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The immune response to citrullinated antigens in autoimmune diseases
Autoimmunity Reviews 4 (2005) 561 – 564 www.elsevier.com/locate/autrev
The immune response to citrullinated antigens in autoimmune diseases P. Migliorini*, F. Pratesi, C. Tommasi, C. Anzilotti Clinical Immunology Unit, Department of Internal Medicine, University of Pisa, Italy Available online 10 May 2005
Abstract Post-translational modifications of proteins occur very frequently. One of these modifications, citrullination, is the result of arginine deimination operated by an enzyme, peptidylarginine deiminase (PAD), whose activity is under strict genetic control. Serum antibodies reactive with citrullinated proteins/peptides are a very sensitive and specific marker for rheumatoid arthritis. Genes encoding for PAD enzymes have been investigated in RA: the PADI4 gene confers susceptibility to RA in Japanese patients, but not in Caucasians. D 2005 Elsevier B.V. All rights reserved. Keywords: Deimination; Citrullinated peptides; PAD
Contents Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Post-translational modifications are very frequent in mammalian proteins, affecting different aminoacids and occurring spontaneously or as the result of enzymatic activity; they are crucial for a number of basic cell functions and also modify the antigenicity of proteins. In fact, post-translationally modified proteins may be differently susceptible to proteolytic cleavage during processing and thus generate a new set of * Corresponding author. E-mail address: [email protected] (P. Migliorini). 1568-9972/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2005.04.007
563 563
peptides able to associate with MHC molecules and induce a T cell response. Alternatively, sequences containing the modified aminoacids may be the target of autoantibodies. A well known post-translational modification is citrullination (or deimination) that is the conversion of arginine residues of proteins into citrulline via the hydrolyzation of the guanido group of arginine giving an ureido group and free ammonia. Citrullination became of interest in autoimmunity when it explained the specificity of two closely asso-
562
P. Migliorini et al. / Autoimmunity Reviews 4 (2005) 561–564
ciated autoantibodies, anti-keratin autoantibodies (AKA) and anti-perinuclear factor (APF). These autoantibodies constitute a specific diagnostic marker of rheumatoid arthritis, which may even precede the onset of the disease and can be found in patients at the initial presentation of the clinical symptoms. Originally considered independent, they were later found to be largely overlapping: their common target is in fact deiminated filaggrin [1–4]. A comparative evaluation of sequences recognized by anti-filaggrin antibodies shows that a critical feature is the presence of citrulline flanked by neutral aminoacids such as glycine, serine or threonin. Similar aminoacid repeats are commonly found in viral proteins [5]. EBNA I, one of the nuclear proteins encoded by Epstein–Barr Virus, whose relationship with RA is still being debated, is characterized by a region (aa 35–58) containing a sixfold Arg–Gly repeat. We tested the hypothesis that deimination of viral sequences containing Arg–Gly repeats could generate epitopes recognized by ACPA. To such extent, we synthesized multiple antigen peptides derived from EBNA I in which a different number of arginines were substituted with citrulline. RA sera were tested on these peptides: the highest binding was obtained when all arginine residues of the 35–58 sequence were substituted with citrulline. Antibodies specific for this peptide were detected in 50% RA sera and in less than 5% normals or disease controls (Pratesi et al., submitted). The enzyme responsible for the conversion of arginine residues into citrulline residues, peptidylarginine deiminase (PAD), has been detected in a wide number of mammalian tissues. cDNA cloning analysis revealed the existence of 5 isoforms in rodents: PAD I expressed in the mouse uterus and epidermis [6] as in the rat epidermis and stomach [7], PAD III in the epidermis and the hair follicles [8], PAD II and PAD IV in stomach, skeletal muscle, salivary glands and in other various tissues [9,10], and PAD VI [11]. As far as the human PAD is concerned, 4 types of the enzyme has been cloned: PAD I [12], PAD II [13], PAD III [14] and PAD V, which is most closely related to the rodent PAD IV [15] and is now named PAD IV. PAD I has been detected in epidermis, PAD II in sweat glands PAD III in hair follicles, while PAD IV has been localised in precursors of macrophages and neu-
