CC BY 4.0 · Semin Thromb Hemost 2020; 46(04): 465-483
DOI: 10.1055/s-0040-1709475
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

Johannes A. Bezuidenhout
1   Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
,
1   Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
› Author Affiliations
Further Information

Publication History

Publication Date:
21 May 2020 (online)

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease of complex etiopathogenic origin and traditionally characterized by chronic synovitis and articular erosions. Furthermore, there is strong evidence that infectious agents, including those that become dormant within the host, play a major role in much of the etiology of RA and its hallmark of inflammation. A combination of genetic predisposition, environmental exposure, and presence of infectious agents may therefore lead to a loss of immune tolerance to citrullinated proteins, which present as self-antigens to the human immune system. This results in generation of highly RA-specific autoantibodies, known as anti-citrullinated protein antibodies (ACPAs). Protein citrullination occurs via posttranslational deamination of arginine residues by peptidylarginine deiminase enzymes, which have confirmed sources of both endogenous and infectious origins. A recognized plasma protein target of citrullination and RA autoantibody generation is fibrin and its soluble precursor fibrinogen, both key components of hemostasis and acute phase reaction. Increased titers of ACPAs that accompany rapid progression to clinical RA disease have been shown to drive a variety of proinflammatory processes, and therefore results in aberrant fibrin clot formation and increased cardiovascular risk. However, the full extent to which hemostasis is affected in RA remains controversial, owing to the differential impact that citrullinated fibrin(ogen) and concurrent systemic inflammation may have on resulting hemostatic outcome. This review highlights key events in initiation of autoimmune-driven inflammatory events, including the role of bacterial infectious agents, which subsequently result in clinical RA disease and associated secondary cardiovascular disease risk, with specific focus on plasma proteins that are heavily involved throughout the immunopathological progression process.

 
  • References

  • 1 Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 376 (9746): 1094-1108
  • 2 Silman AJ. Epidemiology of rheumatoid arthritis. APMIS 1994; 102 (10) 721-728
  • 3 Tedeschi SK, Bermas B, Costenbader KH. Sexual disparities in the incidence and course of SLE and RA. Clin Immunol 2013; 149 (02) 211-218
  • 4 Pratesi F, Panza F, Paolini I. , et al. Fingerprinting of anti-citrullinated protein antibodies (ACPA): specificity, isotypes and subclasses. Lupus 2015; 24 (4-5): 433-441
  • 5 van der Woude D, Catrina AI. HLA and anti-citrullinated protein antibodies: building blocks in RA. Best Pract Res Clin Rheumatol 2015; 29 (06) 692-705
  • 6 Smolen JS, Breedveld FC, Eberl G. , et al. Validity and reliability of the twenty-eight-joint count for the assessment of rheumatoid arthritis activity. Arthritis Rheum 1995; 38 (01) 38-43
  • 7 Sokka T. Work disability in early rheumatoid arthritis. Clin Exp Rheumatol 2003; 21 (05) (Suppl. 31) S71-S74
  • 8 Klareskog L, Rönnelid J, Lundberg K, Padyukov L, Alfredsson L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol 2008; 26: 651-675
  • 9 Ärlestig L, Mullazehi M, Kokkonen H, Rocklöv J, Rönnelid J, Dahlqvist SR. Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden. Ann Rheum Dis 2012; 71 (06) 825-829
  • 10 Kolfenbach JR, Deane KD, Derber LA. , et al. A prospective approach to investigating the natural history of preclinical rheumatoid arthritis (RA) using first-degree relatives of probands with RA. Arthritis Rheum 2009; 61 (12) 1735-1742
  • 11 Roudier J. Association of MHC and rheumatoid arthritis. Association of RA with HLA-DR4: the role of repertoire selection. Arthritis Res 2000; 2 (03) 217-220
  • 12 Picchianti-Diamanti A, Rosado MM, D'Amelio R. Infectious agents and inflammation: the role of microbiota in autoimmune arthritis. Front Microbiol 2018; 8: 2696
  • 13 Salmi M, Andrew DP, Butcher EC, Jalkanen S. Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms. J Exp Med 1995; 181 (01) 137-149
  • 14 Rashid T, Ebringer A. Rheumatoid arthritis is linked to Proteus—the evidence. Clin Rheumatol 2007; 26 (07) 1036-1043
  • 15 Tishler M, Caspi D, Almog Y, Segal R, Yaron M. Increased incidence of urinary tract infection in patients with rheumatoid arthritis and secondary Sjögren's syndrome. Ann Rheum Dis 1992; 51 (05) 604-606
