Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by autoantibodies directed against various biomolecules. The initial immunogens that drive the development of SLE are unknown, but characteristics of the immune response in SLE suggest that it is an antigen-driven response, and a chromatin antigen could be one of the immunogens for the production of antinuclear antibodies (ANA) in SLE. Other factors implicated in the pathogenesis of SLE include nitrogen-free radicals such as nitric oxide and peroxynitrite. The free radical-mediated damage to proteins results in the modification of amino acid residues, cross-linking of side chains and fragmentation. The tyrosine residues in proteins are susceptible to attack by various reactive nitrogen intermediates, including peroxynitrite to form 3-nitrotyrosine (3-NT). The presence of nitrated proteins in vivo indicates that peptides derived from the proteolytic degradation of modified proteins could serve as neoantigens. Histones are highly conserved proteins that are rich in basic amino acids lysine and arginine. Autoantibodies against histones and anti-DNA antibodies are present in SLE. The anti-DNA autoantibodies coexist with anti-histone autoantibodies and may react with chromatin-associated histones and histone complexes. Elevated levels of reactive nitrogen species (RNS) in SLE patients suggest a possible role in the pathogenesis of the disease. The alteration of proteins resulting from photomodification or peroxynitrite could lead to the development of antibodies. Therefore, the modified proteins or photoadducts could have important implications in autoimmunity, and understanding the pathophysiology of peroxynitrite-modified biomolecules could lead to a better understanding of autoimmune phenomenon in SLE.
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Abbreviations
- SLE:
-
Systemic lupus erythematosus
- 3-NT:
-
3-nitrotyrosine
- NO:
-
Nitric oxide
- \( {\text{O}}_{2}^{ \cdot - } \) :
-
Superoxide anion
- RNS:
-
Reactive nitrogen species
- nDNA:
-
Native DNA
- RNOS:
-
Reactive nitrogen oxide species
References
Lahita RG (1999) Systemic lupus erythematosus, 3rd edn. Academic Press, San Diego
Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, Mejia JC, Aydintug AO, Chwalinska-Sadowska H, de Ramon E, Fernandez-Nebro A, Galeazzi M, Valen M, Mathieu A, Houssiau F, Caro N, Alba P, Ramos-Casals M, Ingelmo M, Hughes GR (2003) Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine 82:299–308
Pons-Estel GJ, Alarcon GS, Scofield L, Reinlib L, Cooper GS (2010) Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 39:257–268
Trager J, Ward MM (2001) Mortality and causes of death in systemic lupus erythematosus. Curr Opin Rheumatol 13:345–351
Tsokos GC (2011) Systemic lupus erythematosus. N Engl J Med 365:2110–2121
Jonsen A, Bengtsson AA, Nived O, Truedsson L, Sturfelt G (2007) Gene–environment interactions in the aetiology of systemic lupus erythematosus. Autoimmunity 40:613–617
Simard JF, Costenbader KH, Liang MH, Karlson EW, Mittleman MA (2009) Exposure to maternal smoking and incident SLE in a prospective cohort study. Lupus 18:431–435
Bijl M, Kallenberg CG (2006) Ultraviolet light and cutaneous lupus. Lupus 15:724–727
Ballestar E, Esteller M, Richardson BC (2006) The epigenetic face of systemic lupus erythematosus. J Immunol 176:7143–7147
Lichtman EI, Helfgott SM, Kriegel MA (2012) Emerging therapies for systemic lupus erythematosus–focus on targeting interferon-alpha. Clin Immunol 143(3):210–221
Munoz LE, Gaipl US, Franz S, Sheriff A, Voll RE, Kalden JR, Herrmann M (2005) SLE-disease of clearance deficiency? Rheumatology 44:1101–1107
Herrmann RE Voll, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR (1998) Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41:1241–1250
Janko C, Schorn C, Grossmayer GE, Frey B, Herrmann M, Gaipl US, Munoz LE (2008) Inflammatory clearance of apoptotic remnants in systemic lupus erythematosus (SLE). Autoimmun Rev 8:9–12
