A molecular basis for citrullination dependent rheumatoid arthritis

2014 ◽  
Vol 70 (a1) ◽  
pp. C253-C253
Author(s):  
Stephen Scally ◽  
Jan Petersen ◽  
Soi Cheng Law ◽  
Nadine Dudek ◽  
Hendrick Nel ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Molecular Basis ◽  
Bone Erosion ◽  
Strong Association ◽  
Arginine Deiminase ◽  
Healthy Controls ◽  
Citrullinated Vimentin ◽  
Positively Charged ◽  
Self Antigens

Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease, characterized by inflammation of synovial tissue, joint pannus and bone erosion. The human leukocyte antigen (HLA) locus plays a vital role in immunity, encoding highly polymorphic molecules that present peptides to T cell lymphocytes. RA has a strong association with a region of the HLA-DRB1 locus known as the `shared epitope' (SE) and the presence of autoantibodies specific for citrullinated proteins. The SE maps to a highly polymorphic N-terminal region of the HLA-DRβ chain around amino acids 70-74. This region encodes a positively charged residue at position 71 that is thought to dictate the amino acid that is accommodated in the P4 pocket of the antigen-binding groove. Citrullination, the conversion of positively charged arginine to polar citrulline, is a physiological process catalyzed by peptidyl arginine deiminase. Previous studies have shown that citrullination of self-antigens can significantly increase the affinity of epitopes for SE alleles. Here we provide a molecular basis for how citrullinated vimentin and aggrecan epitopes can be presented by the SE alleles, HLA-DRB1*0401 and HLA-DRB1*0404. Citrulline was accommodated in the electropositive P4 pocket of HLA-DRB1*0401/04, whilst arginine was not. In addition, the RA resistant HLA-DRB1*0402 allomorph was capable of binding both arginine and citrulline in its electronegative P4 pocket. Peptide elution studies revealed that arginine was presented by HLA-DRB1*0402 but not by HLA-DRB1*0401/04. Moreover, citrullinated vimentin showed a greater sensitivity to proteolysis by cathepsin L, when compared to unmodified vimentin, indicating that citrullination can impact the repertoire of self-antigens presented. Using HLA Class II tetramers, we identified citrullinated vimentin and aggrecan specific CD4+ T cells from both HLA-DRB1*0401+ RA patients and healthy controls. In RA patients, the number of autoreactive T cells correlated with disease activity and were deficient in regulatory T cells compared to healthy controls. Together these findings provide significant insight into the role citrullination plays in the pathogenesis of RA[1].

scholarly journals Identification and function of T cells reactive with citrullinated vimentin in HLA-DRB1*0401 humanised mice and rheumatoid arthritis patients

2010 ◽  
Vol 69 (Suppl 2) ◽  
pp. A73-A73
Author(s):  
O Snir ◽  
M Rieck ◽  
K Klich ◽  
L Klareskog ◽  
J H Buckner ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Citrullinated Vimentin ◽  
Humanised Mice ◽  
And Function

Elevated levels of anti-carbamylated protein antibody in patients with rheumatoid arthritis: association with disease activity and bone destruction

2020 ◽  
Vol 68 (6) ◽  
pp. 1186-1192
Author(s):  
Bei Zhang ◽  
Yimeng Lei ◽  
Xin Li ◽  
Ziyu Gao ◽  
Liping Xia ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Erythrocyte Sedimentation Rate ◽  
Antibody Level ◽  
Sedimentation Rate ◽  
Bone Erosion ◽  
Serum Levels ◽  
Double Negative ◽  
Healthy Controls ◽  
Erythrocyte Sedimentation