  • 16 Senior BW, Anderson GA, Morley KD, Kerr MA. Evidence that patients with rheumatoid arthritis have asymptomatic ‘non-significant’ Proteus mirabilis bacteriuria more frequently than healthy controls. J Infect 1999; 38 (02) 99-106
  • 17 Ebringer A, Cunningham P, Ahmadi K, Wrigglesworth J, Hosseini R, Wilson C. Sequence similarity between HLA-DR1 and DR4 subtypes associated with rheumatoid arthritis and proteus/serratia membrane haemolysins. Ann Rheum Dis 1992; 51 (11) 1245-1246
  • 18 Rashid T, Tiwana H, Wilson C, Ebringer A. Rheumatoid arthritis as an autoimmune disease caused by Proteus urinary tract infections: a proposal for a therapeutic protocol. Isr Med Assoc J 2001; 3 (09) 675-680
  • 19 Alexander C, Rietschel ET. Bacterial lipopolysaccharides and innate immunity. J Endotoxin Res 2001; 7 (03) 167-202
  • 20 Benoit R, Rowe S, Watkins SC. , et al. Pure endotoxin does not pass across the intestinal epithelium in vitro. Shock 1998; 10 (01) 43-48
  • 21 Guo S, Al-Sadi R, Said HM, Ma TY. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am J Pathol 2013; 182 (02) 375-387
  • 22 Maeda Y, Kumanogoh A, Takeda K. Altered composition of gut microbiota in rheumatoid arthritis patients. Nihon Rinsho Meneki Gakkai Kaishi 2016; 39 (01) 59-63
  • 23 Zhang X, Zhang D, Jia H. , et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 2015; 21 (08) 895-905
  • 24 Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine 2008; 42 (02) 145-151
  • 25 Koch L, Hofer S, Weigand MA, Frommhold D, Poeschl J. Lipopolysaccharide-induced activation of coagulation in neonatal cord and adult blood monitored by thrombelastography. Thromb Res 2009; 124 (04) 463-467
  • 26 Landsem A, Fure H, Christiansen D. , et al. The key roles of complement and tissue factor in Escherichia coli-induced coagulation in human whole blood. Clin Exp Immunol 2015; 182 (01) 81-89
  • 27 Pretorius E, Mbotwe S, Bester J, Robinson CJ, Kell DB. Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide. J R Soc Interface 2016; 13 (122) 20160539
  • 28 Pretorius E, Akeredolu OO, Soma P, Kell DB. Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability. Exp Biol Med (Maywood) 2017; 242 (04) 355-373
  • 29 Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008; 59 (12) 1690-1697
  • 30 Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 2005; 52 (03) 722-732
  • 31 McEntegart A, Capell HA, Creran D, Rumley A, Woodward M, Lowe GD. Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis. Rheumatology (Oxford) 2001; 40 (06) 640-644
  • 32 del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001; 44 (12) 2737-2745
  • 33 Gallistl S, Mangge H, Neuwirth G, Muntean W. Activation of the haemostatic system in children with juvenile rheumatoid arthritis correlates with disease activity. Thromb Res 1998; 92 (06) 267-272
  • 34 Kwasny-Krochin B, Gluszko P, Undas A. Unfavorably altered fibrin clot properties in patients with active rheumatoid arthritis. Thromb Res 2010; 126 (01) e11-e16
  • 35 So AK, Varisco PA, Kemkes-Matthes B. , et al. Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways. J Thromb Haemost 2003; 1 (12) 2510-2515
  • 36 Habets KL, Trouw LA, Levarht EW. , et al. Anti-citrullinated protein antibodies contribute to platelet activation in rheumatoid arthritis. Arthritis Res Ther 2015; 17 (01) 209
  • 37 Henn V, Slupsky JR, Gräfe M. , et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391 (6667): 591-594
  • 38 Amelot AA, Tagzirt M, Ducouret G, Kuen RL, Le Bonniec BF. Platelet factor 4 (CXCL4) seals blood clots by altering the structure of fibrin. J Biol Chem 2007; 282 (01) 710-720
  • 39 Wohner N. Role of cellular elements in thrombus formation and dissolution. Cardiovasc Hematol Agents Med Chem 2008; 6 (03) 224-228
  • 40 Chen J, Bierhaus A, Schiekofer S. , et al. Tissue factor—a receptor involved in the control of cellular properties, including angiogenesis. Thromb Haemost 2001; 86 (01) 334-345
  • 41 Chen L, Lu Y, Chu Y, Xie J, Ding W, Wang F. Tissue factor expression in rheumatoid synovium: a potential role in pannus invasion of rheumatoid arthritis. Acta Histochem 2013; 115 (07) 692-697
  • 42 Mantovani A, Sozzani S, Vecchi A, Introna M, Allavena P. Cytokine activation of endothelial cells: new molecules for an old paradigm. Thromb Haemost 1997; 78 (01) 406-414
  • 43 Pretorius E, Oberholzer HM, van der Spuy WJ, Swanepoel AC, Soma P. Scanning electron microscopy of fibrin networks in rheumatoid arthritis: a qualitative analysis. Rheumatol Int 2012; 32 (06) 1611-1615
  • 44 Sánchez-Pernaute O, Largo R, Calvo E, Alvarez-Soria MA, Egido J, Herrero-Beaumont G. A fibrin based model for rheumatoid synovitis. Ann Rheum Dis 2003; 62 (12) 1135-1138