trophils and PAD VI in the ovary, testis and peripheral blood leukocytes [16]. The genome-wide linkage study of RA sibpairs conducted in 1998 by the European Consortium for Rheumatoid Arthritis Families (ECRAF) [17] showed suggestive linkage evidence near the locus coding for PAD V (PADI4 locus) and more recently refined analysis confirmed the linkage. In a case-control study, Suzuki et al. found that 8 of 17 SNPs in the PADI4 gene are strongly associated with RA and one haplotype frequently represented in the Japanese population confers susceptibility to the disease [18]. The authors also showed that the stability of the susceptible gene transcripts is higher than that of the non-susceptible ones. On this basis they suggested that the increased stability of the PADI4 mRNA transcripts may lead to the production of a higher amount of enzyme and subsequently to a more extensive protein deimination. We tested the hypothesis that the PADI4 gene may similarly confer susceptibility to RA in a French Caucasian population analyzing 100 French Caucasian trio families composed of one affected subject and the two parents, by powerful and highly reliable family-based association tests. We selected 3 SNPs (PADI4_92, PADI4_96, PADI4_102) that allowed us to describe the 4 haplotypes detected in the Japanese population and also analysed 2 SNPs located very close to one another in the 5V region of the gene. These 5 markers were typed by PCR-RFLP in the 100 RA patients and in their parents: they were not associated with the disease, nor were preferentially transmitted by the TDT and GRR tests. The analysis of the haplotypes showed that six of them have a frequency higher than 5% in our population. No haplotype was associated with the disease by any of the statistical tests used. In particular, despite its similar frequency, the haplotype associated with RA in the Japanese population was not associated with RA in the French Caucasians [19]. Similar negative results were recently reported by another group in the UK that performed a case-control study on 839 RA patients and 481 controls [20]. No association of RA with either a single SNP or haplotypes of the PADI4 gene was detected, even when the patients were stratified according to markers of disease severity or to the presence of the shared epitope.
P. Migliorini et al. / Autoimmunity Reviews 4 (2005) 561–564
Moreover, in 438 inflammatory polyarthritis patients no association between individual PADI4 SNPs or haplotypes and the development or extent of erosions by 5 years was detected [21]. This discrepancy between the studies conducted in different populations by no means negates the importance of the PAD genes in RA, but indicates that other genetic factors such as those affecting tissue-specific expression and/or enzyme activity of PADs should also be investigated.
Take-home messages ! Anti-citrullinated peptides antibodies are a marker of rheumatoid arthritis ! The enzyme responsible for citrullination of proteins is peptidylarginine deiminase (PAD) ! The gene encoding for one of PAD isoforms (PADI4) confers susceptibility to rheumatoid arthritis in a Japanese population, but not in Caucasians.
References [1] Girbal E, Sebbag M, Gomes-Daudrix V, Simon M, Vincent C, Serre G. Characterisation of the rat oesophagus epithelium antigens defined by the so-called dantikeratin antibodiesT, specific for rheumatoid arthritis. Ann Rheum Dis 1993;52: 749 – 57. [2] Simon M, Girbal E, Sebbag M, Gomes-Daudrix V, Vincent C, Salama G, et al. The cytokeratin filament-aggregating protein filaggrin is the target of the so-called bantikeratin antibodies,Q autoantibodies specific for rheumatoid arthritis. J Clin Invest 1993;92:1387 – 93. [3] Sebbag M, Simon M, Vincent C, Masson-Bessiere C, Girbal E, Durieux JJ, et al. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J Clin Invest 1995;95: 2672 – 9. [4] Girbal-Neuhauser E, Durieux JJ, Arnaud M, Dalbon P, Sebbag M, Vincent C, et al. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol 1999;162: 585 – 94. [5] Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998;101: 273 – 81.