To measure the serum levels of anticarbamylated protein (CarP) antibodies in patients with rheumatoid arthritis (RA) in China and to evaluate the association of anti-CarP antibodies with clinical parameters and disease activity. 260 Chinese patients with RA, 40 patients with osteoarthritis (OA), 88 patients with spondyloarthritis (SpA) and 77 healthy controls were included. The serum levels of anti-CarP antibodies were detected by ELISA. Blood tests to detect the anticyclic citrullinated peptide (CCP) antibody level, rheumatoid factor (RF) level, erythrocyte sedimentation rate, C reactive protein level and Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) were performed by standard methods. Bone erosion was assessed by colour Doppler ultrasonography. A total of 18.8% of patients with RA and 9.4% of anti-CCP antibody and RF-double-negative patients were positive for anti-CarP antibody. The anti-CarP antibody level was significantly higher in patients with RA than in patients with OA or SpA and in healthy controls. Univariate and multivariate analyses showed that the level of anti-CarP antibody was positively correlated with DAS28-ESR; the higher a level of serum anti-CarP antibody, the higher the DAS28-ESR score. Anti-CarP-positive patients had higher disease activity scores than anti-CarP-negative patients. Moreover, anti-CarP-positive patients had a higher risk of developing bone erosion. The anti-CarP antibody was found to play an important role in the diagnosis of RA, especially in anti-CCP antibody and RF-double-negative patients. The anti-CarP antibody is a potential marker of disease activity and bone erosion in RA.

scholarly journals A Promoter Region Polymorphism inPDCD-1Gene Is Associated with Risk of Rheumatoid Arthritis in the Han Chinese Population of Southeastern China

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
CuiPing Liu ◽  
JueAn Jiang ◽  
Li Gao ◽  
XiaoHan Hu ◽  
FengMing Wang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Chinese Population ◽  
Direct Sequencing ◽  
Han Chinese ◽  
Chinese Patients ◽  
Sequencing Analysis ◽  
Healthy Controls ◽  
Han Chinese Population ◽  
Increased Risk

Objective. Programmed cell death 1 (PD-1) induces negative signals to T cells during interaction with its ligands and is therefore a candidate gene in the development of autoimmune diseases such as rheumatoid arthritis (RA). Herein, we investigate the association ofPDCD-1polymorphisms with the risk of RA among Chinese patients and healthy controls.Methods. Using the PCR-direct sequencing analysis, 4PDCD-1SNPs (rs36084323, rs11568821, rs2227982, and rs2227981) were genotyped in 320 RA patients and 309 matched healthy controls. Expression of PD-1 was determined in peripheral blood lymphocytes by flow cytometry and quantitative real-time reverse transcriptase polymerase chain reaction.Results. We observed that the GG genotype of rs36084323 was associated with a increased risk for developing RA (OR 1.70, 95% 1.11–2.61,P=0.049). Patients carrying G/G genotype displayed an increased mRNA level of PD-1(P=0.04)compared with A/A genotype and healthy controls. Meanwhile, patients homozygous for rs36084323 had induced basal PD-1 expression on activated CD4+ T cells.Conclusion. ThePDCD-1polymorphism rs36084323 was significantly associated with RA risk in Han Chinese population. This SNP, which effectively influenced the expression of PD-1, may be a biomarker of early diagnosis of RA and a suitable indicator of utilizing PD-1 inhibitor for treatment of RA.

Rheumatoid Arthritis as a New Disease-Target for Bortezomib.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1543-1543
Author(s):  
Evangelia Yannaki ◽  
Anastasia Papadopoulou ◽  
Argyrw Paraskeva ◽  
Panayotis Kaloyannidis ◽  
Evangelia Athanasiou ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Rat Model ◽  
Adjuvant Arthritis ◽  
Advanced Disease ◽  
Bone Erosion ◽  
Osteogenic Potential ◽  
Human Rheumatoid Arthritis ◽  
Pannus Formation ◽  
Arthritic Score