  • 45 Masson-Bessière C, Sebbag M, Durieux JJ. , et al. In the rheumatoid pannus, anti-filaggrin autoantibodies are produced by local plasma cells and constitute a higher proportion of IgG than in synovial fluid and serum. Clin Exp Immunol 2000; 119 (03) 544-552
  • 46 Sebbag M, Moinard N, Auger I. , et al. Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins. Eur J Immunol 2006; 36 (08) 2250-2263
  • 47 Falkenburg WJ, van Schaardenburg D, Ooijevaar-de Heer P, Wolbink G, Rispens T. IgG subclass specificity discriminates restricted IgM rheumatoid factor responses from more mature anti-citrullinated protein antibody-associated or isotype-switched IgA responses. Arthritis Rheumatol 2015; 67 (12) 3124-3134
  • 48 Egeland T, Munthe E. The role of the laboratory in rheumatology. Rheumatoid factors. Clin Rheum Dis 1983; 9 (01) 135-160
  • 49 Trier NH, Holm BE, Heiden J. , et al. The use of synthetic peptides for detection of anti-citrullinated protein antibodies in rheumatoid arthritis. J Immunol Methods 2018; 454: 6-14
  • 50 Nishimura K, Sugiyama D, Kogata Y. , et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 2007; 146 (11) 797-808
  • 51 Lingampalli N, Sokolove J, Lahey LJ. , et al. Combination of anti-citrullinated protein antibodies and rheumatoid factor is associated with increased systemic inflammatory mediators and more rapid progression from preclinical to clinical rheumatoid arthritis. Clin Immunol 2018; 195: 119-126
  • 52 Bugatti S, Bogliolo L, Vitolo B, Manzo A, Montecucco C, Caporali R. Anti-citrullinated protein antibodies and high levels of rheumatoid factor are associated with systemic bone loss in patients with early untreated rheumatoid arthritis. Arthritis Res Ther 2016; 18 (01) 226
  • 53 Trela M, Perera S, Sheeran T, Rylance P, Nelson PN, Attridge K. Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis. Sci Rep 2019; 9 (01) 12068
  • 54 Nevius E, Gomes AC, Pereira JP. Inflammatory cell migration in rheumatoid arthritis: a comprehensive review. Clin Rev Allergy Immunol 2016; 51 (01) 59-78
  • 55 Raijmakers R, van Beers JJ, El-Azzouny M. , et al. Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients. Arthritis Res Ther 2012; 14 (03) R114
  • 56 Tarcsa E, Marekov LN, Mei G, Melino G, Lee SC, Steinert PM. Protein unfolding by peptidylarginine deiminase. Substrate specificity and structural relationships of the natural substrates trichohyalin and filaggrin. J Biol Chem 1996; 271 (48) 30709-30716
  • 57 Masson-Bessière C, Sebbag M, Girbal-Neuhauser E. , et al. The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol 2001; 166 (06) 4177-4184
  • 58 Hagiwara T, Hidaka Y, Yamada M. Deimination of histone H2A and H4 at arginine 3 in HL-60 granulocytes. Biochemistry 2005; 44 (15) 5827-5834
  • 59 Vossenaar ER, Després N, Lapointe E. , et al. Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res Ther 2004; 6 (02) R142-R150
  • 60 Kinloch A, Tatzer V, Wait R. , et al. Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis. Arthritis Res Ther 2005; 7 (06) R1421-R1429
  • 61 Burkhardt H, Sehnert B, Bockermann R, Engström A, Kalden JR, Holmdahl R. Humoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis. Eur J Immunol 2005; 35 (05) 1643-1652
  • 62 Suzuki A, Yamada R, Ohtake-Yamanaka M, Okazaki Y, Sawada T, Yamamoto K. Anti-citrullinated collagen type I antibody is a target of autoimmunity in rheumatoid arthritis. Biochem Biophys Res Commun 2005; 333 (02) 418-426
  • 63 Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. 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. J Immunol 2003; 171 (02) 538-541
  • 64 Suwannalai P, Trouw LA, Toes RE, Huizinga TW. Anti-citrullinated protein antibodies (ACPA) in early rheumatoid arthritis. Mod Rheumatol 2012; 22 (01) 15-20
  • 65 Rantapää-Dahlqvist S, de Jong BA, Berglin E. , et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003; 48 (10) 2741-2749
  • 66 Nielen MM, van Schaardenburg D, Reesink HW. , et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004; 50 (02) 380-386
  • 67 Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet 2009; 373 (9664): 659-672
  • 68 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 (11) 1106-1118
  • 69 Asaga H, Yamada M, Senshu T. Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages. Biochem Biophys Res Commun 1998; 243 (03) 641-646
  • 70 Schwab BL, Guerini D, Didszun C. , et al. Cleavage of plasma membrane calcium pumps by caspases: a link between apoptosis and necrosis. Cell Death Differ 2002; 9 (08) 818-831
  • 71 Szekanecz Z, Soós L, Szabó Z. , et al. Anti-citrullinated protein antibodies in rheumatoid arthritis: as good as it gets?. Clin Rev Allergy Immunol 2008; 34 (01) 26-31
  • 72 Puszczewicz M, Iwaszkiewicz C. Role of anti-citrullinated protein antibodies in diagnosis and prognosis of rheumatoid arthritis. Arch Med Sci 2011; 7 (02) 189-194
