- Review Article
- Published:
Protective molecules and their cognate antibodies: new players in autoimmunity
Autoimmunity Highlights volume 1, pages 63–72 (2010)
Abstract
Impairment of the clearance of apoptotic material seems to contribute to autoantigen exposure, which can initiate or maintain an autoimmune response in predisposed individuals. Complement component C1q, Creactive protein (CRP), serum amyloid P (SAP), mannose-binding lectin (MBL), apolipoprotein A-1 (Apo A-1) and long pentraxin 3 (PTX3) are molecules involved in the removal of apoptotic bodies and pathogens, and in other antiinflammatory pathways. For this reason they have been called “protective” molecules. C1q has a key role in the activation of the complement cascade and acts as a bridging molecule between apoptotic bodies and macrophages favouring phagocytosis. In addition to other functions, CRP, SAP and MBL bind to the surface of numerous pathogens as well as cellular debris and activate the complement cascade, thus stimulating their clearance by immune cells. The role of PTX3 is more controversial. In fact, PTX also promotes the clearance of microorganisms, but the activation of the complement cascade through C1q and removal of apoptotic material can be either stimulated or inhibited by this molecule. Antibodies against protective molecules have been recently reported in systemic lupus erythematosus and other autoimmune rheumatic diseases. Some of them seem to be pathogenetic and others protective. Thus, protective molecules and their cognate antibodies may constitute a regulatory network involved in autoimmunity. Dysregulation of this system might contribute to the development of autoimmune diseases in predisposed individuals.
References
Janko C, Schorn C, Grossmayer GE et al (2008) Inflammatory clearance of apoptotic remnants in systemic lupus erythematosus (SLE). Autoimmun Rev 8:9–12
Coleman ML, Sahai EA, Yeo M et al (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3(4):339–345
McPhillips KA, Erwig LP (2009) Assessment of apoptotic cell phagocytosis by macrophages. Methods Mol Biol 559:247–256
Sontheimer RD, Racila E, Racila DM (2005) C1q: its functions within the innate and adaptive immune responses and its role in lupus autoimmunity. J Invest Dermatol 125(1):14–23
Païdassi H, Tacnet-Delorme P, Garlatti V et al (2008) C1q binds to phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J Immunol 180(4):2329–2338
van de Wetering JK, van Golde LM, Batenburg JJ (2004) Collectins: players of the innate immune system. Eur J Biochem 271(7):1229–1249
Ahmed AE, Veitch J, Whaley K (1990) Mechanism of action of an inhibitor of complement-mediated prevention of immune precipitation. Immunology 70(2):139–144
Botto M (1998) C1q knock-out mice for the study of complement deficiency in autoimmune disease. Exp Clin Immunogenet 15(4):231–234
Botto M, Dell’Agnola C, Bygrave AE et al (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19(1):56–59
Marto N, Bertolaccini ML, Calabuig E et al (2005) Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus. Ann Rheum Dis 64(3):444–448
Bijl M, Reefman E, Horst G et al (2006) Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement. Ann Rheum Dis 65(1):57–63
Sinico RA, Radice A, Ikehata M et al (2005) Anti-C1q autoantibodies in lupus nephritis: prevalence and clinical significance. Ann N Y Acad Sci 1050:193–200
Trendelenburg M (2005) Antibodies against C1q in patients with systemic lupus erythematosus. Springer Semin Immunopathol 27(3):276–285
Moroni G, Radice A, Giammarresi G et al (2009) Are laboratory tests useful for monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus nephritis. Ann Rheum Dis 68(2):234–237
Pepys MB, Hirschfield GM (2003) C-reactive protein: a critical update. J Clin Invest 111(12):1805–1812