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[6] Rus’d AA, Ikejiri Y, Ono H, Yonekawa T, Shiraiwa M, Kawada A, et al. Molecular cloning of cDNAs of mouse peptidylarginine deiminase type I, type III and type IV, and the expression pattern of type I in mouse. Eur J Biochem 1999;259(3):660 – 9. [7] Ishigami A, Asaga H, Ohsawa T, Akiyama K, Maruyama N. Peptydilarginine deiminase type I, type II, type III and type IV, are expressed in rat epidermis. Biomed Res 2001;22: 63 – 5. [8] Nishijyo T, Kawada A, Kanno T, Shiraiwa M, Takahara H. Isolation and molecular cloning of epidermal- and hair follicle-specific peptidylarginine deiminase (type III) from rat. J Biochem 1997;121(5):868 – 75. [9] Yamakoshi A, Ono H, Nishijyo T, Shiraiwa M, Takahara H. Cloning of cDNA encoding a novel isoform (type IV) of peptidylarginine deiminase from rat epidermis. Biochim Biophys Acta 1998;1386(1):227 – 32. [10] Watanabe K, Senshu T. Isolation and characterization of cDNA clones encoding rat skeletal muscle peptidylarginine deiminase. J Biol Chem 1989;264(26):15255 – 60. [11] Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. BioEssays 2003;25: 1106 – 18. [12] Guerrin M, Ishigami A, Mechin MC, Nachat R, Valmary S, Sebbag M, et al. cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type I. Biochem J 2003;370(1):167 – 74. [13] Ishigami A, Ohsawa T, Asaga H, Akiyama K, Kuramoto M, Maruyama N. Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin. Arch Biochem Biophys 2002;407:25 – 31. [14] Kanno T, Kawada A, Yamanouchi J, Yosida-Noro C, Yoshiki A, Shiraiwa M, et al. Human peptidylarginine deiminase type III: molecular cloning and nucleotide sequence of the cDNA, properties of the recombinant enzyme, and immunohistochemical localization in human skin. J Invest Dermatol 2000;115:813 – 23. [15] Nakashima K, Hagiwara T, Ishigami A, Nagata S, Asaga H, Kuramoto M, et al. Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3). J Biol Chem 1999;274: 27786 – 92. [16] Chavanas S, Me´chin MC, Takahara H, Kawada A, Nachat N, Serre G, et al. Comparative analysis of the mouse and human peptidylarginine deiminase gene (PADI) clusters reveals highly conserved non-coding segments and a new human gene, PADI6. Gene 2004;330:19 – 27. [17] Cornelis F, Faure S, Martinez M, Prud’homme JF, Fritz P, Dib Cet, et al. New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Proc Natl Acad Sci U S A 1998;95(18):10746 – 50. [18] Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003;34: 395 – 402.
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P. Migliorini et al. / Autoimmunity Reviews 4 (2005) 561–564
[19] Caponi L, Petit-Teixeira E, Sebbag M, Bongiorni F, Moscato S, Pratesi F, et al. A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann Rheum Dis 2005; 64:587 – 93. [20] Barton A, Bowes J, Eyre S, Spreckley K, Hinks A, John S, et al. Functional haplotype of the PADI4 gene associated with
rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum 2004; 50(4):1117 – 21. [21] Barton A, Bowes J, Eyre S, Symmons D, Worthington J, Silman A. Investigation of polymorphisms in the PADI4 gene in determining severity of inflammatory polyarthritis. Ann Rheum Dis in press.
Modulation of the immune response in pristane-induced lupus by expression of activation and inhibitory Fc. FcgammaRI and III are required for immune complexes to activate inflammatory cells, thereby inciting tissue injury. In contrast, FcgammaRIIB functions as a negative regulator of immune complex-mediated inflammation and autoantibody production. Clynes R. et. al. (Clin Exp Immunol 2005; 141:230-7) investigated the role of FcgammaRI/III vs FcgammaRIIB on pristane-induced lupus in mice. FcgammaRI/III and FcgammaRIIBdeficient (-/-) and control (+/+) BALB/c mice were injected with either pristine or PBS. Proteinuria and glomerular immune deposits were evaluated 9 months after treatment and serial sera were analyzed for total IgG levels and lupus-specific autoantibodies. The incidence of nephritis was higher in pristane-treated FcgammaRIIB (-/-) mice than pristane FcgammaRI/III (-/-) and (+/+) mice. Hypergammaglobulinemia and spontaneous anti-DNA/chromatin autoantibody production were associated with interleukin (IL)-6 over-expression in FcgammaRIIB (-/-) mice and were augmented further by pristane treatment when compared to both FcgammaRI/III (-/-) and (+/+) mice. These results confirm that spontaneous autoimmunity occurs in the absence of FcgammaRIIB. Moreover, the lupus- like syndrome induced by pristane in BALB/c mice was regulated by opposing activating and inhibitory FcgammaRs. FcgammaRIIB may be a key modulator that suppresses cell activation in the inflammatory immune response in SLE in humans.