  • 73 Farid SSh, Azizi G, Mirshafiey A. Anti-citrullinated protein antibodies and their clinical utility in rheumatoid arthritis. Int J Rheum Dis 2013; 16 (04) 379-386
  • 74 Chang X, Xia Y, Pan J, Meng Q, Zhao Y, Yan X. PADI2 is significantly associated with rheumatoid arthritis. PLoS One 2013; 8 (12) e81259
  • 75 Damgaard D, Bawadekar M, Senolt L, Stensballe A, Shelef MA, Nielsen CH. Relative efficiencies of peptidylarginine deiminase 2 and 4 in generating target sites for anti-citrullinated protein antibodies in fibrinogen, alpha-enolase and histone H3. PLoS One 2018; 13 (08) e0203214
  • 76 Holers VM. Autoimmunity to citrullinated proteins and the initiation of rheumatoid arthritis. Curr Opin Immunol 2013; 25 (06) 728-735
  • 77 Bang SY, Lee KH, Cho SK, Lee HS, Lee KW, Bae SC. Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status. Arthritis Rheum 2010; 62 (02) 369-377
  • 78 Mikuls TR, Payne JB, Yu F. , et al. Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheumatol 2014; 66 (05) 1090-1100
  • 79 Mikuls TR, Payne JB, Reinhardt RA. , et al. Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. Int Immunopharmacol 2009; 9 (01) 38-42
  • 80 Shimada A, Kobayashi T, Ito S. , et al. Expression of anti-Porphyromonas gingivalis peptidylarginine deiminase immunoglobulin G and peptidylarginine deiminase-4 in patients with rheumatoid arthritis and periodontitis. J Periodontal Res 2016; 51 (01) 103-111
  • 81 Okada M, Kobayashi T, Ito S. , et al. Periodontal treatment decreases levels of antibodies to Porphyromonas gingivalis and citrulline in patients with rheumatoid arthritis and periodontitis. J Periodontol 2013; 84 (12) e74-e84
  • 82 Reparon-Schuijt CC, van Esch WJ, van Kooten C. , et al. Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. Arthritis Rheum 2001; 44 (01) 41-47
  • 83 Ioan-Facsinay A, el-Bannoudi H, Scherer HU. , et al. Anti-cyclic citrullinated peptide antibodies are a collection of anti-citrullinated protein antibodies and contain overlapping and non-overlapping reactivities. Ann Rheum Dis 2011; 70 (01) 188-193
  • 84 Snir O, Widhe M, von Spee C. , et al. Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles. Ann Rheum Dis 2009; 68 (05) 736-743
  • 85 Li S, Yu Y, Yue Y. , et al. Autoantibodies from single circulating plasmablasts react with citrullinated antigens and Porphyromonas gingivalis in rheumatoid arthritis. Arthritis Rheumatol 2016; 68 (03) 614-626
  • 86 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 (01) 273-281
  • 87 Chibnik LB, Mandl LA, Costenbader KH, Schur PH, Karlson EW. Comparison of threshold cutpoints and continuous measures of anti-cyclic citrullinated peptide antibodies in predicting future rheumatoid arthritis. J Rheumatol 2009; 36 (04) 706-711
  • 88 van de Stadt LA, van der Horst AR, de Koning MH. , et al. The extent of the anti-citrullinated protein antibody repertoire is associated with arthritis development in patients with seropositive arthralgia. Ann Rheum Dis 2011; 70 (01) 128-133
  • 89 van der Woude D, Rantapää-Dahlqvist S, Ioan-Facsinay A. , et al. Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann Rheum Dis 2010; 69 (08) 1554-1561
  • 90 Derksen VF, Ajeganova S, Trouw LA. , et al. Rheumatoid arthritis phenotype at presentation differs depending on the number of autoantibodies present. Ann Rheum Dis 2017; 76 (04) 716-720
  • 91 van der Woude D, Syversen SW, van der Voort EI. , et al. The ACPA isotype profile reflects long-term radiographic progression in rheumatoid arthritis. Ann Rheum Dis 2010; 69 (06) 1110-1116
  • 92 Aletaha D, Neogi T, Silman AJ. , et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62 (09) 2569-2581
  • 93 Nienhuis RL, Mandema E. A new serum factor in patients with rheumatoid arthritis; the antiperinuclear factor. Ann Rheum Dis 1964; 23: 302-305
  • 94 Young BJ, Mallya RK, Leslie RD, Clark CJ, Hamblin TJ. Anti-keratin antibodies in rheumatoid arthritis. BMJ 1979; 2 (6182): 97-99
  • 95 Schellekens GA, Visser H, de Jong BA. , et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; 43 (01) 155-163
  • 96 van Venrooij WJ, Hazes JM, Visser H. Anticitrullinated protein/peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis. Neth J Med 2002; 60 (10) 383-388
  • 97 Okumura N, Haneishi A, Terasawa F. Citrullinated fibrinogen shows defects in FPA and FPB release and fibrin polymerization catalyzed by thrombin. Clin Chim Acta 2009; 401 (1-2): 119-123
  • 98 Nakayama-Hamada M, Suzuki A, Furukawa H, Yamada R, Yamamoto K. Citrullinated fibrinogen inhibits thrombin-catalysed fibrin polymerization. J Biochem 2008; 144 (03) 393-398