Szyper Kravitz M, Shoenfeld Y (2006) Autoimmunity to protective molecules: is it the perpetuum mobile (vicious cycle) of autoimmune rheumatic diseases? Nat Clin Pract Rheumatol 2:481–490
Szyper Kravitz M, Pitashny M, Shoenfeld Y (2005) Protective molecules — C-reactive protein (CRP), serum amyloid P (SAP), pentraxin3 (PTX3), mannose-binding lectin (MBL), and apolipoprotein A1 (Apo A1), and their autoantibodies: prevalence and clinical significance in autoimmunity. J Clin Immunol 25:582–591
Castrejón I, Ortiz AM, García-Vicuña R et al (2008) Are the Creactive protein values and erythrocyte sedimentation rate equivalent when estimating the 28-joint disease activity score in rheumatoid arthritis? Clin Exp Rheumatol 26(5):769–775
Szalai AJ (2002) The antimicrobial activity of C-reactive protein. Microbes Infect 4(2):201–205
Kindmark CO (1971) Stimulating effect of C-reactive protein on phagocytosis of various species of pathogenic bacteria. Clin Exp Immunol 8(6):941–948
Bharadwaj D, Mold C, Markham E et al (2001) Serum amyloid P component binds to Fc gamma receptors and opsonizes particles for phagocytosis. J Immunol 166(11):6735–6741
Mold C, Baca R, Du Clos TW (2002) Serum amyloid P component and C-reactive protein opsonize apoptotic cells for phagocytosis through Fcgamma receptors. J Autoimmun 19(3):147–154
Gershov D, Kim S, Brot N et al (2000) C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J Exp Med 192(9):1353–1364
Ridker PM, Paynter NP, Rifai N et al (2008) C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation 118(22):2243–2251
Bucova M, Bernadic M, Buckingham T (2008) C-reactive protein, cytokines and inflammation in cardiovascular diseases. Bratisl Lek Listy 109(8):333–340
Aukrust P, Halvorsen B, Yndestad A et al (2008) Chemokines and cardiovascular risk. Arterioscler Thromb Vasc Biol 28(11):1909–1919
Gonzalez-Gay MA, Llorca J, Garcia-Unzueta MT et al (2008) High-grade inflammation, circulating adiponectin concentrations and cardiovascular risk factors in severe rheumatoid arthritis. Clin Exp Rheumatol 26(4):596–603
Bultink IE, Turkstra F, Diamant M et al (2008) Prevalence of and risk factors for the metabolic syndrome in women with systemic lupus erythematosus. Clin Exp Rheumatol 26(1):32–38
Taskinen S, Hyvönen M, Kovanen PT et al (2005) C-reactive protein binds to the 3beta-OH group of cholesterol in LDL particles. Biochem Biophys Res Commun 329(4):1208–1216
Du Clos TW, Mold C (2004) C-reactive protein: an activator of innate immunity and a modulator of adaptive immunity. Immunol Res 30(3):261–277
Singh U, Dasu MR, Yancey PG et al (2008) Human C-reactive protein promotes oxidized low density lipoprotein uptake and matrix metalloproteinase-9 release in Wistar rats. J Lipid Res 49(5):1015–1023
Bhakdi S, Torzewski M, Paprotka K et al (2004) Possible protective role for C-reactive protein in atherogenesis: complement activation by modified lipoproteins halts before detrimental terminal sequence. Circulation 109(15):1870–1876
Khreiss T, Jozsef L, Potempa LA et al (2004) Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation 109(16):2016–2022
Schwedler SB, Amann K, Wernicke K et al (2005) Native Creactive protein increases whereas modified C-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice. Circulation 112(7):1016–1023
Bassi N, Zampieri S, Ghirardello A et al (2009) Pentraxins, antipentraxins antibodies, and atherosclerosis. Clin Rev Allerg Immunol 37(1):36–43
Keenan RT, Swearingen CJ, Yazici Y (2008) Erythrocyte sedimentation rate and C-reactive protein levels are poorly correlated with clinical measures of disease activity in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis patients. Clin Exp Rheumatol 26(5):814–819
Meyer O (2010) Anti-CRP antibodies in systemic lupus erythematosus. Joint Bone Spine. DOI: 10.1016/j.jbspin.2010.04.010
