Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antifilaggrin autoantibodies (AFA) are a population of IgG autoantibodies associated to rheumatoid arthritis (RA), which includes the so-called "antikeratin" Abs and antiperinuclear factor. AFA are the most specific serological markers of RA. We previously showed that they recognize human epidermal filaggrin and other profilaggrin-related proteins of various epithelial tissues. Here, we report further characterization of the protein Ags and epitopes targeted by AFA. All the Ags that exhibit numerous neutral/ acidic isoelectric variants were immunochemically demonstrated to be deiminated proteins. In vitro deimination of a recombinant human filaggrin by a peptidylarginine deiminase generated AFA epitopes on the protein. Moreover, two of three filaggrin-derived synthetic peptides with a citrulline in the central position were specifically and widely recognized by AFA affinity-purified from a series of RA sera. These results indicate that citrulline residues are constitutive of the AFA epitopes, but only in the context of specific amino acid sequences of filaggrin. In competition experiments, the two peptides abolished the AFA reactivity of RA sera, showing that they present major AFA epitopes. These data should help in the identification of a putative deiminated AFA-inducing or cross-reactive articular autoantigen and provide new insights into the pathogenesis of RA. They could also open the way toward specific immunosuppressive and/or preventive therapy of RA.
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PMID:The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. 988 36

A new autoantibody activity, which is almost 100% specific for rheumatoid arthritis (RA), has been found. The essential part of the B-cell epitope is a modified form of arginine (ie citrulline). The conversion of protein-contained arginine to citrulline is an enzymatic process that is carried out by peptidylarginine deiminase (PAD), an enzyme that appears to be hormonally controlled. Because of its remarkable specificity, citrullination and related processes might open new possibilities for studying the aetiology of RA.
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PMID:Citrullination: a small change for a protein with great consequences for rheumatoid arthritis. 1109 20

IgG antifilaggrin autoantibodies (AFA) are the most specific serological markers of rheumatoid arthritis. In epithelial tissues, they recognize citrulline-bearing epitopes present on various molecular forms of (pro)filaggrin. Histological analysis of rheumatoid synovial membranes with an Ab to citrulline showed labeling of interstitial amorphous deposits and mononuclear cells of various types. Immunochemical analysis of exhaustive sequential extracts of the same tissues showed that they contain several deiminated (citrulline containing) proteins. Among them, two proteins, p64--78 and p55--61, present in urea-DTT and guanidine extracts, were shown by immunoblotting to be specifically targeted by AFA. By amino-terminal sequencing the proteins were identified as deiminated forms of the alpha- and beta-chains of fibrin, respectively. Their identity was confirmed using several Abs specific for the A alpha- and/or to the B beta-chain of fibrin(ogen). Moreover, AFA-positive rheumatoid arthritis (RA) sera and purified AFA were highly reactive to the A alpha- and B beta-chains of human fibrinogen only after deimination of the molecules by a peptidylarginine deiminase. Autoantibodies affinity purified from a pool of RA sera onto deiminated fibrinogen were reactive toward all of the epithelial and synovial targets of AFA. This confirmed that the autoantibodies to the deiminated A alpha-and B beta-chains of fibrinogen, the autoantibodies to the synovial proteins p64--78 and p55--61, and, lastly, AFA, constitute largely overlapping autoantibody populations. These results show that deiminated forms of fibrin deposited in the rheumatoid synovial membranes are the major target of AFA. They suggest that autoimmunization against deiminated fibrin is a critical step in RA pathogenesis.
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PMID:The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. 1123 69