  • 99 Yermolenko IS, Lishko VK, Ugarova TP, Magonov SN. High-resolution visualization of fibrinogen molecules and fibrin fibers with atomic force microscopy. Biomacromolecules 2011; 12 (02) 370-379
  • 100 Joshua V, Schobers L, Titcombe PJ. , et al. Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells. Arthritis Res Ther 2016; 18 (01) 284
  • 101 Zhao Y, Tian X, Li Z. Prevalence and clinical significance of antibodies to citrullinated fibrinogen (ACF) in Chinese patients with rheumatoid arthritis. Clin Rheumatol 2007; 26 (09) 1505-1512
  • 102 Cantaert T, Teitsma C, Tak PP, Baeten D. Presence and role of anti-citrullinated protein antibodies in experimental arthritis models. Arthritis Rheum 2013; 65 (04) 939-948
  • 103 Shin K, Hong S, Choi E-H. , et al. Role of citrullinated fibrinogen peptides in the activation of CD4 T cells from patients with rheumatoid arthritis. Immune Netw 2013; 13 (04) 116-122
  • 104 Šenolt L, Grassi W, Szodoray P. Laboratory biomarkers or imaging in the diagnostics of rheumatoid arthritis?. BMC Med 2014; 12: 49
  • 105 Gianchecchi E, Crinò A, Giorda E. , et al. Altered B cell homeostasis and toll-like receptor 9-driven response in type 1 diabetes carriers of the C1858T PTPN22 allelic variant: implications in the disease pathogenesis. PLoS One 2014; 9 (10) e110755
  • 106 Giltiay NV, Chappell CP, Clark EA. B-cell selection and the development of autoantibodies. Arthritis Res Ther 2012; 14 (Suppl. 04) S1
  • 107 Menard L, Saadoun D, Isnardi I. , et al. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest 2011; 121 (09) 3635-3644
  • 108 Ho PP, Lee LY, Zhao X. , et al. Autoimmunity against fibrinogen mediates inflammatory arthritis in mice. J Immunol 2010; 184 (01) 379-390
  • 109 Ingegnoli F, Fantini F, Favalli EG. , et al. Inflammatory and prothrombotic biomarkers in patients with rheumatoid arthritis: effects of tumor necrosis factor-alpha blockade. J Autoimmun 2008; 31 (02) 175-179
  • 110 Rooney T, Scherzer R, Shigenaga JK, Graf J, Imboden JB, Grunfeld C. Levels of plasma fibrinogen are elevated in well-controlled rheumatoid arthritis. Rheumatology (Oxford) 2011; 50 (08) 1458-1465
  • 111 Zhao X, Okeke NL, Sharpe O. , et al. Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis. Arthritis Res Ther 2008; 10 (04) R94
  • 112 Nielen MM, van der Horst AR, van Schaardenburg D. , et al. Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis. Ann Rheum Dis 2005; 64 (08) 1199-1204
  • 113 Vander Cruyssen B, Cantaert T, Nogueira L. , et al. Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays. Arthritis Res Ther 2006; 8 (04) R122
  • 114 Hill JA, Bell DA, Brintnell W. , et al. Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. J Exp Med 2008; 205 (04) 967-979
  • 115 van Beers JJBC, Raijmakers R, Alexander L-E. , et al. Mapping of citrullinated fibrinogen B-cell epitopes in rheumatoid arthritis by imaging surface plasmon resonance. Arthritis Res Ther 2010; 12 (06) R219-R219
  • 116 Nakayama-Hamada M, Suzuki A, Kubota K. , et al. Comparison of enzymatic properties between hPADI2 and hPADI4. Biochem Biophys Res Commun 2005; 327 (01) 192-200
  • 117 Sanchez-Pernaute O, Filkova M, Gabucio A. , et al. Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis 2013; 72 (08) 1400-1406
  • 118 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21 (03) 131-142
  • 119 Ohba T, Takase Y, Ohhara M, Kasukawa R. Thrombin in the synovial fluid of patients with rheumatoid arthritis mediates proliferation of synovial fibroblast-like cells by induction of platelet derived growth factor. J Rheumatol 1996; 23 (09) 1505-1511
  • 120 Sebbag M, Chapuy-Regaud S, Auger I. , et al. Clinical and pathophysiological significance of the autoimmune response to citrullinated proteins in rheumatoid arthritis. Joint Bone Spine 2004; 71 (06) 493-502
  • 121 Yamada R, Suzuki A, Chang X, Yamamoto K. Citrullinated proteins in rheumatoid arthritis. Front Biosci 2005; 10: 54-64
  • 122 Henschen A, Lottspeich F, Kehl M, Southan C. Covalent structure of fibrinogen. Ann N Y Acad Sci 1983; 408: 28-43
  • 123 Cohen C, Parry DA. Alpha-helical coiled coils and bundles: how to design an alpha-helical protein. Proteins 1990; 7 (01) 1-15
  • 124 Kollman JM, Pandi L, Sawaya MR, Riley M, Doolittle RF. Crystal structure of human fibrinogen. Biochemistry 2009; 48 (18) 3877-3886
  • 125 Litvinov RI, Faizullin DA, Zuev YF, Weisel JW. The α-helix to β-sheet transition in stretched and compressed hydrated fibrin clots. Biophys J 2012; 103 (05) 1020-1027
  • 126 Zhmurov A, Kononova O, Litvinov RI, Dima RI, Barsegov V, Weisel JW. Mechanical transition from α-helical coiled coils to β-sheets in fibrin(ogen). J Am Chem Soc 2012; 134 (50) 20396-20402
