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PAD Activation in Arthritis

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Protein Deimination in Human Health and Disease

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Abstract

The findings that citrullinated proteins are targeted by the most specific immune response in rheumatoid arthritis, and that citrullination also plays an important role in neurodegenerative diseases and certain cancers, have triggered many researchers to study various aspects of this form of posttranslational modification. This chapter is focused on the conditions that are needed for peptidylarginine deiminases to become active citrullinating enzymes, in particular in relation to joint inflammation as observed in rheumatoid arthritis. After briefly discussing the available methods to study the activity of peptidylarginine deiminases and their substrate specificity, the isoforms that are most relevant for citrullination during inflammation and the factors that are mediating their activation are addressed. Citrullination is crucial for one of the processes that are tightly associated with inflammation, NETosis, which is more extensively discussed in Chap. 8. Finally, peptidylarginine deiminase activation and the resulting citrullination in the context of the inflamed joints in rheumatoid arthritis are described.

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References

  • Arandjelovic, S., McKenney, K. R., Leming, S. S., & Mowen, K. A. (2012). ATP induces protein arginine deiminase 2-dependent citrullination in mast cells through the P2X7 purinergic receptor. Journal of Immunology, 189(8), 4112–4122.

    Article  CAS  Google Scholar 

  • Arita, K., Hashimoto, H., Shimizu, T., Nakashima, K., Yamada, M., & Sato, M. (2004). Structural basis for Ca(2+)-induced activation of human PAD4. Nature Structural & Molecular Biology, 11(8), 777–783.

    Article  CAS  Google Scholar 

  • Asaga, H., Nakashima, K., Senshu, T., Ishigami, A., & Yamada, M. (2001). Immunocytochemical localization of peptidylarginine deiminase in human eosinophils and neutrophils. Journal of Leukocyte Biology, 70(1), 46–51.

    CAS  PubMed  Google Scholar 

  • Assohou-Luty, C., Raijmakers, R., Benckhuijsen, W. E., Stammen-Vogelzangs, J., de, R. A., van Veelen, P. A., Franken, K. L., Drijfhout, J. W., & Pruijn, G. J. (2014). The human peptidylarginine deiminases type 2 and type 4 have distinct substrate specificities. Biochimica et Biophysica Acta, 1844(4), 829–836.

    Article  CAS  PubMed  Google Scholar 

  • Badillo-Soto, M. A., Rodríguez-Rodríguez, M., Pérez-Pérez, M. E., Daza-Benitez, L., Bollain-y-Goytia, J. J., Carrillo-Jiménez, M. A., Avalos-Díaz, E., & Herrera-Esparza, R. (2016). Potential protein targets of the peptidylarginine deiminase 2 and peptidylarginine deiminase 4 enzymes in rheumatoid synovial tissue and its possible meaning. European Journal of Rheumatology, 3(2), 44–49. doi:10.5152/eurjrheum.2015.0055.

    PubMed  PubMed Central  Google Scholar 

  • Barton, A., Bowes, J., Eyre, S., Spreckley, K., Hinks, A., John, S., & Worthington, J. (2004). A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis and Rheumatism, 50(4), 1117–1121.

    Article  CAS  PubMed  Google Scholar 

  • Begovich, A. B., Carlton, V. E., Honigberg, L. A., Schrodi, S. J., Chokkalingam, A. P., Alexander, H. C., Ardlie, K. G., Huang, Q., Smith, A. M., Spoerke, J. M., Conn, M. T., Chang, M., Chang, S. Y., Saiki, R. K., Catanese, J. J., Leong, D. U., Garcia, V. E., McAllister, L. B., Jeffery, D. A., Lee, A. T., Batliwalla, F., Remmers, E., Criswell, L. A., Seldin, M. F., Kastner, D. L., Amos, C. I., Sninsky, J. J., & Gregersen, P. K. (2004). A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. American Journal of Human Genetics, 75(2), 330–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bicker, K. L., Subramanian, V., Chumanevich, A. A., Hofseth, L. J., & Thompson, P. R. (2012). Seeing citrulline: Development of a phenylglyoxal-based probe to visualize protein citrullination. Journal of the American Chemical Society, 134(41), 17015–17018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bjelle, A., Norberg, B., & Sjogren, G. (1982). The cytology of joint exudates in rheumatoid arthritis. Morphology and preparation techniques. Scandinavian Journal of Rheumatology, 11(2), 124–128.

