Journal Article•
Localization of an Fc-binding reactivity to the constant region of human IgG4. Implications for the pathogenesis of rheumatoid arthritis
15 Nov 1995-Journal of Immunology (American Association of Immunologists)-Vol. 155, Iss: 10, pp 5057-5063
TL;DR: These studies demonstrate an example of RF-like Fc-binding reactivity that is conferred by the gamma-4 constant region rather than the classic Ag binding site and suggest that increased production of IgG4 may contribute to the pathogenesis of RA.
Abstract: The majority of plasma cells in rheumatoid arthritis (RA) synovium produce rheumatoid factors (RF). IgG RF predominate in the immune complexes found in RA synovial fluid and have been implicated in the pathogenesis of RA. IgG4 RF are a major component of IgG RF produced in serum and synovium of RA patients, even though this subclass comprises only 4% of the serum IgG. We produced an IgG4 mAb, hRF-1, with RF reactivity from the synovial tissue of a patient with RA. mAb hRF-1 had binding specificity for mammalian IgG similar to Staphylococcus aureus protein A, which is characteristic of RF from patients with RA. To determine the molecular basis of this particular RF reactivity, the heavy and light chain genes of mAb hRF-1 were amplified by PCR, cloned, and ligated into the pSG5 plasmid for expression in COS-7 cells. Chain recombination experiments localized the Fc-binding reactivity to the hRF-1 heavy chain. Using a series of chimeric Ab sequences, the Fc-binding reactivity was mapped to the constant region of IgG4 rather than the variable region involved in classic RF reactivity. Multiple domains, including Hinge, CH2, and CH3 of the IgG4 constant region were required for Fc binding. Our studies demonstrate an example of RF-like Fc-binding reactivity that is conferred by the gamma-4 constant region rather than the classic Ag binding site and suggest that increased production of IgG4 may contribute to the pathogenesis of RA.
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TL;DR: IgG4 by itself is unlikely to be a cause of allergic symptoms, but the presence of allergen‐specific IgG4 indicates that anti‐inflammatory, tolerance‐inducing mechanisms have been activated.
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.
697 citations
TL;DR: A patient with AIP in association with tubulointerstitial nephritis (TIN), which is strongly suspected to be induced by immune complexes containing IgG4, is described here.
Abstract: It has been well documented that autoimmune pancreatitis (AIP) [1], also known as sclerosing pancreatitis [2], is frequently associated with fibrosclerotic diseases, such as Sjögren’s syndrome [3,4], primary biliary cirrhosis [5], primary sclerosing cholangitis [3–5] or retroperitoneal fibrosis [6]. However, as yet, there have been no reports on renal complications of AIP, except for hydronephrosis, caused by retroperitoneal fibrosis. Recently, Hamano et al. [2] reported that the pathogenesis of sclerosing pancreatitis is closely related to the presence of immunoglobulin (Ig) G4. We describe here a patient with AIP in association with tubulointerstitial nephritis (TIN), which is strongly suspected to be induced by immune complexes containing IgG4.
204 citations
Cites background from "Localization of an Fc-binding react..."
...Some kinds of IgG4 have an Fc-binding reactivity in the constant region [9]....
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TL;DR: The large number of treated patients, in combination with these new assays, presents a unique opportunity to study the anti-antibody immune response in man, possibly allowing us to manipulate immunogenicity in the future.
187 citations
TL;DR: The unexpected conformations adopted by functionally important Cγ2 domain loops are discussed, and potential implications for the interaction between IgG4 and FcγRs are speculated about.
Abstract: IgG4, the least represented human IgG subclass in serum, is an intriguing antibody with unique biological properties, such as the ability to undergo Fab-arm exchange and limit immune complex formation. The lack of effector functions, such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, is desirable for therapeutic purposes. IgG4 plays a protective role in allergy by acting as a blocking antibody, and inhibiting mast cell degranulation, but a deleterious role in malignant melanoma, by impeding IgG1-mediated anti-tumor immunity. These findings highlight the importance of understanding the interaction between IgG4 and Fcγ receptors. Despite a wealth of structural information for the IgG1 subclass, including complexes with Fcγ receptors, and structures for intact antibodies, high-resolution crystal structures were not reported for IgG4-Fc until recently. Here, we highlight some of the biological properties of human IgG4, and review the recent crystal structures of IgG4-Fc. We discuss the unexpected conformations adopted by functionally important Cγ2 domain loops, and speculate about potential implications for the interaction between IgG4 and FcγRs.
120 citations
Cites background from "Localization of an Fc-binding react..."
...Fc–Fcmediated IgG interactions have also been documented in rheumatoid arthritis (88) and autoimmune pancreatitis (89), and crystal packing interactions in a number of IgG-Fc crystal structures (e....
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TL;DR: It is proposed that the IgG4-IgG4 Fc interaction resembles an intermediate of the Fab-arm (half-molecule) exchange reaction that is stabilized because one of the Igg4 molecules is coupled to a solid phase.
Abstract: The Fc fragment of IgG4 can interact with the Fc fragment of another IgG molecule. This interaction is a confounding factor when measuring IgG4 rheumatoid factor levels. Recently, we demonstrated that half-molecules of IgG4 can exchange to form a bispecific Ab. We expected these two phenomena to be related and investigated the physicochemical aspects of IgG4 Fc-Fc interactions. We found that IgG4 is >99% monomeric by size-exclusion chromatography; therefore, IgG4 Fc-Fc interactions in the fluid phase (if any) would be short-lived. However, 125I-labeled IgG4 does bind to IgG1 and IgG4 coupled to a solid phase. By contrast, IgG1 does not bind to coupled IgG4. Furthermore, conditions that induce partial unfolding/dissociation of the CH3 domains enhance IgG4 Fc binding, suggesting that Fc binding is primarily CH3 mediated. IgG4 slowly associates with both IgG4 and IgG1 coupled to a biosensor chip. Remarkably, subsequent dissociation was much faster for IgG4 than for IgG1. Moreover, after binding of an IgG4 mAb to Sepharose-coupled Ag, we observed additional binding of IgG4 with irrelevant specificity, whereas similar binding was not observed with Ag-bound IgG1. We propose that the IgG4-IgG4 Fc interaction resembles an intermediate of the Fab-arm (half-molecule) exchange reaction that is stabilized because one of the IgG4 molecules is coupled to a solid phase. By contrast, IgG4 Fc recognizes IgG1 only after a conformational change that renders CH3(IgG1) accessible to an interaction with the CH3(IgG4). Such Fc interactions may enhance Ag binding of IgG4 in vivo.
116 citations
Cites background or methods from "Localization of an Fc-binding react..."
...Interestingly, although generally RF activity involves variable domain-mediated binding to IgG-Fc, it is reported that IgG4 possesses IgG1-Fc binding activity that is located in the constant domains (6)....
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...Previously, IgG4 Fc binding was observed in assays with Fc or intact IgG coupled to a solid support (6) or to IgG subclasses in an immunoblot (9)....
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