  • 127 Purohit PK, Litvinov RI, Brown AE, Discher DE, Weisel JW. Protein unfolding accounts for the unusual mechanical behavior of fibrin networks. Acta Biomater 2011; 7 (06) 2374-2383
  • 128 Greenwald J, Riek R. Biology of amyloid: structure, function, and regulation. Structure 2010; 18 (10) 1244-1260
  • 129 Eisenberg D, Jucker M. The amyloid state of proteins in human diseases. Cell 2012; 148 (06) 1188-1203
  • 130 Pepys MB. Amyloidosis. Annu Rev Med 2006; 57: 223-241
  • 131 Stangou AJ, Banner NR, Hendry BM. , et al. Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation. Blood 2010; 115 (15) 2998-3007
  • 132 Pretorius E, Bester J, Page MJ, Kell DB. The potential of LPS-binding protein to reverse amyloid formation in plasma fibrin of individuals with Alzheimer-type dementia. Front Aging Neurosci 2018; 10: 257
  • 133 Pretorius E, Page MJ, Engelbrecht L, Ellis GC, Kell DB. Substantial fibrin amyloidogenesis in type 2 diabetes assessed using amyloid-selective fluorescent stains. Cardiovasc Diabetol 2017; 16 (01) 141
  • 134 Pretorius E, Page MJ, Mbotwe S, Kell DB. Lipopolysaccharide-binding protein (LBP) can reverse the amyloid state of fibrin seen or induced in Parkinson's disease. PLoS One 2018; 13 (03) e0192121
  • 135 Pretorius E, Page MJ, Hendricks L, Nkosi NB, Benson SR, Kell DB. Both lipopolysaccharide and lipoteichoic acids potently induce anomalous fibrin amyloid formation: assessment with novel Amytracker™ stains. J R Soc Interface 2018; 15 (139) 20170941
  • 136 Page MJ, Thomson GJA, Nunes JM. , et al. Serum amyloid A binds to fibrin(ogen), promoting fibrin amyloid formation. Sci Rep 2019; 9 (01) 3102
  • 137 Osaki D, Hiramatsu H. Citrullination and deamidation affect aggregation properties of amyloid β-proteins. Amyloid 2016; 23 (04) 234-241
  • 138 Sakono M, Zako T. Amyloid oligomers: formation and toxicity of Abeta oligomers. FEBS J 2010; 277 (06) 1348-1358
  • 139 Connolly M, Marrelli A, Blades M. , et al. Acute serum amyloid A induces migration, angiogenesis, and inflammation in synovial cells in vitro and in a human rheumatoid arthritis/SCID mouse chimera model. J Immunol 2010; 184 (11) 6427-6437
  • 140 Cunnane G, Grehan S, Geoghegan S. , et al. Serum amyloid A in the assessment of early inflammatory arthritis. J Rheumatol 2000; 27 (01) 58-63
  • 141 Hwang YG, Balasubramani GK, Metes ID, Levesque MC, Bridges Jr SL, Moreland LW. Differential response of serum amyloid A to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker. Arthritis Res Ther 2016; 18 (01) 108
  • 142 Targońska-Stępniak B, Majdan M. Serum amyloid A as a marker of persistent inflammation and an indicator of cardiovascular and renal involvement in patients with rheumatoid arthritis. Mediators Inflamm 2014; 2014: 793628
  • 143 Cunnane G, Whitehead AS. Amyloid precursors and amyloidosis in rheumatoid arthritis. Best Pract Res Clin Rheumatol 1999; 13 (04) 615-628
  • 144 Husby G, Husebekk A, Skogen B. , et al. Serum amyloid A (SAA)—the precursor of protein AA in secondary amyloidosis. Adv Exp Med Biol 1988; 243: 185-192
  • 145 Steel DM, Whitehead AS. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol Today 1994; 15 (02) 81-88
  • 146 O'Hara R, Murphy EP, Whitehead AS, FitzGerald O, Bresnihan B. Acute-phase serum amyloid A production by rheumatoid arthritis synovial tissue. Arthritis Res 2000; 2 (02) 142-144
  • 147 Kumon Y, Suehiro T, Hashimoto K, Nakatani K, Sipe JD. Local expression of acute phase serum amyloid A mRNA in rheumatoid arthritis synovial tissue and cells. J Rheumatol 1999; 26 (04) 785-790
  • 148 Urieli-Shoval S, Meek RL, Hanson RH, Eriksen N, Benditt EP. Human serum amyloid A genes are expressed in monocyte/macrophage cell lines. Am J Pathol 1994; 145 (03) 650-660
  • 149 Mullan RH, Bresnihan B, Golden-Mason L. , et al. Acute-phase serum amyloid A stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF-kappaB-dependent signal transduction pathway. Arthritis Rheum 2006; 54 (01) 105-114
  • 150 Kell DB, Pretorius E. Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting. Prog Biophys Mol Biol 2017; 123: 16-41
  • 151 Naito M. Porphyromonas gingivalis-induced platelet aggregation in human plasma. Journal of Oral Biosciences. 2007; 49 (03) 173-179
  • 152 Stobernack T, du Teil Espina M, Mulder LM. , et al. A secreted bacterial peptidylarginine deiminase can neutralize human innate immune defenses. MBio 2018; 9 (05) e01704-e01718
  • 153 Abdullah S-N, Farmer E-A, Spargo L, Logan R, Gully N. Porphyromonas gingivalis peptidylarginine deiminase substrate specificity. Anaerobe 2013; 23: 102-108
  • 154 Wegner N, Wait R, Sroka A. , et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum 2010; 62 (09) 2662-2672