Rahman A, Isenberg DA (2008) Systemic lupus erythematosus. N Engl J Med 358:929–939
Koffler D, Schur PH, Kunkel HG (1967) Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med 126:607–624
Ahsan H, Ali A, Ali R (2003) Oxygen free radicals and systemic autoimmunity. Clin Exp Immunol 131(3):398–404
Ahmad R, Ahsan H (2011) Contribution of peroxynitrite, a reactive nitrogen species, in the pathogenesis of autoimmunity. In: Mavragani CP (ed) Autoimmune disorders-pathogenetic aspects. Intech Open Access Publishers, Croatia, pp 141–156
Szabo C (2003) Multiple pathways of peroxynitrite cytotoxicity. Toxicol Lett 140–141:105–112
Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87(1):315–424
Szabo C, Ischiropoulos H, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6(8):662–680
Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide and peroxynitrite: the good the bad and the ugly. Am J Physiol 271:C1424–C1437
Sampson JB, Ye Y, Rosen H, Beckman JS (1998) Myeloperoxidase and horseradish peroxidase catalyze tyrosine nitration in proteins from nitric oxide and hydrogen peroxide. Arch Biochem Biophys 356:207–213
Marletta MA (1988) Mammalian synthesis of nitrite, nitrate, nitric oxide and N-nitrosating agents. Chem Res Toxicol 1:249–257
Miles AM, Gibson M, Krishna M, Cook JC, Pacelli R, Wink DA, Grisham MB (1995) Effects of superoxide on nitric oxide dependent N-nitrosation reactions. Free Radic Res 233:379–390
Liu RH, Baldwin B, Tennant BC, Hotchkiss JH (1991) Elevated formation of nitrate and N-nitrosodimethylamine is wood chucks (Marmota monax) associated with chronic woodchuck hepatitis virus infection. Cancer Res 51:3925–3929
Liu RH, Jacob JR, Tennant BD, Hotchkiss JH (1992) Nitrite and nitrosoamine synthesis by hepatocytes isolated from normal woodchucks, (Marmota Monax) and woodchucks chronically infected with woodchuck hepatitis virus. Cancer Res 52:3925–3929
Merchant K, Chen H, Gonzalez TC, Keefer LK, Shaw BR (1996) Deamination of single stranded DNA cytosine residues in aerobic nitric oxide solution at micromolar total NO exposures. Chem Res Toxicol 9:891–896
Ahmad R, Rasheed Z, Ahsan H (2009) Biochemical and cellular toxicology of peroxynitrite: implications in cell death and autoimmune phenomenon. Immunopharmacol Immunotoxicol 18(7):388–396
Maeda H, Akaike T (1998) Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Moscow) 63(7):854–865
Ohshima H, Bartsch H (1994) Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat Res 305(2):253–264
Rubbo H (1998) Nitric oxide and peroxynitrite in lipid peroxidation. Medicina B Aires 58(4):361–366
Rubbo H, Freeman BA (1996) Nitric oxide regulation of lipid oxidation reactions: formation and analysis of nitrogen-containing oxidized lipid derivatives. Methods Enzymol 269:385–394
Rubbo H, Radi R, Trujillo M, Telleri R, Kalyanaraman B, Barnes S, Kirk M, Freeman BA (1994) Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. J Biol Chem 269(42):26066–26075
Pfeiffer S, Mayer B, Hemmens B (1999) Nitric oxide: chemical puzzles posed by a biological messenger. Angew Chem Int Ed 8:1714–1731
Beckman JS (1996) Oxidative damage and tyrosine nitration by peroxynitrite. Chem Res Toxicol 9:836–844
Eiserich JP, Hristova M, Goss CE, Jones AD, Freeman BA, Halliwell B, Vander Vliet A (1998) Formation of nitric oxide derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391:393–397
Kaur H, Halliwell B (1994) Evidence for nitric oxide mediated oxidative damage in chronic inflammation, nitrotyrosine in serum and synovial fluid from rheumatoid patients. FEBS Lett 350:9–12
Khan F, Siddiqui AA (2006) Prevalence of anti-3-nitrotyrosine antibodies in the joint synovial fluid of patients with rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus. Clin Chim Acta 370:100–107
Radi R, Peluffo G, Alvarez MN, Naviliat M, Cayota A (2001) Unraveling peroxynitrite formation in biological systems. Free Radic Biol Med 30:463–488
Greenacre SAB, Ischiropoulos H (2001) Tyrosine nitration: localization, quantification, consequences for protein function and signal transduction. Free Radic Biol Med 34:541–581
