Anti-citrullinated glucose-6-phosphate isomerase peptide antibodies in patients with rheumatoid arthritis are associated with <i>HLA-DRB1</i> shared epitope alleles and disease activity

Umeda, N.; Matsumoto, Isao; Ito, Ichiaki; Kawasaki, Aya; Tanaka, Yôko; Inoue, Akira; Tsuboi, Hiroto; Suzuki, Takeshi; Hayashi, Taichi; Ito, Satoshi; Tsuchiya, Naoyuki; Sumida, Takayuki

doi:10.1111/cei.12033

Cited by 17 publications

(9 citation statements)

References 37 publications

(57 reference statements)

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“…However, the presentation of intracellular citrullinated proteins in the synovium is specific for RA ( Baeten et al, 2001 ), and is colocalized with PADI2 ( De Rycke, 2005 ). Numerous well-known or suspected intracellular substrates of PADI2 and PADI4 exist, such as vimentin ( Asaga et al, 1998 ; Vossenaar et al, 2004b ), histones ( Nakashima et al, 2002 ), nucleophosmin/B23 ( Hagiwara et al, 2002 ), the F-actin capping protein alpha 1 subunit, cathepsin D, beta-actin ( Matsuo et al, 2006 ), aldolase, alpha-enolase, phosphoglyce-rate kinase 1, calreticulin, the 60-kDa heat shock protein, far upstream element-binding proteins 1 and 2 ( Goëb et al, 2009 ), glucose-6-phosphate isomerase ( Umeda et al, 2013 ), and IKKγ ( Lee et al, 2010 ). Among these, vimentin is the major citrullinated protein in human monocytic leukemia THP-1 cells during macrophage differentiation ( Hojo-Nakashima et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Vimentin Is Involved in Peptidylarginine Deiminase 2-Induced Apoptosis of Activated Jurkat Cells

Hsu¹,

Liao²,

Lin³

et al. 2014

Molecules and Cells

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Peptidylarginine deiminase type 2 (PADI2) deiminates (or citrullinates) arginine residues in protein to citrulline residues in a Ca2+-dependent manner, and is found in lymphocytes and macrophages. Vimentin is an intermediate filament protein and a well-known substrate of PADI2. Citrullinated vimentin is found in ionomycin-induced macrophage apoptosis. Citrullinated vimentin is the target of anti-Sa antibodies, which are specific to rheumatoid arthritis, and play a critical role in the pathogenesis of the disease. To investigate the role of PADI2 in apoptosis, we generated a Jurkat cell line that overexpressed the PADI2 transgene from a tetracycline-inducible promoter, and used a combination of 12-O-tetradecanoylphorbol-13-acetate and ionomycin to activate Jurkat cells. We found that PADI2 overexpression reduced the cell viability of activated Jurkat cells in a dose- and time-dependent manner. The PADI2-overexpressed and -activated Jurkat cells presented typical manifestations of apoptosis, and exhibited greater levels of citrullinated proteins, including citrullinated vimentin. Vimentin overexpression rescued a portion of the cells from apoptosis. In conclusion, PADI2 overexpression induces apoptosis in activated Jurkat cells. Vimentin is involved in PADI2-induced apoptosis. Moreover, PADI2-overexpressed Jurkat cells secreted greater levels of vimentin after activation, and expressed more vimentin on their cell surfaces when undergoing apoptosis. Through artificially highlighting PADI2 and vimentin, we demonstrated that PADI2 and vimentin participate in the apoptotic mechanisms of activated T lymphocytes. The secretion and surface expression of vimentin are possible ways of autoantigen presentation to the immune system.

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Section: Discussionmentioning

confidence: 99%

Vimentin Is Involved in Peptidylarginine Deiminase 2-Induced Apoptosis of Activated Jurkat Cells

Hsu¹,

Liao²,

Lin³

et al. 2014

Molecules and Cells

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“…In striking contrast, because only a very small proportion of patients with UA (<5%) displays anti-CEP-1 antibodies, their usefulness in predicting RA development is negligible [54,55]. Glucose-6-phosphate isomerase (GPI) is another glycolytic enzyme, and antibodies against citrullinated-GPI, targeting different epitopes, have been described in RA [56]. However, when compared to anti-CCP, anti-MCV and anti-AKA, they display a poor specificity (<70%) [30].…”

Section: Antibodies Against Citrullinated Proteins (Acpa)mentioning

confidence: 99%

“…It is worth mentioning that also some isoforms of PADs, the enzymes catalyzing citrullination, may represent a target antigen for auto-Abs in RA [63,64]. Anti-PAD4 Abs are mainly present in anti-CCP positive patients and display a sensitivity ranging from 24% to 37% and a specificity of 95%–100% [47,56,65,66,67], while anti-PAD3 display a very poor sensitivity with a specificity of around 88% [56,67,68]. To note, a subset of anti-PAD3 antibodies cross-reacts with anti-PAD4, and this has been associated with a specific clinical picture as outlined in the next paragraph.…”

