The Immunobiology of Immunoglobulin G4

Abstract

Human immunoglobulin G4 (IgG4) antibodies are in many ways unusual. In this review, an overview is given of the structural and functional aspects of IgG4 antibodies, the consequences of IgG4 antibody formation in various disease settings, and the factors involved in the regulation of IgG4 responses. Unlike most IgG antibodies, IgG4 antibodies exist in a dynamic equilibrium with other IgG4 antibodies, continuously exchanging half-molecules resulting in effectively monovalent antibodies that cannot cross-link. Together with the low affinities to C1q and most Fc receptors, and a generally high affinity for antigen, IgG4 antibodies appear to be nature's way of producing "blocking antibodies." On the one hand, IgG4 may contribute to tolerance to allergens, presumably via competition with IgE. Also, IgG4 immune responses to filarial parasites might prevent excessive immune reactions during such infections. On the other hand, IgG4 autoantibodies may be pathogenic, simply because they inhibit the function of their target molecules. Furthermore, IgG4 antibodies to biologicals may result in secondary loss of response. In addition, IgG4 has been implicated to impair humoral immunity to tumors. The role of high IgG4 serum levels in IgG4-related disease has not yet been established. Regulation of IgG4 responses is most likely a multifactorial process, which in vivo requires prolonged or repeated challenge with antigen, and is associated with regulatory T cells, T helper 2 cells, interleukin- (IL-) 4, and IL-10. In vitro, cytokines like IL-4, IL-13, IL-10, and IL-21 have been shown to differentially influence IgG4 production. The properties of IgG4 B cells have now started to be elucidated, and may provide additional clues to explain the unusual dynamics of IgG4-antibody responses.

Neurological Manifestations of IgG4-Related Disease

“…Despite having over 90% amino acid sequence homology with the other subclasses, IgG4 has a unique structure and function and is generally regarded as non-inflammatory because it does not efficiently engage activating Fc receptors or complement and might be functionally monovalent in vivo [39]. Although IgG4 autoantibodies are known to be pathogenic in a number of diseases including pemphigus vulgaris, thrombotic thrombocytopenic purpura and idiopathic membranous nephropathy, there is growing acceptance that IgG4 itself is unlikely to be pathogenic in IgG4-RD [2••, 40, 41].…”

IgG4‐mediated autoimmune diseases: a niche of antibody‐mediated disorders

“…IgG is further subdivided into subclasses on the basis of their morphological and functional characteristics. Structural determinants in the constant, crystallizable fragment (Fc) of the antibody dictate whether an immunoglobulin G (IgG) molecule is able to activate complement, bind and activate or inhibit Fc receptors and immune cell–mediated cytotoxicity, or interact with other IgGs . On the basis of these characteristics and the type of antigen, human IgG was classified into four subclasses.…”

“…Together, these distinct functional characteristics led IgG4 to be deemed as an anti‐inflammatory antibody. For a comprehensive review on IgG4 morphology and function and the regulation of IgG4 responses, see Lighaam et al …”

“…Structural determinants in the constant, crystallizable fragment (Fc) of the antibody dictate whether an immunoglobulin G (IgG) molecule is able to activate complement, bind and activate or inhibit Fc receptors and immune cell-mediated cytotoxicity, or interact with other IgGs. 1 On the basis of these characteristics and the type of antigen, human IgG was classified into four subclasses. IgG4 is the least prevalent IgG in healthy adults and makes up approximately 5% of the total IgG pool.…”

“…7 Together, these distinct functional characteristics led IgG4 to be deemed as an anti-inflammatory antibody. For a comprehensive review on IgG4 morphology and function and the regulation of IgG4 responses, see Lighaam et al 1 For each of the unique features of IgG4, the (patho-)physiological relevance is largely unclear. Depending on the setting, an IgG4 response can be protective or pathogenic.…”