Turko IV, Murad F (2002) Protein nitration in cardiovascular diseases. Pharmacol Rev 54:619–634
Wink DA, Look JA, Kim S, Vodovotz Y, Pacelli R, Krishna MC, Russo A, Mitchel JB, Jourdheuil D, Miles AM, Grisham MB (1997) Superoxide modulates the oxidation and nitrosation of thiols by nitric oxide derived reactive intermediates. J Biol Chem 272:11147–11151
Islam N, Ali R (1998) Immunological studies on DNA-lysine photoadduct. Biochem Mol Biol Int 45(3):453–464
Ahmad R, Alam K, Ali R (2000) Antigen binding characteristics of antibodies against hydroxyl radical modified thymidine monophosphate. Immunol Lett 71:111–115
Khan MA, Dixit K, Jabeen S, Moinuddin, Alam K (2009) Impact of peroxynitrite modification on structure and immunogenicity of H2A histone. Scan J Immunol 69:99–109
Pisetsky DS (1994) Antinuclear antibodies. Diagn Lab Immunol 14:371–385
Gabler C, Kalden JR, Lorenz HM (2003) The putative role of apoptosis-modified histones for the induction of autoimmunity in systemic lupus erythematosus. Biochem Pharmacol 66:1441–1446
Jog NR, Frisoni L, Shi Q, Monestier M, Hernandez S, Craft J, Prak ET, Caricchio R (2012) Caspase-activated DNase is required for maintenance of tolerance to lupus nuclear autoantigens. Arthritis Rheum 64(4):1247–1256
Morino N, Sakurai H, Yamada A, Yazaki Y, Minota S (1995) Rabbit anti-chromatin antibodies recognize similar epitopes on a histone H1 molecule as lupus autoantibodies. Clin Immunol Immunopathol 77:52–58
Khan F, Khan F, Siddiqui AA, Ali R (2006) Plasmid DNA acquires immunogenicity on exposure to singlet oxygen. Biochemistry (Moscow) 71:871–878
Isenberg D, Shenfeld Y (1997) The origin and significance of anti-DNA antibodies. Immunol Today 8:279–281
Tan EM (1982) Autoantibody to nuclear antigens (ANA): their immunobiology and medicine. Adv Immunol 33:167–208
Pollard KM, Jones JE, Tan EM, Theofilopoulos AN, Dixon FJ, Rubin RL (1986) Polynucleotide specificity of murine monoclonal anti-DNA antibodies. Clin Immunol Immunopathol 40:197–208
Aulak KS, Miyagi M, Yan L (2001) Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. Proc Natl Acad Sci USA 98:12056–12061
Crow JP (1999) Measurement and significance of free and protein-bound 3-nitrotyrosine, 3-chlorotyrosine, and free 3-nitro-4-hydroxyphenylacetic acid in biologic samples: a high-performance liquid chromatography method using electrochemical detection. Methods Enzymol 301:151–160
Habib S, Moinuddin, Ali R (2006) Peroxynitrite-modified DNA: a better antigen for systemic lupus erythematosus anti-DNA autoantibodies. Biotechnol Appl Biochem 43:65–70
Gilkeson G, Cannon C, Oates J, Reilly C, Goldman D, Petri M (1999) Correlation of serum measures of nitric oxide production with lupus disease activity. J Rheumatol 26:318–324
Oates JC, Christensen EF, Reilly CM, Self SE, Gilkeson GS (1999) Prospective measure of serum 3-nitrotyrosine levels in systemic lupus erythematosus: correlation with disease activity. Proc Assoc Am Physicians 111:611–621
Wanchu A, Khullar M, Deodhar SD, Bambery P, Sud A (1998) Nitric oxide synthesis is increased in patients with systemic lupus erythmatosus. Rheumatol Int 18(2):41–43
Oates JC, Ruiz P, Alexander A, Pippen AM, Gilkeson GS (1997) Effect of late modulation of nitric oxide production on murine lupus. Clin Immunol Immunopathol 83(1):86–92
Browne SE, Ferrante RJ, Beal MF (1999) Oxidative stress in Huntington’s disease. Brain Pathol 9(1):147–163
Ahmad R, Rasheed Z, Kaushal E, Singh D, Ahsan H (2008) Biochemical evaluation of human DNA-lysine photoadduct treated with peroxynitrite. Toxicol Mech Method 18:589–595
Pisetsky DS (1992) Anti-DNA antibodies in systemic lupus erythematosus. Rheum Dis Clin North Am 18:437–454
Herrmann M, Winkler TH, Fehr H, Kalden JR (1995) Preferential recognition of specific DNA motifs by anti-double-stranded DNA autoantibodies. Eur J Immunol 25:1897–1904