    Article  CAS  PubMed  Google Scholar 

  • Blachere, N. E., Parveen, S., Fak, J., Frank, M. O., & Orange, D. E. (2015). Inflammatory but not apoptotic death of granulocytes citrullinates fibrinogen. Arthritis Research & Therapy, 17(1), 369.

    Article  Google Scholar 

  • Brooks, W. H. (2013). Increased polyamines alter chromatin and stabilize autoantigens in autoimmune diseases. Frontiers in Immunology, 4, 91.

    Article  PubMed  PubMed Central  Google Scholar 

  • Burr, M. L., Naseem, H., Hinks, A., Eyre, S., Gibbons, L. J., Bowes, J., Wilson, A. G., Maxwell, J., Morgan, A. W., Emery, P., Steer, S., Hocking, L., Reid, D. M., Wordsworth, P., Harrison, P., Thomson, W., Worthington, J., & Barton, A. (2010). PADI4 genotype is not associated with rheumatoid arthritis in a large UK Caucasian population. Annals of the Rheumatic Diseases, 69(4), 666–670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cantaert, T., Coucke, P., De, R. L., Veys, E. M., De, K. F., & Baeten, D. (2005). Functional haplotypes of PADI4: Relevance for rheumatoid arthritis specific synovial intracellular citrullinated proteins and anticitrullinated protein antibodies. Annals of the Rheumatic Diseases, 64(9), 1316–1320.

    Google Scholar 

  • Chang, X., Yamada, R., Suzuki, A., Sawada, T., Yoshino, S., Tokuhiro, S., & Yamamoto, K. (2005). Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford), 44(1), 40–50.

    Article  CAS  Google Scholar 

  • Chang, X., Xia, Y., Pan, J., Meng, Q., Zhao, Y., & Yan, X. (2013). PADI2 is significantly associated with rheumatoid arthritis. PloS One, 8(12), e81259.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang, H. H., Dwivedi, N., Nicholas, A. P., & Ho, I. C. (2015). The W620 polymorphism in PTPN22 disrupts its interaction with peptidylarginine deiminase type 4 and enhances citrullination and NETosis. Arthritis & Rhematology, 67(9), 2323–2334.

    Article  CAS  Google Scholar 

  • Chapuy-Regaud, S., Sebbag, M., Baeten, D., Clavel, C., Foulquier, C., De, K. F., & Serre, G. (2005). Fibrin deimination in synovial tissue is not specific for rheumatoid arthritis but commonly occurs during synovitides. Journal of Immunology, 174(8), 5057–5064.

    Google Scholar 

  • Cherrington, B. D., Zhang, X., McElwee, J. L., Morency, E., Anguish, L. J., & Coonrod, S. A. (2012). Potential role for PAD2 in gene regulation in breast cancer cells. PloS One, 7(7), e41242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Damgaard, D., Senolt, L., Nielsen, M., Pruijn, G., & Nielsen, C. H. (2014). Demonstration of extracellular peptidylarginine deiminase (PAD) activity in synovial fluid of patients with rheumatoid arthritis using a novel assay for citrullination of fibrinogen. Arthritis Research & Therapy, 16(6), 498.

    Article  Google Scholar 

  • Damgaard, D., Bjorn, M. E., Steffensen, M. A., Pruijn, G. J., & Nielsen, C. H. (2016a). Reduced glutathione as a physiological co-activator in the activation of peptidylarginine deiminase. Arthritis Research & Therapy, 18(1), 102.

    Article  Google Scholar 

  • Damgaard, D., Senolt, L., & Nielsen, C. H. (2016b). Increased levels of peptidylarginine deiminase 2 in synovial fluid from anti-CCP-positive rheumatoid arthritis patients: Association with disease activity and inflammatory markers. Rheumatology (Oxford), 55(5), 918–927.

    Article  Google Scholar 

  • Darrah, E., Rosen, A., Giles, J. T., & Andrade, F. (2012). Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: Novel insights into autoantigen selection in rheumatoid arthritis. Annals of the Rheumatic Diseases, 71(1), 92–98.

    Article  CAS  PubMed  Google Scholar 

  • Darrah, E., Giles, J. T., Ols, M. L., Bull, H. G., Andrade, F., & Rosen, A. (2013). Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity. Science Translational Medicine, 5(186), 186ra65.

