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IgG subclasses and allotypes: from structure to effector functions.

Vidarsson G, Dekkers G, Rispens T - Front Immunol (2014)

Bottom Line: The Fc-regions also contain a binding epitope for the neonatal Fc receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces.However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement.How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function will be the focus of the current review.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam , Amsterdam , Netherlands.

ABSTRACT
Of the five immunoglobulin isotypes, immunoglobulin G (IgG) is most abundant in human serum. The four subclasses, IgG1, IgG2, IgG3, and IgG4, which are highly conserved, differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptors (FcγR) and C1q. As a result, the different subclasses have different effector functions, both in terms of triggering FcγR-expressing cells, resulting in phagocytosis or antibody-dependent cell-mediated cytotoxicity, and activating complement. The Fc-regions also contain a binding epitope for the neonatal Fc receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement. How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function will be the focus of the current review.

No MeSH data available.


(A) Crystal structure of an human IgG1 molecule (1HZH) viewed from two different angles, demonstrating the flexibility of the two Fab fragments with respect to each other and the Fc tail. The binding location for FcγR, binding IgG asymmetrically in a 1:1 configuration (46–49), is indicated by the blue circle (lower hinge, upper CH2) on the left, and the location of the binding motifs for FcRn, TRIM21, and the potential site for binding of DC-SIGN on the right (intersection of CH2 and CH3). FcRn, and the potential binding site of DC-SIGN bind IgG in a 2:1 configuration (50–52), respectively, while a dimer of TRIM21 binds IgG in a 1:1 configuration (53). The N-linked glycan at position 297 attached to each of the heavy chains is shown on the right. (B) The N-linked glycan found at position 297 can be found as a core structure, common to all IgG found in human beings and rodents (core structure indicated with a red dashed line), but can be found with either an addition of fucose, bisecting N-acetylglucosamine (GlcNAc), one or two galactose, and one or two sialic acid residues.
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Figure 1: (A) Crystal structure of an human IgG1 molecule (1HZH) viewed from two different angles, demonstrating the flexibility of the two Fab fragments with respect to each other and the Fc tail. The binding location for FcγR, binding IgG asymmetrically in a 1:1 configuration (46–49), is indicated by the blue circle (lower hinge, upper CH2) on the left, and the location of the binding motifs for FcRn, TRIM21, and the potential site for binding of DC-SIGN on the right (intersection of CH2 and CH3). FcRn, and the potential binding site of DC-SIGN bind IgG in a 2:1 configuration (50–52), respectively, while a dimer of TRIM21 binds IgG in a 1:1 configuration (53). The N-linked glycan at position 297 attached to each of the heavy chains is shown on the right. (B) The N-linked glycan found at position 297 can be found as a core structure, common to all IgG found in human beings and rodents (core structure indicated with a red dashed line), but can be found with either an addition of fucose, bisecting N-acetylglucosamine (GlcNAc), one or two galactose, and one or two sialic acid residues.

Mentions: Similar to the other isotypes, the IgG immunoglobulin molecule consists of four polypeptide chains, composed of two identical 50 kDa γ heavy (H) chains and two identical 25 kDa κ or λ light (L) chains, linked together by inter-chain disulfide bonds. Each heavy chain consists of an N-terminal variable domain (VH) and three constant domains (CH1, CH2, CH3), with an additional “hinge region” between CH1 and CH2 (Figure 1A). Similarly, the light chains consist of an N-terminal variable domain (VL) and a constant domain (CL). The light chain associates with the VH and CH1 domains to form a Fab arm (“Fab” = fragment antigen binding), and functionally, the V regions interact to form the in antigen-binding region – acquired through differential assembly of Variable, Diversity (VH only), and Joining gene segments and inclusion of somatic mutations (43–45), although their relative contribution to antigen binding varies greatly. Two heavy chain–light chain heterodimers (HL) combine into a single antibody molecule (H2L2) via disulfide bonds in the hinge region and non-covalent interactions between the CH3 domains (Figure 2A). The part of the antibody formed by the lower hinge region and the CH2/CH3 domains is called “Fc” (“fragment crystalline”).