Abstract Bortezomib (Velcade) is the first proteasome inhibitor that has been introduced into the clinic for the treatment of multiple myeloma. Bortezomib, by inhibiting the NFkB function, results in increased tumor cell sensitivity to chemotherapy and induces apoptosis of alloreactive T-cells. Since NF-kB activation results also in transcription of pro-inflammatory molecules, it is speculated that NF-kB inhibition may also ameliorate inflammatory and autoimmune conditions. Rheumatoid arthritis may be a possible target disease for proteasome inhibitors because the most important pro-inflammatory mediators (TNF-a, IL-1, IL-6, V-CAM-1) are regulated by NF-kB. We investigated the effect of Bortezomib in a rat model of Adjuvant Arthritis (AA) which closely resembles human rheumatoid arthritis. The presence of 5,10,100 nM bortezomib for 72h or the presence of 10 nM bortezomib for 48 and 72 h in culture with ConA–activated T-cells from the spleen of rats after AA induction, significanlty inhibited their proliferation as measured by radioactive thymidine incorporation (p<0,00005 in all concentrations and culture times tested). Likewise, the presence of 10 nM Bortezomib for 48 and 72 h in fibroblast-like synoviocytes (FLS) culture from rats after AA induction, significanlty inhibited proliferation (p<0,00005). Bortezomib’s effect in AA was also explored in vivo by intraperitoneal injections at 0,25mg/kg×2days×2weeks in rats after AA induction by FCA injection in the tail base. Adjuvant artrhitis usually starts to develop at day 11–13 post induction. Bortezomib was administered before the onset of arthritis at the onset of arthritis and in established arthritis. The total arthritic index represented a score based on redness, swelling and deformity of the joint. Arthritis grading was assessed on a 4-point scale per limb with a maximum arthritic score of 16 per rat. The histologic severity of arthritis was also assessed by a histopathological score based on the presence of synovial hyperplasia, inflammatory infiltration, chondroplasia, bone destruction and pannus formation (max score 12 per animal). A significant delay in arthritis onset accompanied by a milder clinical picture was observed in the group which received Bortezomib before the onset of arthritis (mean day21 arthritic score; 1). More importantly, there was a dramatic reduction in the disease score in the group treated with Bortezomib both at the onset of arthritis (mean day26 arthritic score;4,1) and at advanced disease status (mean day30 arthritic score; 3,3) as compared to the untreated AA control group (mean day21, day26 and day30 arthritic score 9,6, 9,9 and 11,3 respectively/p=0,03, p=0,02 and p=0,02, respectively). There was a correlation between the clinical and histopathological assessment of disease severity in Bortezomib-treated animals vs control rats (histological score 3,75 vs 9,8 respectively). A marked reduction in the number of inflammatory cells with little or no bone erosion and limited pannus formation could be seen in the joints of bortezomib-treated rats. A significant reduction of CD3+ cells in the joints and inhibition of NF-kB in spleen sections of Bortezomib-treated rats was detected by immunohistochemistry. Flow cytometry analysis demonstrated a significant increase of CD4+ cells with reduction of CD8+, CD11b+ cells in the blood (p=0,003 and p=0,0002, respectively) and the spleen (p=0,01 and p=0,017, respectively). T-cells from Bortezomib-treated animals exhibited a higher degree of apoptosis measured as Annexin-V + cells, when compared to T-cells from AA control rats. In CT scans before and after treatment with Bortezomib of animals that received bortezomib in advanced disease phase, a significant reduction of soft tissue swelling around the affected joints with restoration of focal osteopenia and bone erosion could be detected. Currently, we are testing the combination of Bortezomib with Mesenchymal Stem Cells in the same disease model, as bortezomib has been shown to enhance the osteogenic potential of MSCs. Our data suggest that Bortezomib exhibits significant anti-inflammatory and proapoptotic activity in a rat model of adjuvant arthritis and human rheumatoid arthritis may represent an important clinical opportunity for this drug

Circulating Dickkopf-1 Is Correlated with Bone Erosion and Inflammation in Rheumatoid Arthritis

2011 ◽  
Vol 38 (5) ◽  
pp. 821-827 ◽  
Author(s):  
SHI-YAO WANG ◽  
YAN-YING LIU ◽  
HUA YE ◽  
JIAN-PING GUO ◽  
RU LI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatic Diseases ◽  
Bone Erosion ◽  
Interleukin 1 ◽  
Healthy Controls ◽  
Serum Samples ◽  
Reactive Protein ◽  
Tnf Α ◽  
Factor Α ◽  
Dickkopf 1