    Article  PubMed  PubMed Central  Google Scholar 

  • Davies, E. V., & Hallett, M. B. (1998). High micromolar Ca2+ beneath the plasma membrane in stimulated neutrophils. Biochemical and Biophysical Research Communications, 248(3), 679–683.

    Article  CAS  PubMed  Google Scholar 

  • De, R. L., Nicholas, A. P., Cantaert, T., Kruithof, E., Echols, J. D., Vandekerckhove, B., Veys, E. M., De, K. F., & Baeten, D. (2005). Synovial intracellular citrullinated proteins colocalizing with peptidyl arginine deiminase as pathophysiologically relevant antigenic determinants of rheumatoid arthritis-specific humoral autoimmunity. Arthritis and Rheumatism, 52(8), 2323–2330.

    Google Scholar 

  • Dixon, B. M., Heath, S. H., Kim, R., Suh, J. H., & Hagen, T. M. (2008). Assessment of endoplasmic reticulum glutathione redox status is confounded by extensive ex vivo oxidation. Antioxidants & Redox Signaling, 10(5), 963–972.

    Article  CAS  Google Scholar 

  • Dreyton, C. J., Knuckley, B., Jones, J. E., Lewallen, D. M., & Thompson, P. R. (2014). Mechanistic studies of protein arginine deiminase 2: Evidence for a substrate-assisted mechanism. Biochemistry, 53(27), 4426–4433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dwivedi, N., & Radic, M. (2014). Citrullination of autoantigens implicates NETosis in the induction of autoimmunity. Annals of the Rheumatic Diseases, 73(3), 483–491.

    Article  CAS  PubMed  Google Scholar 

  • Dwivedi, N., Upadhyay, J., Neeli, I., Khan, S., Pattanaik, D., Myers, L., Kirou, K. A., Hellmich, B., Knuckley, B., Thompson, P. R., Crow, M. K., Mikuls, T. R., Csernok, E., & Radic, M. (2012). Felty’s syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps. Arthritis and Rheumatism, 64(4), 982–992.

    Article  CAS  PubMed  Google Scholar 

  • Foulquier, C., Sebbag, M., Clavel, C., Chapuy-Regaud, S., Al, B. R., Mechin, M. C., Vincent, C., Nachat, R., Yamada, M., Takahara, H., Simon, M., Guerrin, M., & Serre, G. (2007). Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis and Rheumatism, 56(11), 3541–3553.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Romo, G. S., Caielli, S., Vega, B., Connolly, J., Allantaz, F., Xu, Z., Punaro, M., Baisch, J., Guiducci, C., Coffman, R. L., Barrat, F. J., Banchereau, J., & Pascual, V. (2011). Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Science Translational Medicine, 3(73), 73ra20.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ghari, F., Quirke, A. M., Munro, S., Kawalkowska, J., Picaud, S., McGouran, J., Subramanian, V., Muth, A., Williams, R., Kessler, B., Thompson, P. R., Fillipakopoulos, P., Knapp, S., Venables, P. J., & La Thangue, N. B. (2016). Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response. Science Advances, 2(2), e1501257.

    Article  PubMed  PubMed Central  Google Scholar 

  • Griffith, O. W. (1999). Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radical Biology & Medicine, 27(9–10), 922–935.

    Article  CAS  Google Scholar 

  • Hakkim, A., Furnrohr, B. G., Amann, K., Laube, B., Abed, U. A., Brinkmann, V., Herrmann, M., Voll, R. E., & Zychlinsky, A. (2010). Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proceedings of the National Academy of Sciences of the United States of America, 107(21), 9813–9818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hao, G., Wang, D., Gu, J., Shen, Q., Gross, S. S., & Wang, Y. (2009). Neutral loss of isocyanic acid in peptide CID spectra: A novel diagnostic marker for mass spectrometric identification of protein citrullination. Journal of the American Society for Mass Spectrometry, 20(4), 723–727.

    Article  CAS  PubMed  Google Scholar 

  • Harre, U., Georgess, D., Bang, H., Bozec, A., Axmann, R., Ossipova, E., Jakobsson, P. J., Baum, W., Nimmerjahn, F., Szarka, E., Sarmay, G., Krumbholz, G., Neumann, E., Toes, R., Scherer, H. U., Catrina, A. I., Klareskog, L., Jurdic, P., & Schett, G. (2012). Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. The Journal of Clinical Investigation, 122(5), 1791–1802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hensen, S. M., & Pruijn, G. J. (2014). Methods for the detection of peptidylarginine deiminase (PAD) activity and protein citrullination. Molecular & Cellular Proteomics, 13(2), 388–396.

