Immunoglobulin G4: an odd antibody

Abstract

Despite its well-known association with IgE-mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved in a continuous process of half-molecules (i.e. a heavy and attached light-chain) exchange. This process, also referred to as 'Fab-arm exchange', results usually in asymmetric antibodies with two different antigen-combining sites. While these antibodies are hetero- bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T-helper type 2 (Th2) cells, the IgG4 response is largely restricted to non-microbial antigens. This Th2-dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen-blocking effect at the mast cell level and/or at the level of the antigen-presenting cell (preventing IgE-facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL-10 and other anti-inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non-activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti-inflammatory cytokines triggering an overwhelming expansion of IgG4-producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen-specific IgG4 indicates that anti-inflammatory, tolerance-inducing mechanisms have been activated. The existence of the IgG4 subclass, its up-regulation by anti-inflammatory factors and its own anti-inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.

Primary cutaneous marginal zone lymphomas with plasmacytic differentiation show frequent IgG4 expression

“…Specifically, regulatory T cell-associated cytokines IL-10 and IL-21 are supposed to drive the class switch in B cells to IgG4 and their differentiation into IgG4-secreting plasma cells. 31,32 In this context, it was intriguing to study the abundance of regulatory T cells in IgG4-positive primary cutaneous marginal zone lymphomas in comparison with nonIgG4 primary cutaneous marginal zone lymphomas. The finding that the content of FOXP3-positive regulatory T cells did not differ among IgA-, IgG1-3-, and IgG4-positive primary cutaneous marginal zone lymphomas, whereas it was significantly lower in IgM-positive primary cutaneous marginal zone lymphomas in our series, has several implications.…”

A 45‐year‐old man with flank pain and inability to ejaculate

“…IgG4 normally comprises only 3-6% of total IgG, has a low affinity for the target antigen, is unable to bind C1q complement, and is Th2 dependent (41)(42)(43). During acute phase(s) of IgG4-related systemic disease, IgG4 is typically elevated.…”

“…During acute phase(s) of IgG4-related systemic disease, IgG4 is typically elevated. IgG4 is also increased in atopic dermatitis, filariasis, helminthic disease, pemphigus vulgaris, and pemphigus foliaceus (31,41,42,44,45). A feature of successful immunotherapy in allergic individuals is the induction of the allergen-specific IgG4 antibody (46).…”

Autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus is associated with elevated IgG4 but not with low vitamin D

“…17,28 Accordingly, it is generally non-pathogenic. However, purified IgG4 from humans with an endemic form of pemphigus foliaceus has resulted in a similar clinical picture in mice.…”