Longitudinal fluctuation of antibodies to extractable nuclear antigens in systemic lupus erythematosus. The aim of this study was to examine the appearance, persistence, and disappearance of anti-extractable nuclear antigen (ENA, Sm, U1-RNP, Ro/SSA, and La/SSB) and anti-ds DNA antibodies during SLE follow-up. Faria AC. et. al. (J Rheumatol 2005; 32: 1267-72) retrospectively selected one hundred and thirty patients who fulfilled ACR classification criteria for SLE with at least 5 yearly autoantibody tests between 1987-2002. Antibodies to Ro/SSA were present in 47%, U1-RNP in 36%, DNA in 32%, Sm in 23%, and La/SSB in 7% of the patients. Among patients ever positive for a given autoantibody, the frequency of the "always present" pattern was 52% for anti-Ro/SSA, 38% for U1-RNP, 17% for Sm, 11% for La/SSB, and 9% for DNA antibodies; the frequency of positive seroconversion was 56% for anti-La/SSB, 33% for DNA, 26% for Sm, 21% for U1-RNP, and 15% for Ro/SSA. Time to positive seroconversion varied from 1 to 8 years after diagnosis. Antibody data pattern frequency differed significantly among autoantibody specificities except between anti-U1-RNP and Ro/SSA (p = 0.15) and between anti-dsDNA and Sm autoantibodies (p = 0.29). The high frequency of longitudinal fluctuation in anti-ENA antibodies suggests that a periodic reappraisal may be appropriate in seronegative patients with a suspected diagnosis of SLE. The clinical significance of such fluctuation deserves future study.
The immune response to citrullinated antigens in autoimmune diseases P. Migliorini*, F. Pratesi, C. Tommasi, C. Anzilotti Clinical Immunology Unit, Department of Internal Medicine, University of Pisa, Italy Available online 10 May 2005
Abstract Post-translational modifications of proteins occur very frequently. One of these modifications, citrullination, is the result of arginine deimination operated by an enzyme, peptidylarginine deiminase (PAD), whose activity is under strict genetic control. Serum antibodies reactive with citrullinated proteins/peptides are a very sensitive and specific marker for rheumatoid arthritis. Genes encoding for PAD enzymes have been investigated in RA: the PADI4 gene confers susceptibility to RA in Japanese patients, but not in Caucasians. D 2005 Elsevier B.V. All rights reserved. Keywords: Deimination; Citrullinated peptides; PAD
Contents Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Post-translational modifications are very frequent in mammalian proteins, affecting different aminoacids and occurring spontaneously or as the result of enzymatic activity; they are crucial for a number of basic cell functions and also modify the antigenicity of proteins. In fact, post-translationally modified proteins may be differently susceptible to proteolytic cleavage during processing and thus generate a new set of * Corresponding author. E-mail address: [email protected] (P. Migliorini). 1568-9972/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2005.04.007
563 563
peptides able to associate with MHC molecules and induce a T cell response. Alternatively, sequences containing the modified aminoacids may be the target of autoantibodies. A well known post-translational modification is citrullination (or deimination) that is the conversion of arginine residues of proteins into citrulline via the hydrolyzation of the guanido group of arginine giving an ureido group and free ammonia. Citrullination became of interest in autoimmunity when it explained the specificity of two closely asso-
562
P. Migliorini et al. / Autoimmunity Reviews 4 (2005) 561–564