    Article  CAS  Google Scholar 

  • Hensen, S. M., Boelens, W. C., Bonger, K. M., van Cruchten, R. T., van Delft, F. L., & Pruijn, G. J. (2015). Phenylglyoxal-based visualization of citrullinated proteins on Western blots. Molecules, 20(4), 6592–6600.

    Article  CAS  PubMed  Google Scholar 

  • Hill, J. A., Southwood, S., Sette, A., Jevnikar, A. M., Bell, D. A., & Cairns, E. (2003). Cutting edge: The conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA- DRB1*0401 MHC class II molecule. Journal of Immunology, 171(2), 538–541.

    Article  CAS  Google Scholar 

  • Hill, J. A., Bell, D. A., Brintnell, W., Yue, D., Wehrli, B., Jevnikar, A. M., Lee, D. M., Hueber, W., Robinson, W. H., & Cairns, E. (2008). Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. The Journal of Experimental Medicine, 205(4), 967–979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoppe, B., Haupl, T., Gruber, R., Kiesewetter, H., Burmester, G. R., Salama, A., & Dorner, T. (2006). Detailed analysis of the variability of peptidylarginine deiminase type 4 in German patients with rheumatoid arthritis: A case-control study. Arthritis Research & Therapy, 8(2), R34.

    Article  Google Scholar 

  • Jang, B., Kim, H. W., Kim, J. S., Kim, W. S., Lee, B. R., Kim, S., Kim, H., Han, S. J., Ha, S. J., & Shin, S. J. (2015). Peptidylarginine deiminase inhibition impairs Toll-like receptor agonist-induced functional maturation of dendritic cells, resulting in the loss of T cell-proliferative capacity: A partial mechanism with therapeutic potential in inflammatory settings. Journal of Leukocyte Biology, 97(2), 351–362.

    Article  PubMed  Google Scholar 

  • Jones, D. P. (2002). Redox potential of GSH/GSSG couple: Assay and biological significance. Methods in Enzymology, 348, 93–112.

    Article  CAS  PubMed  Google Scholar 

  • Kearney, P. L., Bhatia, M., Jones, N. G., Yuan, L., Glascock, M. C., Catchings, K. L., Yamada, M., & Thompson, P. R. (2005). Kinetic characterization of protein arginine deiminase 4: A transcriptional corepressor implicated in the onset and progression of rheumatoid arthritis. Biochemistry, 44(31), 10570–10582.

    Article  CAS  PubMed  Google Scholar 

  • Khandpur, R., Carmona-Rivera, C., Vivekanandan-Giri, A., Gizinski, A., Yalavarthi, S., Knight, J. S., Friday, S., Li, S., Patel, R. M., Subramanian, V., Thompson, P., Chen, P., Fox, D. A., Pennathur, S., & Kaplan, M. J. (2013). NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Science Translational Medicine, 5(178), 178ra40.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kinloch, A., Lundberg, K., Wait, R., Wegner, N., Lim, N. H., Zendman, A. J., Saxne, T., Malmstrom, V., & Venables, P. J. (2008). Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis. Arthritis and Rheumatism, 58(8), 2287–2295.

    Article  CAS  PubMed  Google Scholar 

  • Knuckley, B., Bhatia, M., & Thompson, P. R. (2007). Protein arginine deiminase 4: Evidence for a reverse protonation mechanism. Biochemistry, 46(22), 6578–6587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knuckley, B., Causey, C. P., Jones, J. E., Bhatia, M., Dreyton, C. J., Osborne, T. C., Takahara, H., & Thompson, P. R. (2010). Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3. Biochemistry, 49(23), 4852–4863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krishnamurthy, A., Joshua, V., Haj, H. A., Jin, T., Sun, M., Vivar, N., Ytterberg, A. J., Engstrom, M., Fernandes-Cerqueira, C., Amara, K., Magnusson, M., Wigerblad, G., Kato, J., Jimenez-Andrade, J. M., Tyson, K., Rapecki, S., Lundberg, K., Catrina, S. B., Jakobsson, P. J., Svensson, C., Malmstrom, V., Klareskog, L., Wahamaa, H., & Catrina, A. I. (2016). Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Annals of the Rheumatic Diseases, 75(4), 721–729.