Early diagnosis of rheumatoid arthritis (RA) is important since aggressive therapy should begin at an early stage. Diagnosis is made on a clinical basis, supported by the determination of rheumatoid factor (RF). However, RF is also positive in healthy subjects, as well as in other autoimmune and infectious diseases. Two other diagnostic markers with a high specificity for RA, antiperinuclear factor (APF) and antikeratin antibodies (AKA), are not in general use because of technical difficulties. APF and AKA are antifilaggrin antibodies (AFA) that bind to determinants rich in the unusual amino acid citrulline, generated by posttranscriptional modification of arginine residues by the enzyme peptidylarginine deiminase (PAD). Enzymatic determination of recombinant filaggrin fragments produces linear peptides, which are recognized by RA-specific autoantibodies. After substitution of serine by cysteine, a cyclic peptide is formed. The conformational change mimics the original structure of the filaggrin and enhances the affinity of the antibodies. Recently, an anti-cyclic citrullinated peptide (anti-CCP) ELISA was developed. The sensitivity of this test is usually 51%-68%, with a specificity of about 96%-98% (significantly higher than that of RF). Together with RF, anti-CCP increases the ability to diagnose patients with early RA. The test might help to predict which patients will develop persistent disease with evidence of radiologic lesions. Implementation of the highly specific anti-CCP test in conjunction with RF would enable reliable early diagnosis in some cases and allow the initiation of aggressive therapy with disease modifying anti-rheumatic drugs (DMARDs).
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PMID:[Anti-cyclic citrullinated peptide antibodies as a diagnostic test for rheumatoid arthritis]. 1269 70

The identification of functionally relevant polymorphisms of peptidylarginine deiminase 4, an enzyme that catalyzes the post-translational citrullination of proteins, as a rheumatoid arthritis gene is one of the most convincing success stories of complex disease gene mapping to date. In addition to an extensive single nucleotide polymorphism-based association study in a Japanese cohort, a range of techniques have been used to validate this finding.
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PMID:Association of PADI4 and rheumatoid arthritis: a successful multidisciplinary approach. 1455 50

Peptidylarginine deiminase (PAD, EC 3.5.3.15) enzymes catalyze the conversion of protein-bound arginine to citrulline. This post-translational modification may have a big impact on the structure and function of the target protein. In this review, we will discuss the effects of citrullination and its involvement in several human diseases, including rheumatoid arthritis and multiple sclerosis. So far, four isotypes of PAD have been described in mammals. We describe the existence of PAD in non-mammalian vertebrates and the existence of a fifth mammalian PAD. In addition, tissue-specific expression, genomic organization and evolutionary conservation of the different PAD isotypes will be discussed in detail. This article contains supplementary material which may be viewed at the BioEssays website at http://www.interscience.wiley.com/jpages/0265-9247/suppmat/2003/25/v25.1106.html.
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PMID:PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. 1457 51

Recent studies using linkage disequilibrium and SNPs uncovered a rheumatoid arthritis (RA)-susceptible haplotype in the gene encoding peptidylarginine deiminase (PADI) type 4. This gene is one of four known PADI genes that encode enzymes to change arginine into citrulline in proteins. Post-translational modifications of proteins, including peptidyl citrullination, are related to autoimmunity, and peptidyl citrulline is a known target of one of the most RA-specific autoantibodies. Further research on PADI4, its citrullination of native peptides, subsequent breakdown of tolerance, and the role of these peptides in the development of RA, is expected to bring a better understanding of autoimmunity and arthritis, and advancements in the medical care of RA.
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PMID:Peptidylarginine deiminase type 4: identification of a rheumatoid arthritis-susceptible gene. 1460 29