  • 155 Potempa J, Pike R, Travis J. The multiple forms of trypsin-like activity present in various strains of Porphyromonas gingivalis are due to the presence of either Arg-gingipain or Lys-gingipain. Infect Immun 1995; 63 (04) 1176-1182
  • 156 McGraw WT, Potempa J, Farley D, Travis J. Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect Immun 1999; 67 (07) 3248-3256
  • 157 Quirke A-M, Lugli EB, Wegner N. , et al. Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Ann Rheum Dis 2014; 73 (01) 263-269
  • 158 Montgomery AB, Kopec J, Shrestha L. , et al. Crystal structure of Porphyromonas gingivalis peptidylarginine deiminase: implications for autoimmunity in rheumatoid arthritis. Ann Rheum Dis 2016; 75 (06) 1255-1261
  • 159 Yamakawa M, Ouhara K, Kajiya M. , et al. Porphyromonas gingivalis infection exacerbates the onset of rheumatoid arthritis in SKG mice. Clin Exp Immunol 2016; 186 (02) 177-189
  • 160 Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A. , et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 2013; 5 (178) 178ra40
  • 161 Bartold PM, Marino V, Cantley M, Haynes DR. Effect of Porphyromonas gingivalis-induced inflammation on the development of rheumatoid arthritis. J Clin Periodontol 2010; 37 (05) 405-411
  • 162 Lönn J, Ljunggren S, Klarström-Engström K, Demirel I, Bengtsson T, Karlsson H. Lipoprotein modifications by gingipains of Porphyromonas gingivalis . J Periodontal Res 2018; 53 (03) 403-413
  • 163 Bale BF, Doneen AL, Vigerust DJ. High-risk periodontal pathogens contribute to the pathogenesis of atherosclerosis. Postgrad Med J 2017; 93 (1098): 215-220
  • 164 Imamura T, Tanase S, Hamamoto T, Potempa J, Travis J. Activation of blood coagulation factor IX by gingipains R, arginine-specific cysteine proteinases from Porphyromonas gingivalis . Biochem J 2001; 353 (Pt 2): 325-331
  • 165 Imamura T, Potempa J, Tanase S, Travis J. Activation of blood coagulation factor X by arginine-specific cysteine proteinases (gingipain-Rs) from Porphyromonas gingivalis . J Biol Chem 1997; 272 (25) 16062-16067
  • 166 Imamura T, Banbula A, Pereira PJ, Travis J, Potempa J. Activation of human prothrombin by arginine-specific cysteine proteinases (Gingipains R) from Porphyromonas gingivalis . J Biol Chem 2001; 276 (22) 18984-18991
  • 167 Guo Y, Nguyen KA, Potempa J. Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon's knife to a meat chopper-like brutal degradation of proteins. Periodontol 2000 2010; 54 (01) 15-44
  • 168 Imamura T, Potempa J, Pike RN, Moore JN, Barton MH, Travis J. Effect of free and vesicle-bound cysteine proteinases of Porphyromonas gingivalis on plasma clot formation: implications for bleeding tendency at periodontitis sites. Infect Immun 1995; 63 (12) 4877-4882
  • 169 Lourbakos A, Yuan YP, Jenkins AL. , et al. Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity. Blood 2001; 97 (12) 3790-3797
  • 170 Adams B, Nunes JM, Page MJ. , et al. Parkinson's disease: a systemic inflammatory disease accompanied by bacterial inflammagens. Front Aging Neurosci 2019; 11 (210) 210
  • 171 McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365 (23) 2205-2219
  • 172 Vossenaar ER, Smeets TJ, Kraan MC, Raats JM, van Venrooij WJ, Tak PP. The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum 2004; 50 (11) 3485-3494
  • 173 van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum 2006; 54 (04) 1117-1121
  • 174 Vossenaar ER, Radstake TR, van der Heijden A. , et al. Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis 2004; 63 (04) 373-381
  • 175 Chang X, Yamada R, Suzuki A. , et al. Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford) 2005; 44 (01) 40-50
  • 176 Smiley ST, King JA, Hancock WW. Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J Immunol 2001; 167 (05) 2887-2894
  • 177 Hsieh JY, Smith TD, Meli VS, Tran TN, Botvinick EL, Liu WF. Differential regulation of macrophage inflammatory activation by fibrin and fibrinogen. Acta Biomater 2017; 47: 14-24
  • 178 Rubel C, Fernández GC, Dran G, Bompadre MB, Isturiz MA, Palermo MS. Fibrinogen promotes neutrophil activation and delays apoptosis. J Immunol 2001; 166 (03) 2002-2010
  • 179 Guo M, Sahni SK, Sahni A, Francis CW. Fibrinogen regulates the expression of inflammatory chemokines through NF-kappaB activation of endothelial cells. Thromb Haemost 2004; 92 (04) 858-866
  • 180 Liu X, Piela-Smith TH. Fibrin(ogen)-induced expression of ICAM-1 and chemokines in human synovial fibroblasts. J Immunol 2000; 165 (09) 5255-5261
  • 181 Weinberg JB, Pippen AM, Greenberg CS. Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 1991; 34 (08) 996-1005