Wetterö J, Nilsson L, Jonasson L, Sjöwall C (2009) Reduced serum levels of autoantibodies against monomeric C-reactive protein (CRP) in patients with acute coronary syndrome. Clin Chim Acta 400(1–2):128–131
Sjöwall C, Bengtsson AA, Sturfelt G et al (2004) Serum levels of autoantibodies against monomeric C-reactive protein are correlated with disease activity in systemic lupus erythematosus. Arthritis Res Ther 6(2):R87–R94
O’Neill SG, Isenberg DA, Rahman A (2007) Could antibodies to C-reactive protein link inflammation and cardiovascular disease in patients with systemic lupus erythematosus? Ann Rheum Dis 66:989–991
Valdivielso P, Gómez-Doblas JJ, Macias M et al (2008) Lupusassociated endothelial dysfunction, disease activity and arteriosclerosis. Clin Exp Rheumatol 26(5):827–833
Avalos I, Rho YH, Chung CP et al (2008) Atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Clin Exp Rheumatol 26(5 Suppl 51):S5–S13
Doria A, Sherer Y, Meroni PL et al (2005) Inflammation and accelerated atherosclerosis — basic mechanisms. Rheum Dis Clin N Am 31:329–354
Doria A, Shoenfeld Y, Pauletto P (2004) Premature coronary disease in systemic lupus. N Engl J Med 350(15):1571–1575
Doria A, Shoenfeld Y, Wu R et al (2003) Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 62:1071–1077
Doria A, Iaccarino L, Ghirardello A et al (2006) Long-term prognosis and causes of death in systemic lupus erythematosus. Am J Med 119:1497–1499
Emsley J, White HE, O’Hara BP et al (1994) Structure of pentameric human serum amyloid P component. Nature 367(6461):338–345
Mold C, Gresham HD, Du Clos TW (2001) Serum amyloid P component and C-reactive protein mediate phagocytosis through murine Fc gamma Rs. J Immunol 166(2):1200–1205
Bickerstaff MC, Botto M, Hutchinson WL et al (1999) Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 5(6):694–697
Zandman-Goddard G, Blank M, Langevitz P et al (2005) Antiserum amyloid component P antibodies in patients with systemic lupus erythematosus correlate with disease activity. Ann Rheum Dis 64(12):1698–1702
Saevarsdottir S, Vikingsdottir T, Valdimarsson H (2004) The potential role of mannan-binding lectin in the clearance of selfcomponents including immune complexes. Scand J Immunol 60(1–2):23–29
Avcin T, Canova M, Guilpain P et al (2008) Infections, connective tissue diseases and vasculitis. Clin Exp Rheumatol 26(1 Suppl 48):S18–S26
Ramos-Casals M, Brito-Zerón P, Soria N et al (2009) Mannosebinding lectin-low genotypes are associated with milder systemic and immunological disease expression in primary Sjögren’s syndrome. Rheumatology (Oxford) 48(1):65–69
Gupta B, Raghav SK, Agrawal C et al (2006) Anti-MBL autoantibodies in patients with rheumatoid arthritis: prevalence and clinical significance. J Autoimmun 27(2):125–133
Saevarsdottir S, Vikingsdottir T, Vikingsson A et al (2001) Low mannose binding lectin predicts poor prognosis in patients with early rheumatoid arthritis. A prospective study. J Rheumatol 28(4):728–734
Ip WK, Lau YL, Chan SY et al (2000) Mannose-binding lectin and rheumatoid arthritis in southern Chinese. Arthritis Rheum 43(8):1679–1687
Graudal NA, Homann C, Madsen HO et al (1998) Mannan binding lectin in rheumatoid arthritis. A longitudinal study. J Rheumatol 25(4):629–635
Garred P, Madsen HO, Marquart H et al (2000) Two edged role of mannose binding lectin in rheumatoid arthritis: a cross sectional study. J Rheumatol 27(1):26–34
Jacobsen S, Madsen HO, Klarlund M et al (2001) The influence of mannose binding lectin polymorphisms on disease outcome in early polyarthritis. TIRA Group. J Rheumatol 28(5):935–942
Graudal NA, Madsen HO, Tarp U et al (2000) The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis. Arthritis Rheum 43(3):515–521