IgG subclasses and allotypes: from structure to effector functions.

Vidarsson G, Dekkers G, Rispens T - Front Immunol (2014)

(A) Crystal structure of an human IgG1 molecule (1HZH) viewed from two different angles, demonstrating the flexibility of the two Fab fragments with respect to each other and the Fc tail. The binding location for FcγR, binding IgG asymmetrically in a 1:1 configuration (46–49), is indicated by the blue circle (lower hinge, upper CH2) on the left, and the location of the binding motifs for FcRn, TRIM21, and the potential site for binding of DC-SIGN on the right (intersection of CH2 and CH3). FcRn, and the potential binding site of DC-SIGN bind IgG in a 2:1 configuration (50–52), respectively, while a dimer of TRIM21 binds IgG in a 1:1 configuration (53). The N-linked glycan at position 297 attached to each of the heavy chains is shown on the right. (B) The N-linked glycan found at position 297 can be found as a core structure, common to all IgG found in human beings and rodents (core structure indicated with a red dashed line), but can be found with either an addition of fucose, bisecting N-acetylglucosamine (GlcNAc), one or two galactose, and one or two sialic acid residues.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4202688&req=5

Figure 1: (A) Crystal structure of an human IgG1 molecule (1HZH) viewed from two different angles, demonstrating the flexibility of the two Fab fragments with respect to each other and the Fc tail. The binding location for FcγR, binding IgG asymmetrically in a 1:1 configuration (46–49), is indicated by the blue circle (lower hinge, upper CH2) on the left, and the location of the binding motifs for FcRn, TRIM21, and the potential site for binding of DC-SIGN on the right (intersection of CH2 and CH3). FcRn, and the potential binding site of DC-SIGN bind IgG in a 2:1 configuration (50–52), respectively, while a dimer of TRIM21 binds IgG in a 1:1 configuration (53). The N-linked glycan at position 297 attached to each of the heavy chains is shown on the right. (B) The N-linked glycan found at position 297 can be found as a core structure, common to all IgG found in human beings and rodents (core structure indicated with a red dashed line), but can be found with either an addition of fucose, bisecting N-acetylglucosamine (GlcNAc), one or two galactose, and one or two sialic acid residues.
Mentions: Similar to the other isotypes, the IgG immunoglobulin molecule consists of four polypeptide chains, composed of two identical 50 kDa γ heavy (H) chains and two identical 25 kDa κ or λ light (L) chains, linked together by inter-chain disulfide bonds. Each heavy chain consists of an N-terminal variable domain (VH) and three constant domains (CH1, CH2, CH3), with an additional “hinge region” between CH1 and CH2 (Figure 1A). Similarly, the light chains consist of an N-terminal variable domain (VL) and a constant domain (CL). The light chain associates with the VH and CH1 domains to form a Fab arm (“Fab” = fragment antigen binding), and functionally, the V regions interact to form the in antigen-binding region – acquired through differential assembly of Variable, Diversity (VH only), and Joining gene segments and inclusion of somatic mutations (43–45), although their relative contribution to antigen binding varies greatly. Two heavy chain–light chain heterodimers (HL) combine into a single antibody molecule (H2L2) via disulfide bonds in the hinge region and non-covalent interactions between the CH3 domains (Figure 2A). The part of the antibody formed by the lower hinge region and the CH2/CH3 domains is called “Fc” (“fragment crystalline”).

Bottom Line: The Fc-regions also contain a binding epitope for the neonatal Fc receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces.However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement.How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function will be the focus of the current review.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam , Amsterdam , Netherlands.

ABSTRACT
Of the five immunoglobulin isotypes, immunoglobulin G (IgG) is most abundant in human serum. The four subclasses, IgG1, IgG2, IgG3, and IgG4, which are highly conserved, differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptors (FcγR) and C1q. As a result, the different subclasses have different effector functions, both in terms of triggering FcγR-expressing cells, resulting in phagocytosis or antibody-dependent cell-mediated cytotoxicity, and activating complement. The Fc-regions also contain a binding epitope for the neonatal Fc receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement. How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function will be the focus of the current review.

No MeSH data available.