    Article  CAS  PubMed  Google Scholar 

  • Lewis, H. D., Liddle, J., Coote, J. E., Atkinson, S. J., Barker, M. D., Bax, B. D., Bicker, K. L., Bingham, R. P., Campbell, M., Chen, Y. H., Chung, C. W., Craggs, P. D., Davis, R. P., Eberhard, D., Joberty, G., Lind, K. E., Locke, K., Maller, C., Martinod, K., Patten, C., Polyakova, O., Rise, C. E., Rudiger, M., Sheppard, R. J., Slade, D. J., Thomas, P., Thorpe, J., Yao, G., Drewes, G., Wagner, D. D., Thompson, P. R., Prinjha, R. K., & Wilson, D. M. (2015). Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nature Chemical Biology, 11(3), 189–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, Y. L., Chiang, Y. H., Liu, G. Y., & Hung, H. C. (2011). Functional role of dimerization of human peptidylarginine deiminase 4 (PAD4). PloS One, 6(6), e21314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Makrygiannakis, D., af, K. E., Lundberg, I. E., Lofberg, R., Ulfgren, A. K., Klareskog, L., & Catrina, A. I. (2006). Citrullination is an inflammation-dependent process. Annals of the Rheumatic Diseases, 65(9), 1219–1222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Makrygiannakis, D., Revu, S., Engstrom, M., af, K. E., Nicholas, A. P., Pruijn, G. J., & Catrina, A. I. (2012). Local administration of glucocorticoids decreases synovial citrullination in rheumatoid arthritis. Arthritis Research & Therapy, 14(1), R20.

    Article  CAS  Google Scholar 

  • Martinez, A., Valdivia, A., Pascual-Salcedo, D., Lamas, J. R., Fernandez-Arquero, M., Balsa, A., Fernandez-Gutierrez, B., de la Concha, E. G., & Urcelay, E. (2005). PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology (Oxford), 44(10), 1263–1266.

    Article  CAS  Google Scholar 

  • Moelants, E. A., Mortier, A., Grauwen, K., Ronsse, I., Van, D. J., & Proost, P. (2013). Citrullination of TNF-alpha by peptidylarginine deiminases reduces its capacity to stimulate the production of inflammatory chemokines. Cytokine, 61(1), 161–167.

    Google Scholar 

  • Mohanan, S., Horibata, S., McElwee, J. L., Dannenberg, A. J., & Coonrod, S. A. (2013). Identification of macrophage extracellular trap-like structures in mammary gland adipose tissue: A preliminary study. Frontiers in Immunology, 4, 67.

    Article  PubMed  PubMed Central  Google Scholar 

  • Muller, S., & Radic, M. (2015). Citrullinated autoantigens: From diagnostic markers to pathogenetic mechanisms. Clinical Reviews in Allergy & Immunology, 49(2), 232–239.

    Article  CAS  Google Scholar 

  • Nakashima, K., Hagiwara, T., & Yamada, M. (2002). Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. The Journal of Biological Chemistry, 277(51), 49562–49568.

    Article  CAS  PubMed  Google Scholar 

  • Nakayama-Hamada, M., Suzuki, A., Kubota, K., Takazawa, T., Ohsaka, M., Kawaida, R., Ono, M., Kasuya, A., Furukawa, H., Yamada, R., & Yamamoto, K. (2005). Comparison of enzymatic properties between hPADI2 and hPADI4. Biochemical and Biophysical Research Communications, 327(1), 192–200.

    Article  CAS  PubMed  Google Scholar 

  • Neeli, I., Khan, S. N., & Radic, M. (2008). Histone deimination as a response to inflammatory stimuli in neutrophils. Journal of Immunology, 180(3), 1895–1902.

    Article  CAS  Google Scholar 

  • Nicholas, A. P., & Whitaker, J. N. (2002). Preparation of a monoclonal antibody to citrullinated epitopes: Its characterization and some applications to immunohistochemistry in human brain. Glia, 37(4), 328–336.