Font J, Ramos-Casals M, Brito-Zerón P et al (2007) Association of mannose-binding lectin gene polymorphisms with antiphospholipid syndrome, cardiovascular disease and chronic damage in patients with systemic lupus erythematosus. Rheumatology (Oxford) 46(1):76–80
Lee YH, Witte T, Momot T et al (2005) The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis. Arthritis Rheum 52(12):3966–3974
Best LG, Ferrell RE, Decroo S et al (2009) Genetic and other factors determining mannose-binding lectin levels in American Indians: the Strong Heart Study. BMC Med Genet 10:5
Hegele RA, Ban MR, Anderson CM et al (2000) Infectionsusceptibility alleles of mannose-binding lectin are associated with increased carotid plaque area. J Investig Med 48(3):198–202
Tsutsumi A, Takahashi R, Sumida T (2005) Mannose binding lectin: genetics and autoimmune disease. Autoimmun Rev 4(6):364–372
Øhlenschlaeger T, Garred P, Madsen HO et al (2004) Mannosebinding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus. N Engl J Med 351(3):260–267
Mok MY, Jack DL, Lau CS et al (2004) Antibodies to mannose binding lectin in patients with systemic lupus erythematosus. Lupus 13(7):522–528
Seelen MA, Trouw LA, van der Hoorn JW et al (2003) Autoantibodies against mannose-binding lectin in systemic lupus erythematosus. Clin Exp Immunol 134(2):335–343
Van Craeyveld E, Lievens J, Jacobs F et al (2009) Apolipoprotein A-I and lecithin: cholesterol acyltransferase transfer induce cholesterol unloading in complex atherosclerotic lesions. Gene Ther 16(6):757–765
Mendez AJ (2010) The promise of apolipoprotein A-I mimetics. Curr Opin Endocrinol Diabetes Obes 17(2):171–176
Bailey D, Jahagidar R, Gordon A et al (2010) RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol 55(23):2580–2589
Papadakis JA, Sidiropoulos PI, Karvounaris SA et al (2009) High prevalence of metabolic syndrome and cardiovascular risk factors in men with ankylosing spondylitis on anti-TNFalpha treatment: correlation with disease activity. Clin Exp Rheumatol 27(2):292–298
Hyka N, Dayer JM, Modoux C et al (2001) Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes. Blood 97(8):2381–2389
Park YB, Lee SK, Lee WK et al (1999) Lipid profiles in untreated patients with rheumatoid arthritis. J Rheumatol 26(8):1701–1704
Doherty NS, Littman BH, Reilly K et al (1998) Analysis of changes in acute-phase plasma proteins in an acute inflammatory response and in rheumatoid arthritis using two-dimensional gel electrophoresis. Electrophoresis 19(2):355–363
Oliviero F, Sfriso P, Baldo G et al (2009) Apolipoprotein A-I and cholesterol in synovial fluid of patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Clin Exp Rheumatol 27(1):79–83
Burger D, Dayer JM (2002) High-density lipoprotein-associated apolipoprotein A-I: the missing link between infection and chronic inflammation? Autoimmun Rev 1(1–2):111–117
Batuca JR, Ames PR, Isenberg DA et al (2007) Antibodies toward high-density lipoprotein components inhibit paraoxonase activity in patients with systemic lupus erythematosus. Ann N Y Acad Sci 1108:137–146
O’Neill SG, Giles I, Lambrianides A et al (2010) Antibodies to apolipoprotein A-I, high-density lipoprotein, and C-reactive protein are associated with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 62(3):845–854
Batuca JR, Ames PR, Amaral M et al (2009) Anti-atherogenic and anti-inflammatory properties of high-density lipoprotein are affected by specific antibodies in systemic lupus erythematosus. Rheumatology (Oxford) 48(1):26–31
Ortega-Hernandez OD, Bassi N, Shoenfeld Y et al (2009) The long pentraxin 3 and its role in autoimmunity. Semin Arthritis Rheum 39(1):38–54
Mantovani A, Garlanda C, Doni A et al (2008) Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol 28(1):1–13
Nauta AJ, Bottazzi B, Mantovani A et al (2003) Biochemical and functional characterization of the interaction between pentraxin3 and C1q. Eur J Immunol 33(2):465–473