ciated autoantibodies, anti-keratin autoantibodies (AKA) and anti-perinuclear factor (APF). These autoantibodies constitute a specific diagnostic marker of rheumatoid arthritis, which may even precede the onset of the disease and can be found in patients at the initial presentation of the clinical symptoms. Originally considered independent, they were later found to be largely overlapping: their common target is in fact deiminated filaggrin [1–4]. A comparative evaluation of sequences recognized by anti-filaggrin antibodies shows that a critical feature is the presence of citrulline flanked by neutral aminoacids such as glycine, serine or threonin. Similar aminoacid repeats are commonly found in viral proteins [5]. EBNA I, one of the nuclear proteins encoded by Epstein–Barr Virus, whose relationship with RA is still being debated, is characterized by a region (aa 35–58) containing a sixfold Arg–Gly repeat. We tested the hypothesis that deimination of viral sequences containing Arg–Gly repeats could generate epitopes recognized by ACPA. To such extent, we synthesized multiple antigen peptides derived from EBNA I in which a different number of arginines were substituted with citrulline. RA sera were tested on these peptides: the highest binding was obtained when all arginine residues of the 35–58 sequence were substituted with citrulline. Antibodies specific for this peptide were detected in 50% RA sera and in less than 5% normals or disease controls (Pratesi et al., submitted). The enzyme responsible for the conversion of arginine residues into citrulline residues, peptidylarginine deiminase (PAD), has been detected in a wide number of mammalian tissues. cDNA cloning analysis revealed the existence of 5 isoforms in rodents: PAD I expressed in the mouse uterus and epidermis [6] as in the rat epidermis and stomach [7], PAD III in the epidermis and the hair follicles [8], PAD II and PAD IV in stomach, skeletal muscle, salivary glands and in other various tissues [9,10], and PAD VI [11]. As far as the human PAD is concerned, 4 types of the enzyme has been cloned: PAD I [12], PAD II [13], PAD III [14] and PAD V, which is most closely related to the rodent PAD IV [15] and is now named PAD IV. PAD I has been detected in epidermis, PAD II in sweat glands PAD III in hair follicles, while PAD IV has been localised in precursors of macrophages and neu-
trophils and PAD VI in the ovary, testis and peripheral blood leukocytes [16]. The genome-wide linkage study of RA sibpairs conducted in 1998 by the European Consortium for Rheumatoid Arthritis Families (ECRAF) [17] showed suggestive linkage evidence near the locus coding for PAD V (PADI4 locus) and more recently refined analysis confirmed the linkage. In a case-control study, Suzuki et al. found that 8 of 17 SNPs in the PADI4 gene are strongly associated with RA and one haplotype frequently represented in the Japanese population confers susceptibility to the disease [18]. The authors also showed that the stability of the susceptible gene transcripts is higher than that of the non-susceptible ones. On this basis they suggested that the increased stability of the PADI4 mRNA transcripts may lead to the production of a higher amount of enzyme and subsequently to a more extensive protein deimination. We tested the hypothesis that the PADI4 gene may similarly confer susceptibility to RA in a French Caucasian population analyzing 100 French Caucasian trio families composed of one affected subject and the two parents, by powerful and highly reliable family-based association tests. We selected 3 SNPs (PADI4_92, PADI4_96, PADI4_102) that allowed us to describe the 4 haplotypes detected in the Japanese population and also analysed 2 SNPs located very close to one another in the 5V region of the gene. These 5 markers were typed by PCR-RFLP in the 100 RA patients and in their parents: they were not associated with the disease, nor were preferentially transmitted by the TDT and GRR tests. The analysis of the haplotypes showed that six of them have a frequency higher than 5% in our population. No haplotype was associated with the disease by any of the statistical tests used. In particular, despite its similar frequency, the haplotype associated with RA in the Japanese population was not associated with RA in the French Caucasians [19]. Similar negative results were recently reported by another group in the UK that performed a case-control study on 839 RA patients and 481 controls [20]. No association of RA with either a single SNP or haplotypes of the PADI4 gene was detected, even when the patients were stratified according to markers of disease severity or to the presence of the shared epitope.