Objective.To explore the potential role of Dickkopf-1 (DKK-1) in rheumatoid arthritis (RA) and to evaluate the effect of a tumor necrosis factor-α (TNF-α) inhibitor (infliximab) and an interleukin 1 receptor antagonist (IL-1Ra; anakinra) on DKK-1 secretion in patients with RA.Methods.Serum samples were collected from 100 patients with RA, 100 patients with other rheumatic diseases (e.g., osteoarthritis and ankylosing spondylitis), and 40 healthy controls. DKK-1 and osteoprotegerin (OPG) levels in serum were detected by ELISA. Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), rheumatoid factor (RF) titers, and anti-cyclic citrullinated peptide antibody were also measured in patients with RA.Results.The serum level of DKK-1 was significantly higher in patients with RA than in healthy controls and those with other rheumatic diseases (p < 0.01); the serum DKK-1 level was correlated with levels of CRP (r = 0.488, p = 0.003) and ESR (r = 0.458, p = 2.4 x 10−4) and the Sharp score of radiologic change (r = 0.449, p = 0.001) in RA. In contrast to the increasing level of OPG, DKK-1 was significantly decreased in RA patients treated with TNF-α inhibitor (p < 0.01). DKK-1 was significantly decreased in RA patients treated with IL-1Ra (p < 0.01).Conclusion.DKK-1, as an important mediator, was correlated with bone erosion and inflammation in RA. The change of DKK-1 level may serve as a biomarker of disease activity and bone erosion.

scholarly journals A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis

2013 ◽  
Vol 210 (12) ◽  
pp. 2569-2582 ◽  
Author(s):  
Stephen W. Scally ◽  
Jan Petersen ◽  
Soi Cheng Law ◽  
Nadine L. Dudek ◽  
Hendrik J. Nel ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Human Leukocyte ◽  
Healthy Individuals ◽  
Leukocyte Antigen ◽  
Cell Numbers ◽  
Autoreactive T Cell ◽  
Drb1 Locus ◽  
Citrullinated Vimentin

Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)-DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLA-DRB1*04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine–containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01+ individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4+ T cells in the peripheral blood of HLA-DRB1*04:01+ RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA.

Association of CD8+ T-cells with bone erosion in patients with rheumatoid arthritis

2017 ◽  
Vol 21 (2) ◽  
pp. 440-446 ◽  
Author(s):  
Young Bin Joo ◽  
Youngho Park ◽  
Kwangwoo Kim ◽  
So-Young Bang ◽  
Sang-Cheol Bae ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd8 T Cells ◽  
Bone Erosion

Clinical Value of Detecting Anti-Mutated Citrullinated Vimentin, Anti-Cyclic Citrullinated Peptide, Red Cell Distribution Width and 25-Hydroxyvitamin D in the Diagnosis of Rheumatoid Arthritis

2020 ◽  
Vol 52 (1) ◽  
pp. 80-85
Author(s):  
Liming Tan ◽  
Yangyang Gong ◽  
Qian Zhang ◽  
Haocheng Zhang ◽  
Xiaoxia Lu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Healthy Controls ◽  
Cell Distribution ◽  
Clinical Value ◽  
Distribution Width ◽  
Hydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Citrullinated Vimentin ◽  
Citrullinated Peptide

Abstract Objectives To investigate the clinical value of detecting anti–mutated citrullinated vimentin (anti-MCV), anti-citrullinated peptide (anti-CCP), red-blood-cell distribution width (RDW), and 25-hydroxyvitamin D (25-[OH]D) in the diagnosis of rheumatoid arthritis (RA). Methods We enrolled 119 patients with RA, 114 control individuals without RA (disease controls), and 40 healthy controls in our study (Han Chinese). Anti-CCP and anti-MCV were detected by enzyme-linked immunosorbent assay (ELISA), 25-(OH)D was detected by electrochemical luminescence, and RDW was calculated by erythrocyte parameters detected via the electric resistance method. Results The serum levels of anti-CCP and anti-MCV in RA were higher than those in disease controls and healthy controls (P &lt;.01). The areas under the curve (AUCs) of anti-MCV, anti-CCP, RDW, and 25-(OH)D were 0.857, 0.890, 0.611, and 0.569 respectively (P &lt;.05). In various combinations of indicators, when RDW, 25-(OH)D, and anti-CCP; or RDW, 25-(OH)D, anti-CCP, and anti-MCV were connected in parallel, the sensitivity was the highest (all 94.1%). Also, when RDW, 25-(OH)D, anti-CCP, and anti-MCV were connected in series, the sensitivity was the lowest (13.4%). Conclusions Anti-CCP and anti-MCV are ideal indices for RA diagnosis. Also, in combination with RDW and 25-(OH)D, the diagnostic level will be improved, as well as the sensitivity and specificity, which is significant for the differential diagnosis of RA.

