Trends in Immunology
ReviewRole of IgG3 in Infectious Diseases
Section snippets
Human IgG3 an Understudied but Highly Potent Immunoglobulin
Antibodies (Abs) play a major role in protection against infections by binding to and inactivating invading pathogens. Although IgG3 constitutes a minor proportion of total human immunoglobulins, a growing number of recent studies have highlighted IgG3 as critical for the control and/or protection of a range of pathogens, including viruses (e.g., HIV 1, 2, 3, 4, 5), bacteria (e.g., Neisseria spp. 6, 7, 8), and parasites (e.g., Plasmodium spp. 9, 10, 11, 12, 13). This review describes the unique
Human IgG3: a Unique Antibody Subclass
The glycoprotein IgG is the most abundant isotype in healthy human plasma, and can be separated into four subclasses: IgG1 (60–70% in plasma), IgG2 (20–30%), IgG3 (5–8%), and IgG4 (1–3%) [17]. The amino acid sequences of the human IgG subclasses are >95% homologous in the constant domains of their heavy chains (Figure 1). IgG3 has a distinct amino acid composition and structure in the hinge region between CH1 and CH2 [18]. The flexibility of the hinge region decreases in the order IgG3 > IgG1 > IgG4
IgG3 Allotypes
Allotypes are polymorphisms in the constant regions of immunoglobulin heavy and light chains (Figure 1B). IgG3 is the most polymorphic subclass with 13 Gm allotypes termed G3m; thought to be due to its higher rapid evolutionary diversification compared with other subclasses [20]. G3 m allotypes are inherited in different combinations or G3 m alleles (encoded by one or several IGHG3 alleles) shared among individuals within populations (Table 2). Several G3 m allotypes consist of a combination of
Glycosylation of IgG3
Glycosylation is a post-translational modification of Abs, which can be regulated by a range of B cell stimuli, including environmental factors, such as stress or disease, cytokine activity, and innate immune signaling receptors, such as Toll-like receptors. Hence, exposure to specific pathogens, antigens, or vaccination has the potential to skew Ab glycan profiles 27, 28. Glycosylation is an inherent mechanism of Ab diversification, on top of V(D)J recombination, somatic hypermutation (SHM),
IgG3 Has Potent Effector Functions
IgG has a number of antigen-specific effector functions, such as immune cell-activation via FcγRs, neutralization, and activation of complement pathways 20, 31. IgG3 is the most functional subclass, closely followed by IgG1, due to its superior affinity to FcγR [41]. However, IgG2 also plays an important role in targeting polysaccharides and is commonly induced during bacterial infections [42], while IgG4 is often induced in response to allergens [43] (Table 1 and Figure 2, Key Figure).
Generation of IgG3 during Various Infections
IgG3 is often one of the earliest subclasses to be elicited against protein antigens upon infection 3, 56, 57, 58, due to its genetic locus positioning among immunoglobulin heavy constant chains (IGHC) in humans 59, 60. IgG3 is the first IGHG gene located within the locus, sequentially followed by IgG1 (gene order as follows: IGHG3, IGHG1, IGHA1, IGHG2, IGHG4, IGHE, and IGHA2 from 5′ to 3′ 59, 60); thus, IgG3 responses are often closely followed by IgG1 responses 61, 62, 63, 64. With potent Fc
Current State of Play
By the end of 2018, there were approximately 80 approved therapeutic Abs (thAbs) on the market [97]. However, only three monoclonal thAbs are currently licensed for the treatment of infectious diseases: palivizumab, a humanized IgG1 mAb against respiratory syncytial virus [98]; raxibacumab, a humanized IgG1 mAb against Bacillus anthracis [99]; and ibalizumab, a humanized IgG4 mAb, which inhibits HIV-1 from entering host cells [100]. Currently, a limited number of IgG-based thAbs are in
Concluding Remarks
In summary, the critical role of IgG3 in the control and/or protection against a range of infectious diseases is evident from numerous studies highlighted herein 1, 2, 3, 4, 5, 9, 91, 119. This ability is mainly due to the inherit unique molecular properties of IgG3 that can confer highly functional potent effector responses. Although numerous questions remain (see Outstanding Questions), increasing our molecular understanding of IgG3 and its functional properties may improve the engineering
Acknowledgments
We thank Milla McClean and Ester Lopez for their assistance revising this manuscript. This work was supported by funding from the University of Melbourne (T.D.), National Health and Medical Research Council of Australia (NHMRC) (S.J.R., S.J.K., A.W.C.), by the Australian Centre for Research Excellence in Malaria Elimination (ACREME) (S.J.R.) and the American Foundation for AIDS Research (amfAR) Mathilde Krim Fellowship (A.W.C.).
Glossary
- Antibody-dependent cell cytotoxicity (ADCC)
- killing of an Ab-coated target cell by a cytotoxic effector cell through a nonphagocytic process.
- Antibody-dependent cellular inhibition (ADCI)
- a process by which Abs can inhibit Plasmodium growth in the presence of monocytes.
- Antibody-dependent cellular viral inhibition (ADCVI)
- Fcγ-receptor-mediated antiviral activity, occurring when Ab bound to virus-infected target cells engages FcγR-bearing effector cells, (e.g., NK cells, monocytes, or macrophages).
References (121)
Dissecting polyclonal vaccine-induced humoral immunity against HIV using systems serology
Cell
(2015)Properties of mouse and human IgG receptors and their contribution to disease models
Blood
(2012)Computer models of the human immunoglobulins: Binding sites and molecular interactions
Immunol. Today
(1986)Crystallohydrodynamics for solving the hydration problem for multi-domain proteins: open physiological conformations for human IgG
Biophys. Chem.
(2001)Dynamics of inter-heavy chain interactions in human immunoglobulin G (IgG) subclasses studied by kinetic Fab arm exchange
J. Biol. Chem.
(2014)The influence of glycosylation on the thermal stability and effector function expression of human IgG1-Fc: properties of a series of truncated glycoforms
Mol. Immunol.
(2000)IgG subclass-independent improvement of antibody-dependent cellular cytotoxicity by fucose removal from Asn297-linked oligosaccharides
J. Immunol. Methods
(2005)Hinge-region O-glycosylation of human immunoglobulin G3 (IgG3)
Mol. Cell. Proteomics
(2015)Mannan binding lectin and its interaction with immunoglobulins in health and in disease
Immunol. Lett.
(2006)Solution conformation of wild-type and mutant IgG3 and IgG4 immunoglobulins using crystallohydrodynamics: possible implications for complement activation
Biophys. J.
(2007)