Low concentrations of IgG2 often occur in association with a deficiency in IgG4 and/or IgA1 and IgA2 ( 17).Īn extensive analysis of anti-carbohydrate reactivities in intravenous immunoglobulin revealed that although IgG2 indeed represents the bulk of the reactivity to many glycans, this is not always the case ( 18). An increased susceptibility to certain bacterial infections is associated with IgG2 deficiency, suggesting a role of IgG2 in the defense to these pathogens ( 16). Immunoglobulin G-antibody responses to bacterial capsular polysaccharide antigens can be almost completely restricted to IgG2 ( 9, 11– 13), and IgG2 deficiency may result in the virtual absence of IgG anti-carbohydrate antibodies ( 14), although these responses can also be compensated for by enhanced levels of other IgG subclasses, in particularly by elevated IgG1 and IgG3 levels ( 15). The relatively terminal position of the Cγ4 cassette may be one of the reasons why IgG4 responses tend to occur after repeated antigen exposure ( 8). B-cells undergoing class switching in a primary or secondary immune reaction can also go through subsequent class switching ( 7), but those events are limited by the availability of remaining heavy chain genes, not excised from the genome in previous class-switching events. On the other hand, in the absence of T-cell help, polysaccharide antigens may induce class switching to IgG2 in particular. For those antigens, class switching tends to be IgG1 or IgG3, but can also be IgG4 or IgE. For example, protein antigens usually trigger B-cells receiving T-cell help through MHC-class II expressed by the B-cell. Besides direct B-cell triggering by the antigen itself, a number of secondary signals will influence differentiation of the B-cell, including recognition by pattern-recognition receptors like Toll-like receptors and cytokines produced by other lymphocytes and antigen-presenting cells ( 5, 6).
The route by which an antigen enters our body and its chemical composition steers the (secondary) immune reaction into preferential patterns of class switching. Although they are more than 90% identical on the amino acid level, each subclass has a unique profile with respect to antigen binding, immune complex formation, complement activation, triggering of effector cells, half-life, and placental transport. Differences in structure and function of IgG subclasses are summarized in Table Table1.
The subclasses of IgG were discovered in the 1960s following extensive studies using specific rabbit antisera against human IgG myeloma proteins ( 1). IgG can be further divided in four subclasses, named, in order of decreasing abundance IgG1, IgG2, IgG3, and IgG4 ( 1). These closely related glycoproteins, composed of 82–96% protein and 4–18% carbohydrate, differ in heavy chain structure and have different effector functions. It is the major class of the five classes of immunoglobulins in human beings, IgM, IgD, IgG, IgA, and IgE. Immunoglobulin G (IgG) is one of the most abundant proteins in human serum, accounting for about 10–20% of plasma protein. 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. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and 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. 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. These regions are involved in binding to both IgG-Fc receptors (FcγR) and C1q. 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.
Of the five immunoglobulin isotypes, immunoglobulin G (IgG) is most abundant in human serum.
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