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How MHC molecules grab citrullinated peptides to foster rheumatoid arthritis.

ABSTRACT: The molecular immunologist's dream is to elucidate a fundamental biochemical process that explains the basis of an affliction that affects millions of people, and that, precisely understood, might yield a rational approach to diagnosis, prevention, or therapy. In this issue of JBC, Ting et al. report proteomic, biochemical, and structural analyses that better explain how the antigen-presenting HLA-DR4 molecules bind citrullinated peptides to provoke rheumatoid arthritis (RA), a chronic autoimmune disease that affects 0.5-1% of the population.

SUBMITTER: Margulies DH

PROVIDER: S-EPMC5836129 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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How MHC molecules grab citrullinated peptides to foster rheumatoid arthritis.

Margulies David H DH

The Journal of biological chemistry 20180301 9

The molecular immunologist's dream is to elucidate a fundamental biochemical process that explains the basis of an affliction that affects millions of people, and that, precisely understood, might yield a rational approach to diagnosis, prevention, or therapy. In this issue of JBC, Ting <i>et al.</i> report proteomic, biochemical, and structural analyses that better explain how the antigen-presenting HLA-DR4 molecules bind citrullinated peptides to provoke rheumatoid arthritis (RA), a chronic au ...[more]

PMID: 29500270

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Screening of rheumatoid arthritis patients sera against citrullinated fibrinogen peptides using ImmunoCAP ISAC system

Project description:Citrullinated and unmodified peptides (>95% purity, ProImmune AB) were immobilized onto a chemically modified glass slide, sera from RA patients and healthy controls were applied into the reactions sites and fluorescence intensity after incubation with anti-human IgG antibody was acquired in a laser scanner. Final results for each citrullinated peptide were calculated by subtracting the intensity values of corresponding arginine containing control peptide from citrullinated peptide for all RA patients and controls.

2015-10-25 | E-MTAB-3606 | biostudies-arrayexpress

Targeting of anti-citrullinated protein/peptide antibodies in rheumatoid arthritis using peptides mimicking endogenously citrullinated fibrinogen antigens.

Project description:We have previously identified endogenously citrullinated peptides derived from fibrinogen in rheumatoid arthritis (RA) synovial tissues. In this study, we have investigated the auto-antigenicity of four of those citrullinated peptides, and explored their feasibility to target anti-citrullinated protein/peptide antibodies (ACPA).The autoantigenic potential of the fibrinogen peptides was investigated by screening 927 serum samples from the Epidemiological Investigation of RA (EIRA) cohort on a peptide microarray based on the ImmunoCAP ISAC® system. In order to assay for ACPA blocking, two independent pools of purified ACPA were incubated with the respective targeting peptide prior to binding to cyclic citrullinated peptide (CCP)2 using the CCPlus® ELISA kit.Two peptides derived from the fibrinogen ? chain, Arg573Cit (563-583) and Arg591Cit (580-600), referred to as Cit573 and Cit591, and two peptides from the fibrinogen ? chain, Arg72Cit (62-81) and Arg74Cit (62-81) (Cit72 and Cit74), displayed 65%, 15%, 35%, and 53% of immune reactivity among CCP2-positive RA sera, respectively. In CCP2-negative RA sera, a positive reactivity was detected in 5% (Cit573), 6% (Cit591), 8% (Cit72), and 4% (Cit74). In the competition assay, Cit573 and Cit591 peptides reduced ACPA binding to CCP2 by a maximum of 84% and 63% respectively. An additive effect was observed when these peptides were combined. In contrast, Cit74 and Cit72 were less effective. Cyclization of the peptide structure containing Cit573 significantly increased the blocking efficiency.Here we demonstrate extensive autoantibody reactivity against in vivo citrullinated fibrinogen epitopes, and further show the potential use of these peptides for antagonizing ACPA.

| S-EPMC4484629 | biostudies-literature

Shared recognition of citrullinated tenascin-C peptides by T and B cells in rheumatoid arthritis.

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Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients.

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Are antibodies to fine specificities of citrullinated peptides/proteins useful for stratification of rheumatoid arthritis patients?

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Autoimmunity to citrullinated type II collagen in rheumatoid arthritis.