    Article  PubMed  Google Scholar 

  • Okada, Y., Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K., Kochi, Y., Ohmura, K., Suzuki, A., Yoshida, S., Graham, R. R., Manoharan, A., Ortmann, W., Bhangale, T., Denny, J. C., Carroll, R. J., Eyler, A. E., Greenberg, J. D., Kremer, J. M., Pappas, D. A., Jiang, L., Yin, J., Ye, L., Su, D. F., Yang, J., Xie, G., Keystone, E., Westra, H. J., Esko, T., Metspalu, A., Zhou, X., Gupta, N., Mirel, D., Stahl, E. A., Diogo, D., Cui, J., Liao, K., Guo, M. H., Myouzen, K., Kawaguchi, T., Coenen, M. J., van Riel, P. L., van de Laar, M. A., Guchelaar, H. J., Huizinga, T. W., Dieude, P., Mariette, X., Bridges, S. L., Jr., Zhernakova, A., Toes, R. E., Tak, P. P., Miceli-Richard, C., Bang, S. Y., Lee, H. S., Martin, J., Gonzalez-Gay, M. A., Rodriguez-Rodriguez, L., Rantapaa-Dahlqvist, S., Arlestig, L., Choi, H. K., Kamatani, Y., Galan, P., Lathrop, M., Eyre, S., Bowes, J., Barton, A., de, V. N., Moreland, L. W., Criswell, L. A., Karlson, E. W., Taniguchi, A., Yamada, R., Kubo, M., Liu, J. S., Bae, S. C., Worthington, J., Padyukov, L., Klareskog, L., Gregersen, P. K., Raychaudhuri, S., Stranger, B. E., De Jager, P. L., Franke, L., Visscher, P. M., Brown, M. A., Yamanaka, H., Mimori, T., Takahashi, A., Xu, H., Behrens, T. W., Siminovitch, K. A., Momohara, S., Matsuda, F., Yamamoto, K., & Plenge, R. M. (2014). Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature, 506(7488), 376–381.

    Article  CAS  PubMed  Google Scholar 

  • Olivares-Martinez, E., Hernandez-Ramirez, D. F., Nunez-Alvarez, C. A., Cabral, A. R., & Llorente, L. (2016). The amount of citrullinated proteins in synovial tissue is related to serum anti-cyclic citrullinated peptide (anti-CCP) antibody levels. Clinical Rheumatology, 35(1), 55–61.

    Article  PubMed  Google Scholar 

  • Parker, H., & Winterbourn, C. C. (2012). Reactive oxidants and myeloperoxidase and their involvement in neutrophil extracellular traps. Frontiers in Immunology, 3, 424.

    PubMed  Google Scholar 

  • Plenge, R. M., Padyukov, L., Remmers, E. F., Purcell, S., Lee, A. T., Karlson, E. W., Wolfe, F., Kastner, D. L., Alfredsson, L., Altshuler, D., Gregersen, P. K., Klareskog, L., & Rioux, J. D. (2005). Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. American Journal of Human Genetics, 77(6), 1044–1060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Proost, P., Loos, T., Mortier, A., Schutyser, E., Gouwy, M., Noppen, S., Dillen, C., Ronsse, I., Conings, R., Struyf, S., Opdenakker, G., Maudgal, P. C., & Van, D. J. (2008). Citrullination of CXCL8 by peptidylarginine deiminase alters receptor usage, prevents proteolysis, and dampens tissue inflammation. The Journal of Experimental Medicine, 205(9), 2085–2097.

    Google Scholar 

  • Raijmakers, R., van Beers, J. J., El-Azzouny, M., Visser, N. F., Bozic, B., Pruijn, G. J., & Heck, A. J. (2012). Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients. Arthritis Research & Therapy, 14(3), R114.

    Article  CAS  Google Scholar 

  • Salisbury, A. K., Duke, O., & Poulter, L. W. (1987). Macrophage-like cells of the pannus area in rheumatoid arthritic joints. Scandinavian Journal of Rheumatology, 16(4), 263–272.

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Pernaute, O., Filkova, M., Gabucio, A., Klein, M., Maciejewska-Rodrigues, H., Ospelt, C., Brentano, F., Michel, B. A., Gay, R. E., Herrero-Beaumont, G., Gay, S., Neidhart, M., & Juengel, A. (2013). Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts. Annals of the Rheumatic Diseases, 72(8), 1400–1406.

    Article  CAS  PubMed  Google Scholar 

  • Scally, S. W., Petersen, J., Law, S. C., Dudek, N. L., Nel, H. J., Loh, K. L., Wijeyewickrema, L. C., Eckle, S. B., van, H. J., Pike, R. N., McCluskey, J., Toes, R. E., La Gruta, N. L., Purcell, A. W., Reid, H. H., Thomas, R., & Rossjohn, J. (2013). A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. The Journal of Experimental Medicine, 210(12), 2569–2582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seefeldt, T., Zhao, Y., Chen, W., Raza, A. S., Carlson, L., Herman, J., Stoebner, A., Hanson, S., Foll, R., & Guan, X. (2009). Characterization of a novel dithiocarbamate glutathione reductase inhibitor and its use as a tool to modulate intracellular glutathione. The Journal of Biological Chemistry, 284(5), 2729–2737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Senshu, T., Sato, T., Inoue, T., Akiyama, K., & Asaga, H. (1992). Detection of citrulline residues in deiminated proteins on polyvinylidene difluoride membrane. Analytical Biochemistry, 203(1), 94–100.