P. Migliorini et al. / Autoimmunity Reviews 4 (2005) 561–564
Moreover, in 438 inflammatory polyarthritis patients no association between individual PADI4 SNPs or haplotypes and the development or extent of erosions by 5 years was detected [21]. This discrepancy between the studies conducted in different populations by no means negates the importance of the PAD genes in RA, but indicates that other genetic factors such as those affecting tissue-specific expression and/or enzyme activity of PADs should also be investigated.
Take-home messages ! Anti-citrullinated peptides antibodies are a marker of rheumatoid arthritis ! The enzyme responsible for citrullination of proteins is peptidylarginine deiminase (PAD) ! The gene encoding for one of PAD isoforms (PADI4) confers susceptibility to rheumatoid arthritis in a Japanese population, but not in Caucasians.
References [1] Girbal E, Sebbag M, Gomes-Daudrix V, Simon M, Vincent C, Serre G. Characterisation of the rat oesophagus epithelium antigens defined by the so-called dantikeratin antibodiesT, specific for rheumatoid arthritis. Ann Rheum Dis 1993;52: 749 – 57. [2] Simon M, Girbal E, Sebbag M, Gomes-Daudrix V, Vincent C, Salama G, et al. The cytokeratin filament-aggregating protein filaggrin is the target of the so-called bantikeratin antibodies,Q autoantibodies specific for rheumatoid arthritis. J Clin Invest 1993;92:1387 – 93. [3] Sebbag M, Simon M, Vincent C, Masson-Bessiere C, Girbal E, Durieux JJ, et al. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J Clin Invest 1995;95: 2672 – 9. [4] Girbal-Neuhauser E, Durieux JJ, Arnaud M, Dalbon P, Sebbag M, Vincent C, et al. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol 1999;162: 585 – 94. [5] Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998;101: 273 – 81.
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[6] Rus’d AA, Ikejiri Y, Ono H, Yonekawa T, Shiraiwa M, Kawada A, et al. Molecular cloning of cDNAs of mouse peptidylarginine deiminase type I, type III and type IV, and the expression pattern of type I in mouse. Eur J Biochem 1999;259(3):660 – 9. [7] Ishigami A, Asaga H, Ohsawa T, Akiyama K, Maruyama N. Peptydilarginine deiminase type I, type II, type III and type IV, are expressed in rat epidermis. Biomed Res 2001;22: 63 – 5. [8] Nishijyo T, Kawada A, Kanno T, Shiraiwa M, Takahara H. Isolation and molecular cloning of epidermal- and hair follicle-specific peptidylarginine deiminase (type III) from rat. J Biochem 1997;121(5):868 – 75. [9] Yamakoshi A, Ono H, Nishijyo T, Shiraiwa M, Takahara H. Cloning of cDNA encoding a novel isoform (type IV) of peptidylarginine deiminase from rat epidermis. Biochim Biophys Acta 1998;1386(1):227 – 32. [10] Watanabe K, Senshu T. Isolation and characterization of cDNA clones encoding rat skeletal muscle peptidylarginine deiminase. J Biol Chem 1989;264(26):15255 – 60. [11] Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. BioEssays 2003;25: 1106 – 18. [12] Guerrin M, Ishigami A, Mechin MC, Nachat R, Valmary S, Sebbag M, et al. cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type I. Biochem J 2003;370(1):167 – 74. [13] Ishigami A, Ohsawa T, Asaga H, Akiyama K, Kuramoto M, Maruyama N. Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin. Arch Biochem Biophys 2002;407:25 – 31. [14] Kanno T, Kawada A, Yamanouchi J, Yosida-Noro C, Yoshiki A, Shiraiwa M, et al. Human peptidylarginine deiminase type III: molecular cloning and nucleotide sequence of the cDNA, properties of the recombinant enzyme, and immunohistochemical localization in human skin. J Invest Dermatol 2000;115:813 – 23. [15] Nakashima K, Hagiwara T, Ishigami A, Nagata S, Asaga H, Kuramoto M, et al. Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3). J Biol Chem 1999;274: 27786 – 92. [16] Chavanas S, Me´chin MC, Takahara H, Kawada A, Nachat N, Serre G, et al. Comparative analysis of the mouse and human peptidylarginine deiminase gene (PADI) clusters reveals highly conserved non-coding segments and a new human gene, PADI6. Gene 2004;330:19 – 27. [17] Cornelis F, Faure S, Martinez M, Prud’homme JF, Fritz P, Dib Cet, et al. New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Proc Natl Acad Sci U S A 1998;95(18):10746 – 50. [18] Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003;34: 395 – 402.