Seven single nucleotide polymorphisms (SNPs) of the peptidylarginine deiminase 4 (PADI4) gene have recently been reported to be strongly associated with rheumatoid arthritis in Japanese individuals. These SNPs are located in or close to exons 2-4 of PADI4 and are organized in at least four different haplotypes. However, a detailed sequencing-based characterization of the PADI4 gene in other populations is still lacking. We therefore analyzed exons 2-4 of the PADI4 gene in 102 healthy white Germans individuals by DNA sequencing and characterized new variants and haplotypes by a novel haplotype-specific sequencing-based approach. The haplotypes 2/3 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*T, padi4_95*C, padi4_96*C), and haplotype 4 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*C, padi4_95*G, padi4_96*T) conferring susceptibility to rheumatoid arthritis were detected at frequencies of 30.9% and 7.8%, respectively. In addition, three novel coding SNPs in exons 2, 3, and 4, and three SNPs in introns 2 and 3 located near the exon-intron boundaries were identified in 11 individuals (10.8%). The so-called nonsusceptibility haplotype 1 (padi4_89*A, padi4_90*C, padi4_92*C, padi4_94*C, padi4_104*C, padi4_95*G, padi4_96*T) occurred at a frequency of 58.3%. Additionally, we identified a closely related novel haplotype, haplotype 1B (2.9%), that differs from haplotype 1 only by padi4_92*G/padi4_96*C. This haplotype was not described in the Japanese population. Our results indicate that the PADI4 gene exhibits a remarkable variability and a rather complex haplotypic organization. Further studies on disease association of PADI4 should be performed by haplotype-specific sequencing-based approaches to identify the exact genotype of the PADI4 fragment of interest.
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PMID:High variability of peptidylarginine deiminase 4 (PADI4) in a healthy white population: characterization of six new variants of PADI4 exons 2-4 by a novel haplotype-specific sequencing-based approach. 1533 34

Citrullinated proteins that are produced by enzymatic deimination of arginine residues in proteins by peptidylarginine deiminases (PADIs) are of particular interest in the pathogenesis of rheumatoid arthritis (RA). First, peptidylarginine deiminase type 4 (PADI4) gene, which codes one of the PADI enzyme isotypes, has a genetic variant that increases susceptibility to RA. The RA-susceptible variant of PADI4 seems to increase the risk of RA by increasing its enzymatic activity. Second, this post-translational protein modification unfolds proteins by loss of a positive charge in arginine residues, with a subsequent change in antigenicity of the self-proteins. Third, these citrullinated proteins are recognized by anti-citrullinated peptide antibodies that are the most RA-specific autoantibodies. Finally, the expression of the PADI enzyme, citrullination of proteins, and production of anti-citrullinated protein antibodies occur in synovium. These data suggest that citrullination of proteins by PADI is related to alteration of antigenicity of peptides and very closely linked to pathogenesis of RA autoimmunity.
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PMID:Citrullinated proteins in rheumatoid arthritis. 1557 47

Rheumatoid arthritis (RA) is the most frequent human autoimmune disease, affecting about 1% of the adult population worldwide. A better knowledge of the autoimmune mechanisms involved is essential. We identified the epithelial targets of various autoantibodies specifically associated to RA, as variants of (pro)filaggrin. We also showed that these targets correspond to deiminated ("citrullinated") proteins, of which arginyl residues have been posttranslationally transformed into citrullyl residues by a peptidylarginine deiminase (PAD). Moreover, we and others established that citrullyl residues are indispensable elements of the epitopes recognized by these autoantibodies but only in the context of specific aminoacid sequences. We also demonstrated that these autoantibodies to citrullinated proteins (ACPA) are secreted by plasma cells of the synovial tissue and that their major targets correspond to citrullinated forms of the alpha- and beta-chains of fibrin, abundant in the tissue. These results have allowed the development of new efficient immunochemical methods for the detection of ACPA. Some of them are already commercially available. These new methods have permitted the high diagnostic value of ACPA which are present very early in the course of the disease, and also their prognostic value, to be confirmed. ACPA detection should therefore prove to be also a very valuable tool to guide the choice of therapeutic strategies, from the earliest stages of the disease. The synthesis of ACPA in the rheumatoid synovial tissue and the existence therein of a specific antigenic target constitute a strong argument for the involvement of this specific immunological conflict in the pathophysiology of RA. Indeed, it could lead to activation of effector mechanisms with pro-inflammatory effects, thus to formation in the tissue of new fibrin deposits, secondarily citrullinated. We therefore, propose a new pathophysiological model accounting for the self-maintenance and chronicity of rheumatoid inflammation. Numerous questions about the pathophysiological significance of the autoimmune response to deiminated proteins in RA remain to be answered to confirm this model.
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PMID:Clinical and pathophysiological significance of the autoimmune response to citrullinated proteins in rheumatoid arthritis. 1558 29


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