Muller S, Isabey A, Cooppez M, Plaue S, Sommermeyer G, Van Regenmortel MH (1987) Specificity of antibodies raised against triacetylated histone H4. Mol Immunol 24:779–789
Gheidira I, Andolsi H, Mankai A, Fabien N, Jeddi M (2006) Anti-histone antibodies in systemic lupus erythmatosus, comparison of three assays: ELISA, dot blot and immunoblot. Pathol Biol 54:148–154
Ahsan H, Abdi S, Ali A (2002) Recognition of DNA-arginine photoadduct by anti-DNA auto-antibodies in systemic lupus erythematosus. Ind J Med Res 115:201–211
Dixit K, Moinuddin, Ali A (2005) Immunological studies on peroxynitrite modified DNA. Life Sci 77(21):2626–2642
Burney S, Caulfield JL, Niles JC, Wishnok JS, Tannenbaum SR (1999) The chemistry of DNA damage from nitric oxide and peroxynitrite. Mutat Res 424(1–2):37–49
Habib S, Moinuddin, Ali R (2005) Acquired antigenicity of DNA after modification with peroxynitrite. Int J Biol Macromol 35(3–4):221–225
Ahmad R, Yadav N, Chaudhary K, Heming T, Ahsan H (2012) Analysis of human DNA-arginine photoadduct modified with peroxynitrite. Nucleosides Nucleotides Nucleic Acids 31:377–387
Davies KJ (1987) Protein damage and degradation by oxygen radicals. I. General aspects. J Biol Chem 262:9895–9901
Davies KJ, Delsignore ME, Lin SW (1987) Protein damage and degradation by oxygen radicals. II. Modification of amino acids. J Biol Chem 262:9902–9907
Davies KJ, Delsignore ME (1987) Protein damage and degradation by oxygen radicals. III. Modification of secondary and tertiary structure. J Biol Chem 262:9908–9913
Tsikas D, Caidahl K (2005) Recent methodological advances in the mass spectrometric analysis of free and protein-associated 3-nitrotyrosine in human plasma. J Chromatogr B Anal Technol Biomed Life Sci 814:1–9
Xiao GG, Nel AE, Loo JA (2005) Nitrotyrosine-modified proteins and oxidative stress induced by diesel exhaust particles. Electrophoresis 26:280–292
Reynolds MR, Berry RW, Binder LI (2005) Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: implications for Alzheimer’s disease. Biochemistry 44:1690–1700
Brito C, Naviliat M, Tiscornia AC, Vuillier F, Gualco G, Dighiero G, Radi R, Cayota AM (1999) Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death. J Immunol 162:3356–3366
Heijnen HF, van Donselaar E, Slot JW, Fries DM, Blachard-Fillion B, Hodara R, Lightfoot R, Polydoro M, Spielberg D, Thomson L, Regan EA, Crapo J, Ischiropoulos H (2006) Subcellular localization of tyrosine-nitrated proteins is dictated by reactive oxygen species generating enzymes and by proximity to nitric oxide synthase. Free Radic Biol Med 40:1903–1913
Fries DM, Paxinou E, Themistocleous M, Swanberg E, Griendling KK, Salvemini D, Slot JW, Heijnen HF, Hazen SL, Ischiropoulos H (2003) Expression of inducible nitric-oxide synthase and intracellular protein tyrosine nitration in vascular smooth muscle cells: role of reactive oxygen species. J Biol Chem 278:22901–22907
Anderton SM (2004) Post-translational modifications of self antigens: implications for autoimmunity. Curr Opin Immunol 16:753–758
Ohmori H, Oka M, Nishikawa Y (2005) Immunogenicity of autologous IgG bearing the inflammation-associated marker 3-nitrotyrosine. Immunol Lett 96:47–54
Ramezanian MS, Padmaja S, Koppenol WH (1996) Nitration and hydroxylation of phenolic compounds by Peroxynitrite. Chem Res Toxicol 9(1):232–240
Ramezanian MS, Padmaja S, Koppenol WH (1996) Nitration and hydroxylation of phenolic compounds by peroxynitrite. Methods Enzymol 269:195–201
Alvarez B, Radi R (2003) Peroxynitrite reactivity with amino acids and proteins. Amino Acids 25(3–4):295–311
Luxford C, Morin B, Dean RT, Davies MJ (1999) Histone H1 and other protein- and amino acid-hydroperoxides can give rise to free radicals which oxidize DNA. Biochem J 344(1):125–134
van Holde KE (1989) Chromatin. In: Rich A (ed) Springer series in molecular biology. Springer, New York
Burlingame RW, Rubin RL, Balderas RS, Theofilopoulos AN (1993) Genesis and evolution of antichromatin autoantibodies in murine lupus implicates T-dependent immunization with self antigen. J Clin Invest 91:1687–1696
