (as recommended by the manufacturer), sensitivity and specificity of the anti-MCV ELISA were 69.5% (95% CI 61.9%-76.5%) and 90.8% (86.9%-93.8%), respectively, compared with 70.1% (62.5%-77.0%) and 98.7% (96.7%-99.6%) of the anti-CCP2 assay. Using the cutoff values of 19.0 U/ml and 81.5 U/ml for the anti-MCV test to obtain a sensitivity and specificity identical to the anti-CCP2 assay, showed a reduced specificity (89.8%; 85.8%-92.9%) and sensitivity (53.7%; 45.7%-61.5%), respectively, of the anti-MCV ELISA compared with the anti-CCP2 test. In conclusion, the serum ELISA testing for anti-MCV antibodies as well as the anti-CCP-2 assay perform comparably well in the diagnosis of RA. In the high-specificity range, however, the anti-CCP2 assay appears to be superior to the anti-MCV test. 相似文献
15.
Okazaki Y Suzuki A Sawada T Ohtake-Yamanaka M Inoue T Hasebe T Yamada R Yamamoto K 《Biochemical and biophysical research communications》2006,341(1):94-100
Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis. We previously reported that functional variants of the gene encoding peptidylarginine deiminase type 4 were closely associated with RA. The purpose of this study was to investigate the citrullinated autoantigens recognized by serum samples from patients with RA. The human chondrocyte cDNA expression library was citrullinated by PADI4 and was immunoscreened with anti-modified citrulline antibodies and sera from patients with rheumatoid arthritis. One immunoreactive cDNA clone containing a 2480-base pair insert was isolated and sequence analysis revealed that the cDNA included a part of the eukaryotic translation initiation factor 4G1. Immunoreactivity against a recombinant citrullinated eIF4G1 fragment was observed with high specificity in 50.0% of RA patients. The levels of antibodies against citrullinated eIF4G1 were correlated with those of anti-CCP antibodies. Citrullinated eIF4G1 was identified as a candidate citrullinated autoantigen in RA patients. Citrullination of eIF4G1 may thus be involved in the pathogenesis of RA. 相似文献
16.
Nicole Hartwig Trier Catharina Essendrup Dam Dorthe Tange Olsen Paul Robert Hansen Gunnar Houen 《PloS one》2015,10(12)
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, affecting approximately 1–2% of the world population. One of the characteristic features of RA is the presence of autoantibodies. Especially the highly specific anti-citrullinated peptide antibodies (ACPAs), which have been found in up to 70% of RA patients’ sera, have received much attention. Several citrullinated proteins are associated with RA, suggesting that ACPAs may react with different sequence patterns, separating them from traditional antibodies, whose reactivity usually is specific towards a single target. As ACPAs have been suggested to be involved in the development of RA, knowledge about these antibodies may be crucial. In this study, we examined the influence of peptide backbone for ACPA reactivity in immunoassays. The antibodies were found to be reactive with a central Cit-Gly motif being essential for ACPA reactivity and to be cross-reactive between the selected citrullinated peptides. The remaining amino acids within the citrullinated peptides were found to be of less importance for antibody reactivity. Moreover, these findings indicated that the Cit-Gly motif in combination with peptide backbone is essential for antibody reactivity. Based on these findings it was speculated that any amino acid sequence, which brings the peptide into a properly folded structure for antibody recognition is sufficient for antibody reactivity. These findings are in accordance with the current hypothesis that structural homology rather than sequence homology are favored between citrullinated epitopes. These findings are important in relation to clarifying the etiology of RA and to determine the nature of ACPAs, e.g. why some Cit-Gly-containing sequences are not targeted by ACPAs. 相似文献
17.