Section: Antibodies Against Citrullinated Proteins (Acpa)mentioning

confidence: 99%

Post-Translational Modifications of Proteins: Novel Insights in the Autoimmune Response in Rheumatoid Arthritis

Carubbi

Alunno

Gerli

et al. 2019

Cells

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Post-translational modifications (PTM) are chemical changes mostly catalyzed by enzymes that recognize specific target sequences in specific proteins. These modifications play a key role in regulating the folding of proteins, their targeting to specific subcellular compartments, their interaction with ligands or other proteins, and eventually their immunogenic properties. Citrullination is the best characterized PTM in the field of rheumatology, with antibodies anticyclic citrullinated peptides being the gold standard for the diagnosis of rheumatoid arthritis (RA). In recent years, growing evidence supports not only that a wide range of proteins are subject to citrullination and can trigger an autoimmune response in RA, but also that several other PTMs such as carbamylation and acetylation occur in patients with this disease. This induces a wide spectrum of autoantibodies, as biomarkers, with different sensitivity and specificity for diagnosis, which may be linked to peculiar clinical manifestations and/or response to treatment. The purpose of this review article is to critically summarize the available literature on antibodies against post-translationally modified proteins, in particular antibodies against citrullinated proteins (ACPA) and antibodies against modified proteins (AMPA), and outline their diagnostic and prognostic role to be implemented in clinical practice for RA patients.

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“…ACPA recognize various citrullinated proteins, such as vimentin, α-enolase, fibrinogen, fibronectin, and glucose-6-phosphate isomerase (GPI) [ 2 , 4 ]. High levels of citrullinated proteins have been found in RA joints [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel biomarker as citrullinated inter-alpha-trypsin inhibitor heavy chain 4, specifically increased in sera with experimental and rheumatoid arthritis

et al. 2018

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BackgroundAnticitrullinated protein antibodies (ACPA) and citrullinated proteins play key roles in the pathogenesis of rheumatoid arthritis (RA). Many candidate citrullinated antigens have been identified in joints, but citrullinated proteins in sera are mostly uncertain in patients with RA. We explored the expression of citrullinated proteins in joints and sera of experimental arthritis, and we further investigated their specific expression correlated with the disease activity in patients with RA.MethodsCitrullinated protein expression in tissues was examined by IHC in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA). Serum citrullinated proteins from pGIA were examined by Western blotting, and the sequence was identified by MS. With the same methods, serum citrullinated proteins were analyzed in patients with RA, primary Sjögren’s syndrome, systemic lupus erythematosus, and osteoarthritis as well as in healthy subjects, by Western blotting and MS. In patients with RA, the relationship between the expression of the identified protein (inter-alpha-trypsin inhibitor heavy chain 4 [ITIH4]) and clinical features was evaluated, and the levels of citrullinated ITIH4 were compared before and after biological treatment. The antibody response against citrullinated ITIH4 peptide was measured by enzyme-linked immunosorbent assay.ResultsCitrullinated proteins were detected specifically in arthritic joints and sera from pGIA relative to controls. In sera, a common band of citrullinated protein at 120 kDa was revealed, and it fluctuated in parallel with arthritis score of pGIA by Western blotting. Interestingly, in 82% of RA patient sera, similar bands of citrullinated protein were specifically detected. These proteins were identified as citrullinated ITIH4, and especially the R438 site was commonly citrullinated between mice and humans. Citrullinated ITIH4 levels were associated with clinical parameters such as C-reactive protein (CRP), rheumatoid factor, and Disease Activity Score in 28 joints as measured by CRP in patients with RA. Its levels were decreased in correlation with the reduction of disease activity score after effective treatment in patients with RA. Moreover, antibody response to citrullinated epitope in ITIH4 was specifically observed in patients with RA.ConclusionsOur results suggest that serum citrullinated ITIH4 was specifically increased in patients with RA and could be a novel biomarker for assessing disease activity in patients with RA.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1562-7) contains supplementary material, which is available to authorized users.

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Anti-citrullinated glucose-6-phosphate isomerase peptide antibodies in patients with rheumatoid arthritis are associated with HLA-DRB1 shared epitope alleles and disease activity

Cited by 17 publications

References 37 publications

Vimentin Is Involved in Peptidylarginine Deiminase 2-Induced Apoptosis of Activated Jurkat Cells

Vimentin Is Involved in Peptidylarginine Deiminase 2-Induced Apoptosis of Activated Jurkat Cells

Post-Translational Modifications of Proteins: Novel Insights in the Autoimmune Response in Rheumatoid Arthritis

Identification of novel biomarker as citrullinated inter-alpha-trypsin inhibitor heavy chain 4, specifically increased in sera with experimental and rheumatoid arthritis

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