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P. Migliorini et al. / Autoimmunity Reviews 4 (2005) 561–564
[19] Caponi L, Petit-Teixeira E, Sebbag M, Bongiorni F, Moscato S, Pratesi F, et al. A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Ann Rheum Dis 2005; 64:587 – 93. [20] Barton A, Bowes J, Eyre S, Spreckley K, Hinks A, John S, et al. Functional haplotype of the PADI4 gene associated with
rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum 2004; 50(4):1117 – 21. [21] Barton A, Bowes J, Eyre S, Symmons D, Worthington J, Silman A. Investigation of polymorphisms in the PADI4 gene in determining severity of inflammatory polyarthritis. Ann Rheum Dis in press.
Modulation of the immune response in pristane-induced lupus by expression of activation and inhibitory Fc. FcgammaRI and III are required for immune complexes to activate inflammatory cells, thereby inciting tissue injury. In contrast, FcgammaRIIB functions as a negative regulator of immune complex-mediated inflammation and autoantibody production. Clynes R. et. al. (Clin Exp Immunol 2005; 141:230-7) investigated the role of FcgammaRI/III vs FcgammaRIIB on pristane-induced lupus in mice. FcgammaRI/III and FcgammaRIIBdeficient (-/-) and control (+/+) BALB/c mice were injected with either pristine or PBS. Proteinuria and glomerular immune deposits were evaluated 9 months after treatment and serial sera were analyzed for total IgG levels and lupus-specific autoantibodies. The incidence of nephritis was higher in pristane-treated FcgammaRIIB (-/-) mice than pristane FcgammaRI/III (-/-) and (+/+) mice. Hypergammaglobulinemia and spontaneous anti-DNA/chromatin autoantibody production were associated with interleukin (IL)-6 over-expression in FcgammaRIIB (-/-) mice and were augmented further by pristane treatment when compared to both FcgammaRI/III (-/-) and (+/+) mice. These results confirm that spontaneous autoimmunity occurs in the absence of FcgammaRIIB. Moreover, the lupus- like syndrome induced by pristane in BALB/c mice was regulated by opposing activating and inhibitory FcgammaRs. FcgammaRIIB may be a key modulator that suppresses cell activation in the inflammatory immune response in SLE in humans.
Longitudinal fluctuation of antibodies to extractable nuclear antigens in systemic lupus erythematosus. The aim of this study was to examine the appearance, persistence, and disappearance of anti-extractable nuclear antigen (ENA, Sm, U1-RNP, Ro/SSA, and La/SSB) and anti-ds DNA antibodies during SLE follow-up. Faria AC. et. al. (J Rheumatol 2005; 32: 1267-72) retrospectively selected one hundred and thirty patients who fulfilled ACR classification criteria for SLE with at least 5 yearly autoantibody tests between 1987-2002. Antibodies to Ro/SSA were present in 47%, U1-RNP in 36%, DNA in 32%, Sm in 23%, and La/SSB in 7% of the patients. Among patients ever positive for a given autoantibody, the frequency of the "always present" pattern was 52% for anti-Ro/SSA, 38% for U1-RNP, 17% for Sm, 11% for La/SSB, and 9% for DNA antibodies; the frequency of positive seroconversion was 56% for anti-La/SSB, 33% for DNA, 26% for Sm, 21% for U1-RNP, and 15% for Ro/SSA. Time to positive seroconversion varied from 1 to 8 years after diagnosis. Antibody data pattern frequency differed significantly among autoantibody specificities except between anti-U1-RNP and Ro/SSA (p = 0.15) and between anti-dsDNA and Sm autoantibodies (p = 0.29). The high frequency of longitudinal fluctuation in anti-ENA antibodies suggests that a periodic reappraisal may be appropriate in seronegative patients with a suspected diagnosis of SLE. The clinical significance of such fluctuation deserves future study.