scholarly journals Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients

2011 ◽  
Vol 63 (10) ◽  
pp. 2873-2883 ◽  
Author(s):  
Omri Snir ◽  
Mary Rieck ◽  
John A. Gebe ◽  
Betty B. Yue ◽  
Crystal A. Rawlings ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Functional Characterization ◽  
Humanized Mice ◽  
Citrullinated Vimentin

scholarly journals AB0093 PORPHYROMONAS GINGIVALIS - PERIODONTAL PATHOGEN WITH POTENTIAL ROLL IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1346.2-1346
Author(s):  
P. Selimov ◽  
E. Firkova ◽  
L. Damjanovska-Krstikj ◽  
A. Batalov ◽  
A. Maneva ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Porphyromonas Gingivalis ◽  
Strong Association ◽  
Elisa Test ◽  
Periodontal Pathogen ◽  
Healthy Controls ◽  
Related Article ◽  
Link Type ◽  
Article Type ◽  
Increased Risk

Background:In recent literature, a strong association between periodontal disease (PD) and rheumatoid arthritis (RA) has been reported. PD is a common, progressive inflammatory disease, initiated by a bacterial infection that engages the supporting structures of the teeth and leads to tooth loss. A number of common features have been identified between PD and RA.One of the most important associations is the process of citrullination, which is caused by the production of PG specific enzyme so called Porphyromonas Gingivalis Peptydil Deminase (PPAD)Objectives:The aim of the study was to show the incidence of PG in RA patients, and to compare it with patients with osteoarthritis (OA) and healthy controls (HC) and to evaluate the possible correlation between the presence of PG in patients with RA and the positivity of anti CCP and anti MCV antibodies in RA patients.Methods:The study included 30 patients with RA which fulfilled RA classification criteria from 2010, 26 patients with osteoarthritis (OA) and 24 healthy controls. All participants were genetically analyzed for the presence of PG by Chelex®100 method and polymerase chain reaction (PCR), by isolating amplified sequences of DNA in a sub gingival biofilm taken from the deep periodontal pockets. The presence of anti CCP and anti MCV autoantibodies was detected in the sera of RA patients with ELISA test.Results:The average ages of the patients in the 3 groups were as follows -51 years for RA, 52 for OA and 58 years for HC. Seventy two percent of RA patients were females.Significantly higher levels of PG were found in the periodontal pockets of.RA patients.Eighty percent of RA patients (80% or 24 RA patients) were PG positive in comparison with 35% of OA patients and 2% healthy controls.Of the PG-positive RA patients, 83% had positive and 17% had anti-CCP negative test, while of the PG-negative patients, a positive anti-CCP test was present in 33% and a negative anti-CCP test was present in 67%.Accordingly, in PG-positive RA patients positive anti-MCV test was present in 79% and negative anti-MCV test was present in 21%, and in PG-negative RA patients anti-MCV test was positive in 17% and negative in 83% patients.Table 1.Patient’s groupsRAOAHCSignificancePorphyromonas gingivalis positive24 (80%)9 (35%)7 (29%)RA→OA(p < 0.0001)RA→HC(p < 0.0001)OA→HC(p0,65)Porphyromonas gingivalis negative6 (24%)17 (65%)17(71%)Total302624Conclusion:The results of our study indicate that PG is found more frequently in periodontal pockets of patients with rheumatoid arthritis, which implies the important role of oral microbioma in RA pathogenesis, treatment and prevention.References:[1]Mikuls T. R., Thiele G. M., Deane K. D. et al. (2012). Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis. Arthritis & Rheumatism, 64(11), 3522-3530.[2]Mikuls T.R., Payne J.B., Yu F. et al. Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014; 66(5): 1090–1100Disclosure of Interests:Pavel Selimov: None declared, Elena Firkova: None declared, Ljubinka Damjanovska-Krstikj Grant/research support from: Roche, Speakers bureau: Pfizer, Anastas Batalov: None declared, Ana Maneva: None declared, Rositsa Karalilova: None declared, Ginka Delcheva: None declared, Katia Stefanova: None declared, Teodora Stankova: None declared

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