Kim J, Koh JK, Lee EY et al (2009) Serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and pentraxin 3 (PTX3) as markers of infection in febrile patients with systemic lupus erythematosus. Clin Exp Rheumatol 27(5):773–778
Reading PC, Bozza S, Gilbertson B et al (2008) Antiviral activity of the long chain pentraxin PTX3 against influenza viruses. J Immunol 180(5):3391–3398
Sprong T, Peri G, Neeleman C et al (2009) Pentraxin 3 and Creactive protein in severe meningococcal disease. Shock 31(1):28–32
He X, Han B, Liu M et al (2007) Long pentraxin 3 in pulmonary infection and acute lung injury. Am J Physiol Lung Cell Mol Physiol 292(5):L1039–L1049
Garlanda C, Hirsch E, Bozza S et al (2002) Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature 420(6912):182–186
Mauri T, Bellani G, Patroniti N et al (2010) Persisting high levels of plasma pentraxin 3 over the first days after severe sepsis and septic shock onset are associated with mortality. Intensive Care Med 36(4):621–629
Bozza S, Bistoni F, Gaziano R et al (2006) Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation. Blood 108(10):3387–3396
Soares AC, Souza DG, Pinho V et al (2006) Dual function of the long pentraxin PTX3 in resistance against pulmonary infection with Klebsiella pneumoniae in transgenic mice. Microbes Infect 8(5):1321–1329
Inforzato A, Peri G, Doni A et al (2006) Structure and function of the long pentraxin PTX3 glycosidic moiety: fine-tuning of the interaction with C1q and complement activation. Biochemistry 45(38):11540–11551
Franz S, Gaipl US, Munoz LE et al (2006) Apoptosis and autoimmunity: when apoptotic cells break their silence. Curr Rheumatol Rep 8(4):245–247
Camozzi M, Zacchigna S, Rusnati M et al (2005) Pentraxin 3 inhibits fibroblast growth factor 2-dependent activation of smooth muscle cells in vitro and neointima formation in vivo. Arterioscler Thromb Vasc Biol 25:1837–1842
Zanetti M, Bosutti A, Ferreira C et al (2009) Circulating pentraxin 3 levels are higher in metabolic syndrome with subclinical atherosclerosis: evidence for association with atherogenic lipid profile. Clin Exp Med 9(3):243–248
Augusto JF, Onno C, Blanchard S et al (2009) Detection of anti-PTX3 autoantibodies in systemic lupus erythematosus. Rheumatology (Oxford) 48(4):442–444
Bassi N, Ghirardello A, Blank M et al (2010) IgG anti-pentraxin3 antibodies in systemic lupus erythematosus. Ann Rheum Dis 69(9):1704–1710
Sherer Y, Gorstein A, Fritzler MJ et al (2004) Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum 34:501–537
Sjowall C, Wettero J (2007) Pathogenic implications for autoantibodies against C-reactive protein and other acute phase proteins. Clin Chim Acta 378:13–23
Rovere P, Peri G, Fazzini F et al (2000) The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen presenting dendritic cells. Blood 96:4300–4306
Bussolati B, Peri G, Salvidio G et al (2003) The long pentraxin PTX3 is synthesized in IgA glomerulonephritis and activates mesangial cells. J Immunol 170:1466–1472
Lalvani A, Meroni PL, Millington KA et al (2008) Recent advances in diagnostic technology: applications in autoimmune and infectious diseases. Clin Exp Rheumatol 26(1 Suppl 48):S62–S66
Doria A, Briani C (2008) Primary prevention of systemic lupus erythematosus. Nat Clin Pract Rheumatol 4(11):576–577
Doria A, Arienti S, Rampudda M et al (2008) Preventive strategies in systemic lupus erythematosus. Autoimmun Rev 7:192–197
Doria A, Briani C (2008) Lupus: improving long-term prognosis. Lupus 17:166–170
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zen, M., Bassi, N., Campana, C. et al. Protective molecules and their cognate antibodies: new players in autoimmunity. Autoimmun Highlights 1, 63–72 (2010). https://doi.org/10.1007/s13317-010-0010-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13317-010-0010-8