Differential Binding of Histidine-rich Glycoprotein (HRG) to Human IgG Subclasses and IgG Molecules Containing κ and λ Light Chains

Gorgani, Nick N.; Parish, Christopher R.; Altin, Joseph G.

doi:10.1074/jbc.274.42.29633

Cited by 41 publications

(57 citation statements)

References 36 publications

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“…It also regulates macrophage phagocytosis of opsonized sheep erythrocytes and complement activation (14,15). Other interesting functions of HRG are inhibition of insoluble immune complex (IC) formation (27), blocking of rheumatoid factor binding to ICs (28), and enhanced binding of IgG1-and IgG2-containing ICs to Fc␥RI on monocytes (19,29). In this study, we demonstrate a novel function for HRG, namely its capacity to specifically bind to apoptotic T cells and mature human monocytederived macrophages (HMDM), and to potentiate the ingestion of apoptotic cells.…”

Section: Histidine-rich Glycoprotein Binds To Dna and Fc␥ri Andmentioning

confidence: 93%

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Histidine-Rich Glycoprotein Binds to DNA and FcγRI and Potentiates the Ingestion of Apoptotic Cells by Macrophages

Gorgani

Smith

Kono

et al. 2002

The Journal of Immunology

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Histidine-rich glycoprotein (HRG) is an abundant serum protein that exhibits many functions in diverse biological systems. In this study, we show that HRG potentiates the ingestion of apoptotic cells by mature human monocyte-derived macrophages (HMDM). HRG bound specifically to apoptotic Jurkat cells and mature HMDM in a saturable and concentration-dependent manner. Purified HRG or HRG in sera increased the number of HMDM-containing apoptotic cells and accelerated the ingestion, while neutralization or depletion of HRG from sera reduced this effect. Anti-FcγRI mAb inhibited HRG binding to HMDM, while DNA, but not chromatin, inhibited HRG binding to apoptotic cells, and either anti-FcγRI or DNA abrogated the HRG-dependent ingestion. The findings indicate that HRG, by acting as a bridge between DNA on apoptotic cells and FcγRI on HMDM, is a key physiological mediator of apoptotic cell clearance by macrophages.

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Section: Histidine-rich Glycoprotein Binds To Dna and Fc␥ri Andmentioning

confidence: 93%

“…Human HRG was purified by passing freshly prepared plasma through a phosphocellulose column, and eluting bound HRG by 2 M NaCl, as detailed previously (29). All HRG preparations were Ͼ95% pure, as judged by SDS-PAGE.…”

Section: Hrg Anti-hrg Abs and Hrg-depleted Serummentioning

confidence: 99%

Histidine-Rich Glycoprotein Binds to DNA and FcγRI and Potentiates the Ingestion of Apoptotic Cells by Macrophages

Gorgani

Smith

Kono

et al. 2002

The Journal of Immunology

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“…Although deposited 1HZH coordinates were numbered in Kabat and Wu format, the residue numbering in this figure is in Eu format, the same as in Table 1 equal amounts for IgG2 and IgG2. Previous reports (4,32,33) have shown that the LC type can impact antigen/receptor binding and in vivo clearance. Some of these results were linked to specific differences in flexibility between the -and -LC, and, as we have shown in this report, may also be attributed to different distribution of IgG2 isoforms.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass

Dillon

Ricci

Vezina

et al. 2008

Journal of Biological Chemistry

252

323

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we have identified that the human IgG2 subclass exists as an ensemble of distinct isoforms, designated IgG2-A, -B, and -A/B, which differ by the disulfide connectivity at the hinge region. In this report, we studied the structural and functional properties of the IgG2 disulfide isoforms and compared them to IgG1. Human monoclonal IgG1 and IgG2 antibodies were designed with identical antigen binding regions, specific to interleukin-1 cell surface receptor type 1. In vitro biological activity measurements showed an increased activity of the IgG1 relative to the IgG2 in blocking interleukin-1␤ ligand from binding to the receptor, suggesting that some of the IgG2 isoforms had lower activity. Under reduction-oxidation conditions, the IgG2 disulfide isoforms converted to IgG2-A when 1 M guanidine was used, whereas IgG2-B was enriched in the absence of guanidine. The relative potency of the antibodies in cell-based assays was: IgG1 > IgG2-A > IgG2 Ͼ Ͼ IgG2-B. This difference correlated with an increased hydrodynamic radius of IgG2-A relative to IgG2-B, as shown by biophysical characterization. The enrichment of disulfide isoforms and activity studies were extended to additional IgG2 monoclonal antibodies with various antigen targets. All IgG2 antibodies displayed the same disulfide conversion, but only a subset showed activity differences between IgG2-A and IgG2-B. Additionally, the distribution of isoforms was influenced by the light chain type, with IgG2 composed mostly of IgG2-A. Based on crystal structure analysis, we propose that IgG2 disulfide exchange is caused by the close proximity of several cysteine residues at the hinge and the reactivity of tandem cysteines within the hinge. Furthermore, the IgG2 isoforms were shown to interconvert in whole blood or a "bloodlike" environment, thereby suggesting that the in vivo activity of human IgG2 may be dependent on the distribution of isoforms.