Project description:The production of autoantibodies to citrullinated type II collagen and the citrullination of type II collagen were analyzed in rheumatoid arthritis. Autoantibodies to citrullinated type II collagen were detected in 78.5% of serum samples from 130 rheumatoid arthritis patients. Autoantibodies to native noncitrullinated type II collagen were detected in 14.6% of serum samples, all of which were positive for anti-citrullinated type II collagen antibodies. Serum samples were also positive for anti-citrullinated type II collagen antibodies in 1 of 31 systemic lupus erythematosus patients and 2 of 55 patients with osteoarthritis of the knee. In contrast, sera samples from 24 systemic sclerosis patients, 21 dermatomyositis/polymyositis patients, 21 ankylosing spondylitis patients, and 18 psoriatic arthritis patients were all negative for anti-citrullinated type II collagen antibodies. Anti-citrullinated type II collagen antibodies and fragments of citrullinated type II collagen were found in the synovial fluid obtained from affected knee joints of 15 rheumatoid arthritis patients. Moreover, anti-citrullinated type II collagen antibodies were isolated from the synovium of affected knee joints in 8 rheumatoid arthritis patients using antigen/antibody immunocomplex dissociation buffer but not by using standard buffers. These findings indicate that autoantibodies that react with citrullinated type II collagen are specifically produced and that immunocomplexes composed of fragments of citrullinated type II collagen and autoantibodies are deposited in the inflamed articular synovium in rheumatoid arthritis patients. Assaying for the presence of anti-citrullinated type II collagen antibodies may therefore be useful for diagnosing rheumatoid arthritis, and the deposition of these immunocomplexes in the articular synovium may be involved in pathogenesis.

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Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin.

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| S-EPMC400433 | biostudies-literature

Identification of citrullinated peptides in the synovial fluid of patients with rheumatoid arthritis using LC-MALDI-TOF/TOF.

Project description:The objective of the study is to investigate potential citrullinated autoantigens as targets of anti-citrullinated protein antibodies (ACPAs) response in synovial fluids (SFs) of patients with rheumatoid arthritis (RA). SFs from six RA patients and six osteoarthritis (OA) patients as controls were collected. The citrullinated proteins in SFs were extracted by immunoprecipitation with rabbit anti-citrulline antibodies. Matrix-assisted laser desorption/ionization time of flight mass spectrometry/time of flight mass spectrometry (MALDI-TOF/TOF) mass spectrometry was subsequently performed to discover a characteristic neutral loss to finally determine citrullinated autoantigens. A total of 182 citrullinated peptides and 200 citrullinated sites were identified in RA SFs, while 3 citrullinated peptides and 4 citrullinated sites were identified in OA SFs. The 182 citrullinated peptides from RA SFs and the 3 citrullinated peptides from OA SFs were derived from 83 and 3 autoantigens, respectively. Eighty-three autoantigens except protein-arginine deiminase type-2 (PADI2) and protein-arginine deiminase type-2 (PADI4) were over-citrullinated compared with controls, and the citrullinated sites of PADI2 and PADI4 were different in two groups. Interestingly, citrullinated histone H3.3 (H3F3A) was found in OA controls, but not in RA groups. The differential citrullinated proteins identified in RA SFs suggested potential autoantigens were targeted for ACPAs response and might contribute to the induction and perpetuation of complement activation and joint inflammation in RA.

| S-EPMC4989008 | biostudies-literature

Impact of Cyclic Citrullinated Peptide Antibody Level on Progression to Rheumatoid Arthritis in Clinically Tested Cyclic Citrullinated Peptide Antibody-Positive Patients Without Rheumatoid Arthritis.

Project description:OBJECTIVE:To investigate the risk of progression to rheumatoid arthritis (RA) in patients who were cyclic citrullinated peptide (CCP) antibody positive without RA at initial presentation. METHODS:We performed a retrospective cohort study of CCP+ individuals seen at a US tertiary care system between 2009 and 2018 who were without RA or other systemic rheumatic disease by medical record review at the time of CCP antibody positivity. Progression to classifiable RA was determined through medical record review. We investigated the risk of progression to RA overall and stratified by CCP antibody level (low: >1 to 2× the upper limit of normal [ULN]; medium: >2 to 3× ULN; high: >3× ULN). Multivariable Cox regression estimated the hazard ratio (HR) and 95% confidence interval (95% CI) for RA by CCP antibody level. RESULTS:We identified 340 CCP+ patients who were without RA or other rheumatic disease at baseline. During 1,047 person-years of follow-up, 73 patients (21.5%) developed RA. The risk of progression to RA increased with CCP antibody level, with 46.0% (95% CI 34.7-55.3) of patients with high-level CCP antibodies progressing to RA by 5 years. Compared to low CCP antibody level, medium (HR 3.00 [95% CI 1.32-6.81]) and high (HR 4.83 [95% CI 2.51-9.31]) CCP antibody levels were strongly associated with progression to RA, adjusting for age, sex, body mass index, smoking, family history of RA, and rheumatoid factor level. CONCLUSION:Among CCP+ patients without RA, the risk for progression to RA increased substantially with increasing CCP antibody level. This study provides further support for close monitoring for development of RA among CCP+ patients and identifying strategies to mitigate this risk.

| S-EPMC6586539 | biostudies-literature

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