  • 182 Clavel C, Ceccato L, Anquetil F, Serre G, Sebbag M. Among human macrophages polarised to different phenotypes, the M-CSF-oriented cells present the highest pro-inflammatory response to the rheumatoid arthritis-specific immune complexes containing ACPA. Ann Rheum Dis 2016; 75 (12) 2184-2191
  • 183 Sokolove J, Zhao X, Chandra PE, Robinson WH. Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis Rheum 2011; 63 (01) 53-62
  • 184 Zhu W, Li X, Fang S. , et al. Anti-citrullinated protein antibodies induce macrophage subset disequilibrium in RA patients. Inflammation 2015; 38 (06) 2067-2075
  • 185 Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007; 81 (01) 1-5
  • 186 Hu F, Li Y, Zheng L. , et al. Toll-like receptors expressed by synovial fibroblasts perpetuate Th1 and th17 cell responses in rheumatoid arthritis. PLoS One 2014; 9 (06) e100266
  • 187 Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 2010; 233 (01) 233-255
  • 188 Makarov SS. NF-kappa B in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res 2001; 3 (04) 200-206
  • 189 Smolen JS, Redlich K, Zwerina J, Aletaha D, Steiner G, Schett G. Pro-inflammatory cytokines in rheumatoid arthritis: pathogenetic and therapeutic aspects. Clin Rev Allergy Immunol 2005; 28 (03) 239-248
  • 190 Siebert S, Tsoukas A, Robertson J, McInnes I. Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. Pharmacol Rev 2015; 67 (02) 280-309
  • 191 Bystrom J, Clanchy FI, Taher TE. , et al. TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases. Cytokine 2018; 101: 4-13
  • 192 Rho YH, Chung CP, Oeser A. , et al. Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis. Arthritis Rheum 2009; 61 (11) 1580-1585
  • 193 Kawashima M, Miossec P. Effect of treatment of rheumatoid arthritis with infliximab on IFN gamma, IL4, T-bet, and GATA-3 expression: link with improvement of systemic inflammation and disease activity. Ann Rheum Dis 2005; 64 (03) 415-418
  • 194 Pawlik A, Ostanek L, Brzosko I. , et al. Therapy with infliximab decreases the CD4+CD28-T cell compartment in peripheral blood in patients with rheumatoid arthritis. Rheumatol Int 2004; 24 (06) 351-354
  • 195 Abbas S, Zhang YH, Clohisy JC, Abu-Amer Y. Tumor necrosis factor-alpha inhibits pre-osteoblast differentiation through its type-1 receptor. Cytokine 2003; 22 (1-2): 33-41
  • 196 Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000; 106 (12) 1481-1488
  • 197 Pignatelli P, De Biase L, Lenti L. , et al. Tumor necrosis factor-alpha as trigger of platelet activation in patients with heart failure. Blood 2005; 106 (06) 1992-1994
  • 198 Chen W, Wang Q, Ke Y, Lin J. Neutrophil function in an inflammatory milieu of rheumatoid arthritis. J Immunol Res 2018; 2018: 8549329
  • 199 Khawaja AA, Pericleous C, Ripoll VM, Porter JC, Giles IP. Autoimmune rheumatic disease IgG has differential effects upon neutrophil integrin activation that is modulated by the endothelium. Sci Rep 2019; 9 (01) 1283
  • 200 Thieblemont N, Wright HL, Edwards SW, Witko-Sarsat V. Human neutrophils in auto-immunity. Paper presented at: Seminars in Immunology; 2016
  • 201 Brinkmann V, Reichard U, Goosmann C. , et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663): 1532-1535
  • 202 Zou Y, Chen X, Xiao J. , et al. Neutrophil extracellular traps promote lipopolysaccharide-induced airway inflammation and mucus hypersecretion in mice. Oncotarget 2018; 9 (17) 13276-13286
  • 203 Clark SR, Ma AC, Tavener SA. , et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13 (04) 463-469
  • 204 Keshari RS, Jyoti A, Dubey M. , et al. Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition. PLoS One 2012; 7 (10) e48111
  • 205 Spengler J, Lugonja B, Ytterberg AJ. , et al. Release of active peptidyl arginine deiminases by neutrophils can explain production of extracellular citrullinated autoantigens in rheumatoid arthritis synovial fluid. Arthritis Rheumatol 2015; 67 (12) 3135-3145
  • 206 Varjú I, Kolev K. Networks that stop the flow: a fresh look at fibrin and neutrophil extracellular traps. Thromb Res 2019; 182: 1-11
  • 207 Fuchs TA, Brill A, Duerschmied D. , et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107 (36) 15880-15885
  • 208 Varjú I, Longstaff C, Szabó L. , et al. DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thromb Haemost 2015; 113 (06) 1289-1298
  • 209 Chang X, Yamada R, Sawada T, Suzuki A, Kochi Y, Yamamoto K. The inhibition of antithrombin by peptidylarginine deiminase 4 may contribute to pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 2005; 44 (03) 293-298
  • 210 Longstaff C, Varjú I, Sótonyi P. , et al. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem 2013; 288 (10) 6946-6956
  • 211 Xaus J, Comalada M, Valledor AF. , et al. LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-alpha. Blood 2000; 95 (12) 3823-3831