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“…In contrast, few proteins have been identified that can specifically opsonize necrotic cells. Histidine-rich glycoprotein (HRG) 3 (13) is a 75-kDa plasma glycoprotein (ϳ100 g/ml) that binds to numerous ligands, including heparan sulfate on the cell surface and in extracellular matrices (14 -16), plasminogen (17)(18)(19)(20), thrombospondin (21)(22)(23), tropomyosin (24,25), IgG (26,27), C1q (26), and Fc receptor (28,29). HRG is a multidomain molecule consisting of an amino-terminal domain composed of two cystatin-like modules (N1N2), a central histidine-rich region, and a carboxyl-terminal domain (30,31).…”

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confidence: 99%

Histidine-rich Glycoprotein Specifically Binds to Necrotic Cells via Its Amino-terminal Domain and Facilitates Necrotic Cell Phagocytosis

Jones

Poon

Hulett

et al. 2005

Journal of Biological Chemistry

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Cells that become necrotic or apoptotic through tissue damage or during normal cellular turnover are usually rapidly cleared from the circulation and tissues by phagocytic cells. A number of soluble proteins have been identified that facilitate the phagocytosis of apoptotic cells, but few proteins have been defined that selectively opsonize necrotic cells. Previous studies have shown that histidinerich glycoprotein (HRG), an abundant (ϳ100 g/ml) 75-kDa plasma glycoprotein, binds to cell surface heparan sulfate on viable cells and cross-links other ligands, such as plasminogen, to the cell surface. In this study we have demonstrated that HRG also binds very strongly, in a heparan sulfate-independent manner, to cytoplasmic ligand(s) exposed in necrotic cells. This interaction is mediated by the amino-terminal domain of HRG and results in enhanced phagocytosis of the necrotic cells by a monocytic cell line. In contrast, it was found that HRG binds poorly to and does not opsonize early stage apoptotic cells. Thus, HRG has the unique property of selectively recognizing necrotic cells and may play an important physiological role in vivo by facilitating the uptake and clearance of necrotic, but not apoptotic, cells by phagocytes.Cell death is vital for the morphological shaping of tissues during development and for the sculpting of functionally appropriate cellular repertoires as well as for protecting an individual from viral infections and pathogenic microorganisms (1, 2). Selective cell death continues to play a role in the homeostasis of mature tissues, such as the deletion of immune cells in the attenuation of an immune response (3) and the elimination of cells that have become functionally inappropriate, including virally infected and transformed cells (4). Apoptosis and necrosis represent two different forms of cell death and are characterized by distinct morphologies. Rapid and efficient phagocytic removal of dying cells is a key feature of apoptosis, whereas the role and extent of phagocytosis in the clearance of necrotic cells is not well documented. It is thought, however, that by engulfing necrotic and apoptotic cells phagocytes of the innate immune system not only provide a first line of defense against microbial pathogens but also dispose of self-antigens that are released from dying cells (5).Apoptosis is characterized by an orderly sequence of internal events, including chromatin condensation that precedes the loss of cellular integrity (6). Apoptotic cells also display phosphatidylserine and altered membrane carbohydrates on their surface. Multiple ligands and receptors have been implicated in the recognition and uptake of apoptotic cells by phagocytes prior to membrane lysis, thus preventing release of potentially toxic and immunogenic intracellular substances into tissues. In addition, the binding and/or uptake of apoptotic cells inhibits proinflammatory cytokine production (7). When there are disturbances in either apoptosis or the phagocytosis of apoptotic cells, antibodies against subsequently exp...

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Differential Binding of Histidine-rich Glycoprotein (HRG) to Human IgG Subclasses and IgG Molecules Containing κ and λ Light Chains

Cited by 41 publications

References 36 publications

Histidine-Rich Glycoprotein Binds to DNA and FcγRI and Potentiates the Ingestion of Apoptotic Cells by Macrophages

Histidine-Rich Glycoprotein Binds to DNA and FcγRI and Potentiates the Ingestion of Apoptotic Cells by Macrophages

Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass

Histidine-rich Glycoprotein Specifically Binds to Necrotic Cells via Its Amino-terminal Domain and Facilitates Necrotic Cell Phagocytosis

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