Burlingame RW, Boey ML, Starkebaum G (1994) The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus. J Clin Invest 94:184–192
Losman MJ, Fasy TM, Novick KE, Monestier M (1992) Monoclonal autoantibodies to subnucleosomes from a MRL/MP- +/+ mouse. Oligoclonality of the antibody response and recognition of a determinant composed of histones H2A, H2B and DNA. J Immunol 48:1561–1569
Losman MJ, Fasy TM, Novick KE (1993) Relationships among antinuclear antibodies from autoimmune MRL mice reacting with histone H2A–H2B dimers and DNA. Int Immunol 5:513–523
Marc M, Thomas M, Lothar B, Frank SL (1991) Anti-histone antibodies in subacute sensory neuropathy. J Neurooncol 11:71–75
Masahidi K, Hironobu I, Norhito Y, Shinichi S, Kanako K, Kunihiko T (1999) Prevalence and antigen specificity of anti-histone antibodies in patients with polymyositis/dermatomyositis. J Invest Dermatol 112:1523–1747
Zhang W, Reichlin M (2005) A peptide DNA surrogate that binds and inhibits anti-dsDNA antibodies. Clin Immunol 117:214–220
Drew B, Leeuwenburg C (2002) Aging and the role of reactive nitrogen species. Ann N Y Acad Sci 959:66–81
Oates JC, Gilkeson GS (2006) The biology of nitric oxide and other reactive intermediates in systemic lupus erythematosus. Clin Immunol 121:243–250
Ohshima H, Friesen M, Brouet I, Bartsch H (1999) Nitrotyrosine as new marker for endogenous nitrosation and nitration of proteins. Food Chem Toxicol 28:647–652
Dixit K, Ali R (2004) Role of nitric oxide modified DNA in the etiopathogenesis of systemic lupus erythematosus. Lupus 13(2):95–100
Wigand R, Meyer J, Busse R, Hecker M (1997) Increased serum NG-hydroxy-l-arginine in patients with rheumatoid arthritis and systemic lupus erythematosus as an index of an increased nitric oxide synthase activity. Ann Rheum Dis 56:330–332
Khan F, Ali R (2006) Antibodies against nitric oxide damaged poly-l-tyrosine and 3-nitrotyrosine levels in systemic lupus erythematosus. J Biochem Mol Biol 39(2):189–196
Sandhu JK, Robertson S, Birnboim HC, Goldstein R (2003) Distribution of protein nitrotyrosine in synovial tissues of patients with rheumatoid arthritis and osteoarthritis. J Rheumatol 30(6):1173–1181
Dixit K, Khan MA, Sharma YD, Moinuddin, Alam K (2011) Peroxynitrite-induced modification of H2A histone presents epitopes which are strongly bound by human anti-DNA autoantibodies: role of peroxynitrite-modified-H2A in SLE induction and progression. Hum Immunol 72(3):219–225
Khan M, Dixit K, Moinuddin, Malik A, Alam K (2012) Role of peroxynitrite-modified H2A histone in the induction and progression of rheumatoid arthritis. Scan J Rheumatol 1–8 (in press)
Nissim A, Winyard PG, Corrigall V, Fatah R, Perrett D, Pinayi G, Chernajovsky Y (2005) Generation of neoantigenic epitopes after posttranslational modification of type II collagen by factors present within the inflamed joint. Arthritis Rheum 52(12):3829–3838
Lowenstein CJ, Dinerman JL, Snyder SH (1994) Nitric oxide: a physiologic messenger. Ann Intern Med 120:227–237
Ballestar E, Esteller M, Richardson BC (2006) The epigenetic face of systemic lupus erythematosus. J Immunol 176:7143–7147
Radi R (2004) Nitric oxide, oxidants, and protein tyrosine nitration. Proc Natl Acad Sci USA 101:4003–4008
Ischiropoulos H (1998) Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys 356:1–11
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RA is grateful to the administration of Oman Medical College, Sohar Campus, Oman for the continued support during the preparation of this manuscript. We express our sincere regrets if citations of some authors may have been inadvertently missed in the review article.
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Ahmad, R., Ahsan, H. Role of peroxynitrite-modified biomolecules in the etiopathogenesis of systemic lupus erythematosus. Clin Exp Med 14, 1–11 (2014). https://doi.org/10.1007/s10238-012-0222-5
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DOI: https://doi.org/10.1007/s10238-012-0222-5