Abstract
Histidine-rich glycoprotein (HRG) is plasma glycoprotein that has a multidomain structure, interacts with many ligands, and exhibit many modulatory functions in diverse biological systems. HRG ligands include Zn2+, tropomyosin, heparin and heparan sulphate, plasminogen, plasmin, fibrinogen, thrombospondin, IgG, FcgR, and complement. In many cases, the histidine-rich region of the molecule enhances ligand binding after interaction with Zn2+ or exposure to low pH, conditions associated with sites of tissue injury or tumor growth. The multidomain nature of HRG and diverse ligand binding properties indicates that it can act as an extracellular adaptor protein, bridging together different ligands mainly on cell surfaces. Apart from cell surface molecules, HRG can differentially target IgG, preventing generation of insoluble immune complexes. HRG binds to most cells primarily via heparan sulphate proteoglycans. HRG can enhance clearance of apoptotic and necrotic phagocytes as well as immune complexes. The anti-angiogenic properties of HRG are well established in vitro and in vivo. HRG can modulate other physiological processes such as cell adhesion and migration, fibrinolysis and coagulation, complement activation. This review presents an update on the molecular, structural, biological, and clinical properties of HRG and associated autoimmunity conditions.
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References
Heimburger N, Haupt H, Kranz T, Baudner S (1972) Human serum proteins with high affinity to carboxymethylcellulose. II. Physico-chemical and immunological characterization of a histidine-rich 3,8S-2-glycoprotein (CM-protein I). Hoppe-Seylers Z Physiol Chem 353:1133–1139
Nair PS, Robinson WE (1999) Purification and characterization of a histidine-rich glycoprotein that binds cadmium from the blood plasma of the bivalve Mytilusedulis. Arch Biochem Biophys 366:8–14
Leung LL, Harpel PC, Nachman RL, Rabellino EM (1983) Histidine-rich glycoprotein is present in human. platelets and is released following thrombin stimulation. Blood 62:1016–1021
Jones AL, Hulett MD, Parish CR (2005) Histidine rich glycoprotein: a novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems. Immunol Cell Biol 83:106–118
Leung LL, Nachman RL, Harpel PC (1984) Complex formation of platelet thrombospondin with histidine-rich glycoprotein. J Clin Invest 73:5–12
Gorgani NN, Parish CR, Easterbrook Smith SB (1997) Histidine-rich glycoprotein binds to human IgG and C1q and inhibits the formation of insoluble immune complexes. Biochemistry 36:6653–6662
Jones AL, Hulett MD, Parish CR (2004) Histidine-rich glycoprotein binds to cell-surface heparan sulfate via its N-terminal domain following Zn2+ chelation. J Biol Chem 279:30114–30122
Olsen HM, Parish CR, Altin JG (1996) Histidine-rich glycoprotein binding to T-cell lines and its effect on T-cell substratum adhesion is strongly potentiated by zinc. Immunology 88:198–206
Gorgani NN, Altin JG, Parish CR (1999) Histidine-rich glycoprotein regulates the binding of monomeric IgG and immune complexes to monocytes. Int Immunol 11:1275–1282
Chang NS, Leu RW, Anderson JK, Mole JE (1994) Role of N-terminal domain of histidine-rich glycoprotein in modulation of macrophage Fcγ receptor-mediated phagocytosis. Immunology 81:296–302
Jones AL, Poon IK, Hulett MD, Parish CR (2005) Histidine-rich glycoprotein specifically binds to necrotic cells via its amino-terminal domain and facilitates necrotic cell phagocytosis. J Biol Chem 280:35733–35741
Kluszynski BA, Kim C, Faulk WP (1997) Zinc as a cofactor for heparin neutralization by histidine-rich glycoprotein. J Biol Chem 272:13541–13547
Gorgani NN, Parish CR, Easterbrook Smith SB, Altin JG (1997) Histidine-rich glycoprotein binds to human IgG and C1q and inhibits the formation of insoluble immune complexes. Biochemistry 36:6653–6662
Gorgani NN, Smith BA, Kono DH, Theofilopoulos AN (2002) Histidine-rich glycoprotein binds to human IgG and C1q and inhibits the formation of insoluble immune complexes. J Immunol 169:4745–4751
Gorgani NN, Theofilopoulos AN (2007) Contribution of histidine-rich glycoprotein in clearance of immune complexes and apoptotic cells: implications for ameliorating autoimmune diseases. Autoimmunity 40:260–266