    Article  CAS  PubMed  Google Scholar 

  • Slade, D. J., Subramanian, V., Fuhrmann, J., & Thompson, P. R. (2014). Chemical and biological methods to detect post-translational modifications of arginine. Biopolymers, 101(2), 133–143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slade, D. J., Fang, P., Dreyton, C. J., Zhang, Y., Fuhrmann, J., Rempel, D., Bax, B. D., Coonrod, S. A., Lewis, H. D., Guo, M., Gross, M. L., & Thompson, P. R. (2015). Protein arginine deiminase 2 binds calcium in an ordered fashion: Implications for inhibitor design. ACS Chemical Biology, 10(4), 1043–1053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sokolove, J., Zhao, X., Chandra, P. E., & Robinson, W. H. (2011). Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcgamma receptor. Arthritis and Rheumatism, 63(1), 53–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spengler, J., Lugonja, B., Jimmy, Y. A., Zubarev, R. A., Creese, A. J., Pearson, M. J., Grant, M. M., Milward, M., Lundberg, K., Buckley, C. D., Filer, A., Raza, K., Cooper, P. R., Chapple, I. L., & Scheel-Toellner, D. (2015). Release of active peptidyl arginine deiminases by neutrophils can explain production of extracellular citrullinated autoantigens in rheumatoid arthritis synovial fluid. Arthritis & Rhematology, 67(12), 3135–3145.

    Article  CAS  Google Scholar 

  • Stenberg, P., & Roth, B. (2015). Zinc is the modulator of the calcium-dependent activation of post-translationally acting thiol-enzymes in autoimmune diseases. Medical Hypotheses, 84(4), 331–335.

    Article  CAS  PubMed  Google Scholar 

  • Stensland, M. E., Pollmann, S., Molberg, O., Sollid, L. M., & Fleckenstein, B. (2009). Primary sequence, together with other factors, influence peptide deimination by peptidylarginine deiminase-4. Biological Chemistry, 390(2), 99–107.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki, A., Yamada, R., Chang, X., Tokuhiro, S., Sawada, T., Suzuki, M., Nagasaki, M., Nakayama-Hamada, M., Kawaida, R., Ono, M., Ohtsuki, M., Furukawa, H., Yoshino, S., Yukioka, M., Tohma, S., Matsubara, T., Wakitani, S., Teshima, R., Nishioka, Y., Sekine, A., Iida, A., Takahashi, A., Tsunoda, T., Nakamura, Y., & Yamamoto, K. (2003). Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nature Genetics, 34(4), 395–402.

    Article  CAS  PubMed  Google Scholar 

  • Takahara, H., Okamoto, H., & Sugawara, K. (1986). Calcium-dependent properties of peptidylarginine deiminase from rabbit skeletal muscle. Agricultural and Biological Chemistry, 50, 2899–2904.

    CAS  Google Scholar 

  • Terakawa, H., Takahara, H., & Sugawara, K. (1991). Three types of mouse peptidylarginine deiminase: Characterization and tissue distribution. Journal of Biochemistry, 110(4), 661–666.

    Article  CAS  PubMed  Google Scholar 

  • Tutturen, A. E., Fleckenstein, B., & de Souza, G. A. (2014). Assessing the citrullinome in rheumatoid arthritis synovial fluid with and without enrichment of citrullinated peptides. Journal of Proteome Research, 13(6), 2867–2873.

    Google Scholar 

  • Tutturen, A. E., Holm, A,, Jorgensen, M,, Stadtmuller, P., Rise, F., & Fleckenstein, B. (2010). A technique for the specific enrichment of citrulline-containing peptides. Analytical Biochemistry, 403, 43–51.

    Google Scholar 

  • van Beers, J. J., Raijmakers, R., Alexander, L. E., Stammen-Vogelzangs, J., Lokate, A. M., Heck, A. J., Schasfoort, R. B., & Pruijn, G. J. (2010). Mapping of citrullinated fibrinogen B-cell epitopes in rheumatoid arthritis by imaging surface plasmon resonance. Arthritis Research & Therapy, 12(6), R219.