Elena Ossipova Cátia Fernandes Cerqueira Evan Reed Nastya Kharlamova Lena Israelsson Rikard Holmdahl Kutty Selva Nandakumar Marianne Engstr?m Ulrike Harre Georg Schett Anca I Catrina Vivianne Malmstr?m Yngve Sommarin Lars Klareskog Per-Johan Jakobsson Karin Lundberg 《Arthritis research & therapy》2014,16(4)
Introduction
A major subset of patients with rheumatoid arthritis (RA) is characterized by the presence of circulating autoantibodies directed to citrullinated proteins/peptides (ACPAs). These autoantibodies, which are commonly detected by using an enzyme-linked immunosorbent assay (ELISA) based on synthetic cyclic citrullinated peptides (CCPs), predict clinical onset and a destructive disease course. In the present study, we have used plasma and synovial fluids from patients with RA, for the affinity purification and characterization of anti-CCP2 reactive antibodies, with an aim to generate molecular tools that can be used in vitro and in vivo for future investigations into the pathobiology of the ACPA response. Specifically, this study aims to demonstrate that the surrogate marker CCP2 can capture ACPAs that bind to autoantigens expressed in vivo in the major inflammatory lesions of RA (that is, in the rheumatoid joint).Methods
Plasma (n = 16) and synovial fluid (n = 26) samples were collected from RA patients with anti-CCP2 IgG levels of above 300 AU/mL. Total IgG was isolated on Protein G columns and subsequently applied to CCP2 affinity columns. Purified anti-CCP2 IgG was analyzed for reactivity and specificity by using the CCPlus® ELISA, in-house peptide ELISAs, Western blot, and immunohisto-/immunocytochemistry.Results
Approximately 2% of the total IgG pool in both plasma and synovial fluid was CCP2-reactive. Purified anti-CCP2 reactive antibodies from different patients showed differences in binding to CCP2 and differences in binding to citrullinated peptides from α-enolase, vimentin, fibrinogen, and collagen type II, illustrating different ACPA fine-specificity profiles. Furthermore, the purified ACPA bound not only in vitro citrullinated proteins but, more importantly, in vivo-generated epitopes on synovial fluid cells and synovial tissues from patients with RA.Conclusions
We have isolated ACPAs from plasma and synovial fluid and demonstrated that the CCP2 peptides, frequently used in diagnostic ELISAs, de facto act as surrogate antigens for at least four different, well-characterized, largely non-cross-reactive, ACPA fine specificities. Moreover, we have determined the concentration and proportion of CCP2-reactive IgG molecules in rheumatoid plasma and synovial fluid, and we have shown that the purified ACPAs can be used to detect both in vitro- and in vivo-generated citrullinated epitopes by various techniques. We anticipate that these antibodies will provide us with new opportunities to investigate the potential pathogenic effects of human ACPAs. 相似文献18.
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19.
Sanna Turunen Pekka Hannonen Marja-Kaisa Koivula Leila Risteli Juha Risteli 《Arthritis research & therapy》2015,17(1)
IntroductionOur objective was to find out if there are antibodies binding to homocitrulline-containing type I and II collagen carboxyterminal telopeptides in sera of patients with rheumatoid arthritis (RA), and if these antibodies cross-react with citrulline and homocitrulline in the same peptide sequence.MethodsA total of 72 RA and 72 control sera were analyzed for binding using enzyme-linked immunosorbent assay to citrulline- or homocitrulline-containing type I and II collagen carboxyterminal telopeptides, as well as to cyclic citrullinated peptide (CCP) and to mutated citrullinated vimentin (MCV). Specificities of the antibodies were tested using inhibition-ELISA.ResultsOf the RA sera, 39 (54%) and 41 (57%) were positive for binding to CCP and MCV, respectively. Further, 34 (47%) and 30 (42%) of the patients had specific antibodies binding to and being inhibited by citrulline-containing type I collagen telopeptides and by citrulline-containing type II collagen carboxyterminal telopeptides, respectively. The corresponding figures regarding homocitrulline-containing type I and homocitrulline-containing type II collagen telopeptides were 16 (22%) and 14 (19%). Most of the patients, who were seropositive for citrullinated peptides, showed binding in multiple assays. A total of 10 (14%) RA patients were positive for all the tested peptide pairs, while 28 (39%) of them had antibodies that contained overlapping specifities between citrulline and homocitrulline in the same peptide sequence.ConclusionsAntibodies to both citrulline and homocitrulline containing type I and II collagen telopeptides can be found in sera of RA patients. These antibodies are not constant from one RA patient to another, but contain separate or overlapping specificities within the same peptide sequence varying between individuals. Our results suggest some relationship between citrulline and homocitrulline-recognizing antibodies, since homocitrulline antibodies exist mainly in individuals seropositive to anti-CCP and anti-MCV.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0515-z) contains supplementary material, which is available to authorized users. 相似文献20.
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