Juarez JC, Guan X, Shipulina NV, Plunkett ML, Parry GC, Shaw DE, Zhang JC, Rabbani SA, McCrae KR, Mazar AP, Morgan WT, Donate F (2002) Histidine-proline-rich glycoprotein has potent antiangiogenic activity mediated through the histidine-proline-rich domain. Cancer Res 62:5344–5350
Olsson AK, Larsson H, Dixelius J, Johansson I, Lee C, Oellig C, Bjork I, Claesson-Welsh LA (2004) A fragment of histidine-rich glycoprotein is a potent inhibitor of tumor vascularization. Cancer Res 64:599–605
Simantov R, Febbraio M, Silverstein RL (2005) The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein. Matrix Biol 24:27–34
Rydengard V, Olsson AK, Morgelin M, Schmidtchen A (2007) Histidine-rich glycoprotein exerts antibacterial activity. FEBS J 274:377–389
Cohen IR (2007) Biomarkers, self-antigens and the immunological homunculus. J Autoimmun 29:246–249
Wandstrat AE, Carr-Johnson F, Branch V, Gray H, Fairhurst AM, Reimold A, Karp D, Wakeland EK, Olsen NJ (2006) Autoantibody profiling to identify individuals at risk for systemic lupus erythematosus. J Autoimmun 27:153–160
Gorgani NN, Parish CR, Altin JG (1999) Differential binding of histidine-rich glycoprotein (HRG) to human IgG subclasses and IgG molecules containing kappa and lambda light chains. J Biol Chem 274:29633–29640
Gorgani NN, Altin JG, Parish CR (1999) Histidine-rich glycoprotein prevents the formation of insoluble immune complexes by rheumatoid factor. Immunology 98:456–463
Chang NS, Leu RW, Rummage RA, Anderson JK, Mole JE (1992) Regulation of macrophage Fc receptor expression and phagocytosis by histidine-rich glycoprotein. Immunology 77:532–538
Licht R, Dieker JW, Jacobs CW, Tax WJ, Berden JH (2004) Decreased phagocytosis of apoptotic cells in diseased SLE mice. J Autoimmun 22:139–145
Sanford AN, Dietzmann K, Sullivan KE (2005) Apoptotic cells, autoantibodies, and the role of HMGB1 in the subcellular localization of an autoantigen. J Autoimmun 25:264–271
Gaipl US, Voll RE, Sheriff A, Franz S, Kalden JR, Herrmann M (2005) Clearance deficiency and systemic lupus erythematosus (SLE). Autoimmun Rev 4:189–194
Gershov D, Kim S, Brot N, Elkon KB (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 192:1353–1364
Jones AL, Poon IK, Hulett MD, Parish CR (2005) Histidine-rich glycoprotein specifically binds to necrotic cells via its amino-terminal domain and facilitates necrotic cell phagocytosis. J Biol Chem 280:35733–35741
Castel M, Horellou MH, Conard J, Samama M (1983) Immunochemical determination of histidine-rich glycoprotein in healthy subjects and in a clinical population. In: Davidson JF, Bachmann F, Bouvier CA, Kruithof EKO (eds) Progress in fibrinolysis. Churchill Livingstone, London, pp 370–373
Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674
Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257
Zhang JC, Claffey K, Sakthivel R, Darzynkiewicz Z, Shaw DE, Leal J, Wang YC, Lu FM, McCrae KR (2000) Two-chain high molecular weight kininogen induces endothelial cell apoptosis and inhibits angiogenesis: partial activity within domain 5. FASEB J 14:2589–2600
Olsson AK, Larsson H, Dixelius J, Johansson I, Lee C, Oellig C, Björk I, Claesson-Welsh L (2004) A fragment of histidine-rich glycoprotein is a potent inhibitor of tumor vascularization. Cancer Res 64:599–605
Lee C, Dixelius J, Thulin A, Kawamura H, Claesson-Welsh L, Olsson AK (2006) Signal transduction in endothelial cells by the angiogenesis inhibitor histidine-rich glycoprotein targets focal adhesions. Exp Cell Res 312:2547–2556
Simantov R, Febbraio M, Crombie R, Asch AS, Nachman RL, Silverstein RL (2001) Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1. J Clin Invest 107:45–52
Shigekiyo T (1998) Congenital histidine-rich glycoprotein deficiency. Ryoikibetsu Shokogun Shirizu 21:491–493
Tsuchida-Straeten N, Ensslen S, Schäfer C, Wöltje M, Denecke B, Moser M, Gräber S, Wakabayashi S, Koide T, Jahnen-Dechent W (2005) Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich glycoprotein (HRG). J Thromb Haemost 3:865–872
Lijnen HR, VanHoef B, Collen D (1984) Histidine-rich glycoprotein modulates the anticoagulant activity of heparin in human plasma. Thromb Haemost 51:266–268
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Blank, M., Shoenfeld, Y. Histidine-Rich Glycoprotein Modulation of Immune/Autoimmune, Vascular, and Coagulation Systems. Clinic Rev Allerg Immunol 34, 307–312 (2008). https://doi.org/10.1007/s12016-007-8058-6
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DOI: https://doi.org/10.1007/s12016-007-8058-6