    Article  Google Scholar 

  • van Beers, J. J., Schwarte, C. M., Stammen-Vogelzangs, J., Oosterink, E., Bozic, B., & Pruijn, G. J. (2013). The rheumatoid arthritis synovial fluid citrullinome reveals novel citrullinated epitopes in apolipoprotein E, myeloid nuclear differentiation antigen, and beta-actin. Arthritis and Rheumatism, 65(1), 69–80.

    Article  PubMed  Google Scholar 

  • van Venrooij, W. J., & Pruijn, G. J. (2008). An important step towards completing the rheumatoid arthritis cycle. Arthritis Research & Therapy, 10(5), 117.

    Article  Google Scholar 

  • Vossenaar, E. R., Zendman, A. J., van Venrooij, W. J., & Pruijn, G. J. (2003). PAD, a growing family of citrullinating enzymes: Genes, features and involvement in disease. BioEssays, 25(11), 1106–1118.

    Article  CAS  PubMed  Google Scholar 

  • Vossenaar, E. R., Radstake, T. R., van der Heijden, A., van Mansum, M. A., Dieteren, C., de Rooij, D. J., Barrera, P., Zendman, A. J., & van Venrooij, W. J. (2004a). Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Annals of the Rheumatic Diseases, 63(4), 373–381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vossenaar, E. R., Smeets, T. J., Kraan, M. C., Raats, J. M., van Venrooij, W. J., & Tak, P. P. (2004b). The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis and Rheumatism, 50(11), 3485–3494.

    Article  CAS  PubMed  Google Scholar 

  • Wang, F., Chen, F. F., Gao, W. B., Wang, H. Y., Zhao, N. W., Xu, M., Gao, D. Y., Yu, W., Yan, X. L., Zhao, J. N., & Li, X. J. (2016). Identification of citrullinated peptides in the synovial fluid of patients with rheumatoid arthritis using LC-MALDI-TOF/TOF. Clinical Rheumatology, 35(9), 2185–2194.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yoshida, S., Katoh, T., Tetsuka, T., Uno, K., Matsui, N., & Okamoto, T. (1999). Involvement of thioredoxin in rheumatoid arthritis: Its costimulatory roles in the TNF-alpha-induced production of IL-6 and IL-8 from cultured synovial fibroblasts. Journal of Immunology, 163(1), 351–358.

    CAS  Google Scholar 

  • Yoshida, K., Korchynskyi, O., Tak, P. P., Isozaki, T., Ruth, J. H., Campbell, P. L., Baeten, D. L., Gerlag, D. M., Amin, M. A., & Koch, A. E. (2014). Citrullination of epithelial neutrophil-activating peptide 78/CXCL5 results in conversion from a non-monocyte-recruiting chemokine to a monocyte-recruiting chemokine. Arthritis & Rhematology, 66(10), 2716–2727.

    Article  CAS  Google Scholar 

  • Zendman, A. J., Raijmakers, R., Nijenhuis, S., Vossenaar, E. R., Tillaart, M., Chirivi, R. G., Raats, J. M., van Venrooij, W. J., Drijfhout, J. W., & Pruijn, G. J. (2007). ABAP: Antibody-based assay for peptidylarginine deiminase activity. Analytical Biochemistry, 369(2), 232–240.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Claus H. Nielsen (Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark) for the critical reading of and helpful comments on this chapter.

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Authors and Affiliations

  1. Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Dres Damgaard

  2. Department of Biomolecular Chemistry, Radboud Institute for Molecular Life Sciences and Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands

    Ger J. M. Pruijn

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Correspondence to Ger J. M. Pruijn .

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  1. Department of Neurology, University of Alabama at Birmingham and The Birmingham Veterans Administration Medical Center, Birmingham, Alabama, USA

    Anthony P. Nicholas

  2. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA

    Sanjoy K. Bhattacharya

  3. Department of Biochemistry and Molecular Pharmacology, UMASS Medical School, Worcester, Massachusetts, USA

    Paul R. Thompson

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Damgaard, D., Pruijn, G.J.M. (2017). PAD Activation in Arthritis. In: Nicholas, A., Bhattacharya, S., Thompson, P. (eds) Protein Deimination in Human Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-58244-3_5

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