Specificity of mouse and human Fcgamma receptors and their polymorphic variants for IgG subclasses of different species

Abstract

IgG is the predominant antibody class generated during infections and used for the generation of therapeutic antibodies. Antibodies are mainly characterized in or generated from animal models that support particular infections, respond to particular antigens or allow the generation of hybridomas. Due to the availability of numerous transgenic mouse models and the ease of performing bioassays with human blood cells in vitro, most antibodies from species other than mice and humans are tested in vitro using human cells and/or in vivo using mice. In this process, it is expected, but not yet systematically documented, that IgG from these species interact with human or mouse IgG receptors (FcγRs). In this study, we undertook a systematic assessment of binding specificities of IgG from various species to the families of mouse and human FcγRs including their polymorphic variants. Our results document the specific binding patterns for each of these IgG (sub)classes, reveal possible caveats of antibody-based immunoassays, and will be a useful reference for the transition from one animal model to preclinical mouse models or human cell-based bioassays.

IgG subclass and Fc glycosylation shifts are linked to the transition from pre- to inflammatory autoimmune conditions

“…Human IgG4 and murine IgG1 show higher affinities to the only classical IgG inhibitory receptor FcyRIIB than to their classical activating FcyRs ( 16 – 18 ). Furthermore, human IgG4 and murine IgG1 cannot activate C1q, but seem to be able to disturb hexamer formation of the C1q-activating IgG subclasses ( 15 ).…”

“…Human IgG1 and IgG3 as well as murine IgG2a and IgG2b show the highest affinities to the classical activating FcyRs and C1q, the starting molecule of the classical complement activation pathway ( 16 – 18 ). These IgG subclasses seem to be able to form hexamers facilitating the interaction with the six-arm C1q molecule ( 15 , 19 – 23 ).…”

“…These IgG subclasses seem to be able to form hexamers facilitating the interaction with the six-arm C1q molecule ( 15 , 19 – 23 ). Human IgG2 and murine IgG3 hardly interact with classical FcyRs and C1q and their effector functions are mostly unclear ( 16 – 18 ). They are induced for instance by T cell-independent antigens.…”

Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies

“…Studying the role of Fc core fucosylation using small animal models is complicated by the fact that mice express different set of FcɣRs compared to humans (5,(118)(119)(120). The more recently discovered mouse FcɣRIV molecule has been shown several years ago to be the murine ortholog of human FcɣRIIIA and to be an important mediator of human IgG1 efficacy in mice.…”

The impact of type 2 immunity and allergic diseases in atherosclerosis

“…68,69 On the other hand, the number of IgG subtypes and diverse functionality of Fcγ receptors (activating vs inhibitory) have made it challenging to ascertain its role, which is also influenced by its specificity toward atherosclerosis-derivedantigens. [70][71][72] As it pertains to IgG1, high serum concentrations have been observed in ApoE −/− mice 73 and atherosclerotic mechanisms have been reported involving Fcγ receptors and macrophages. 74 Noteworthy, oxLDL-specific IgG has been detected in human plaques, 70 and different experimental strategies support the therapeutic role of oxLDL-(or atherosclerosis-derived-antigen)-specific IgG1 for plaque progression or stabilization.…”