The unique properties of IgG4 and its roles in health and disease

Abstract

IgG4 is the least abundant subclass of IgG in human serum and has unique functional features. IgG4 is largely unable to activate antibody-dependent immune effector responses and, furthermore, undergoes Fab (fragment antigen binding)-arm exchange, rendering it bispecific for antigen binding and functionally monovalent. These properties of IgG4 have a blocking effect, either on the immune response or on the target protein of IgG4. In this Review, we discuss the unique structural characteristics of IgG4 and how these contribute to its roles in health and disease. We highlight how, depending on the setting, IgG4 responses can be beneficial (for example, in responses to allergens or parasites) or detrimental (for example, in autoimmune diseases, in antitumour responses and in anti-biologic responses). The development of novel models for studying IgG4 (patho)physiology and understanding how IgG4 responses are regulated could offer insights into novel treatment strategies for these IgG4-associated disease settings.

Fig. 1. The onset and evolution of IgG4 responses.

IgG4 responses are most often observed upon repeated or prolonged exposure to certain classes of antigen, including food antigens, parasites, therapeutic proteins and certain autoantigens. IgG4 responses are T cell dependent, with a role for IL-4 and/or IL-13, IL-10, IL-21 and regulatory T (T_reg) cells in their induction. The absence of certain pathogen-associated molecular patterns (PAMPs) associated with viral or bacterial infection may favour IgG4 development for unknown reasons. Class-switching to IgG4 may occur directly from IgM⁺ B cells, or indirectly via IgG1⁺ intermediates, but the relative contribution of these routes is not clear. Although IgG4 can be induced by specific immunotherapy to alleviate IgE-mediated allergic symptoms, the shift towards an IgG4-dominated antibody response is not the result of IgE⁺ B cells class-switching towards IgG4, as this is not possible in light of the class-switch order of immunoglobulin heavy-chain constant region segments in the genome (see inset; once a segment has been removed by prior class-switching, a B cell cannot express it anymore). IgG4⁺ B cells have phenotypic traits that are distinct from those of IgG1⁺ B cells, including an altered chemokine receptor profile, with lower levels of expression of CXCR3, CXCR4, CXCR5, CCR6 and CCR7 — chemokine receptors involved in germinal centre reactions and the generation of long-lived plasma cells — which therefore likely results in the increased efflux of IgG4⁺ B cells from germinal centres and influx into other tissues, and might also have a role in the overall reduced longevity of IgG4-switched B cells. Inset box adapted from Fig. 1 of ref. , Springer Nature Limited.

Fig. 2. Structural and functional characteristics of IgG4.

IgG4 has several unique structural features compared with other IgG subclasses, including specific biases in the IgG4 response repertoire (high affinity and increased levels of Fab (fragment antigen binding) glycosylation), functional monovalency (owing to Fab-arm exchange (FAE)) and a reduced ability to induce effector functions mediated by interactions in the Fc (fragment crystallizable) region. Important residues mediating Fab-arm exchange of IgG4 are serine at position 228 (S228) and arginine at position 409 (R409); C1q and Fc receptor binding are particularly reduced by phenylalanine at position 234 (F234), glycine at position 327 (G327) and serine at position 331 (S331) of IgG4, although residues at other positions may also contribute to the altered binding patterns of IgG4. The functional consequences of these structural features include reduced ability to mediate the Fc-dependent effector functions of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), a poor ability to activate complement through the Fc domain and interference with immune complex formation through the inability to cross-link antigen. SHM, somatic hypermutation.

Fig. 3. Physiological and potentially beneficial effects of IgG4.

The effects of IgG4 can be beneficial to the host. a, In the case of allergy, repeated exposure to an allergen such as bee venom may at first elicit an antibody response dominated by IgE and IgG1, which stimulate inflammation and mast cell degranulation, causing a hypersensitivity response. Continued exposure to the same allergen may result in an increase in type 2 cytokines such as IL-4 and IL-13 and in regulatory cytokines such as IL-10, which stimulate class-switching to IgG4. The increased amounts of IgG4 compete with IgE for binding to allergen, thus preventing mast cell degranulation and inhibiting antigen presentation to T cells by IgE on B cells, which blocks the inflammatory loop and results in tolerance. b, In parasitic infections, the IgE-mediated and IgG1-mediated inflammatory process can be detrimental to host tissue. Worms can secrete immune modulators that skew host cytokine production towards a type 2 profile (also including the regulatory cytokine IL-10), resulting in class-switching to IgG4 and, hence, obstruction of the inflammatory processes directed at the worm as well as reduced inflammatory damage to the host. Such events generally result in asymptomatic symbiosis. APC, antigen-presenting cell.

Fig. 4. Pathological effects of IgG4 in three IgG4-associated disease settings.

a, Pemphigus is one of the first-described IgG4 autoimmune diseases (IgG4-AIDs). There are indications that for some forms of pemphigus, exposure to a fly antigen causes an initial, non-pathogenic antibody response that is found also in asymptomatic individuals. In some individuals, epitope spreading occurs and a secondary, pathogenic antibody response develops in which the antibodies cross-react with desmogleins, proteins that are crucial for skin cell adhesion. Further affinity maturation of the autoimmune response results in high-affinity, predominantly IgG4 antibodies that physically obstruct the interaction of desmogleins with other cell adhesion molecules, leading to skin blistering. In some cases, the high-affinity IgG4 antibodies to desmogleins still cross-react with the fly antigen. b, In melanoma, tumour growth can be obstructed by IgG antibodies that cause inflammation and destruction or growth inhibition of tumour cells. Some tumours, in turn, produce IL-4 and IL-10, which stimulate class-switching of local B cells and increased IgG4 production. High levels of high-affinity IgG4 compete with other antibody (sub)classes for binding to the tumour and prevent further inflammation and tumour destruction owing to their anti-inflammatory nature, leading to increased disease progression. c, In patients with chronic inflammatory diseases such as rheumatoid arthritis, the tumour necrosis factor (TNF) inhibitor adalimumab is often used to reduce inflammation. In some individuals, continuous exposure to adalimumab induces an IgG4 response against the variable domain of the therapeutic antibody, which thereby blocks the activity of the biologic and limits its therapeutic efficacy.