IgG4‐mediated autoimmune diseases: a niche of antibody‐mediated disorders

Abstract

Immunoglobulin 4 (IgG4) is one of four human IgG subclasses and has several unique functional characteristics. It exhibits low affinity for complement and for most Fc receptors. It furthermore has generally high affinity for its antigen, with binding occurring in a monovalent fashion, as IgG4 can exchange Fab-arms with other IgG4 molecules. Because of these characteristics, IgG4 is believed to block its targets and prevent inflammation, which, depending on the setting, can have a protective or pathogenic effect. One example of IgG4 pathogenicity is muscle-specific kinase (MuSK) myasthenia gravis (MG), in which patients develop IgG4 MuSK autoantibodies, resulting in muscle weakness. As a consequence of the distinct IgG4 characteristics, the pathomechanism of MuSK MG is very different from IgG1-and IgG3-mediated autoimmune diseases, such as acetylcholine receptor MG. In recent years, new autoantibodies in a spectrum of autoimmune diseases have been discovered. Interestingly, some were found to be predominantly IgG4. These IgG4-mediated autoimmune diseases share many pathomechanistic aspects with MuSK MG, suggesting that IgG4-mediated autoimmunity forms a separate niche among the antibody-mediated disorders. In this review, we summarize the group of IgG4-mediated autoimmune diseases, discuss the role of IgG4 in MuSK MG, and highlight interesting future research questions for IgG4-mediated autoimmunity.

Serological and experimental studies in different forms of myasthenia gravis

“…67 These findings appeared to provide an adequate explanation for the pathogenic effect of IgG4 antibodies and suggested that the coexisting IgG1-3 antibodies were irrelevant. 68 The inhibition of LRP4 binding to MuSK by IgG4 antibodies was also shown by coimmunoprecipitation and western blotting. 64 The IgG1-3 fractions did not inhibit LRP4 binding to MuSK.…”

“…Subsequent experiments by that group showed that, in a solid support assay, MuSK IgG4 antibodies inhibited the binding of LRP4 to MuSK and prevented agrin–LRP4–induced MuSK phosphorylation . These findings appeared to provide an adequate explanation for the pathogenic effect of IgG4 antibodies and suggested that the coexisting IgG1–3 antibodies were irrelevant …”

Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

“…Loss of appropriate pre-and postsynaptic alignment is also known to contribute to the NMJ dysfunction seen in MG animal models (Cole et al, 2008;Huijbers et al, 2018;Klooster et al, 2012).…”

“…Our data show that rendering the IgG4s bispecific and thereby functionally monovalent for the MuSK autoantigen serves as a mechanism that exacerbates the autoantibodies pathogenic potential. This may be relevant for the growing number of IgG4mediated autoimmune diseases and other disease settings where IgG4 plays a pathogenic role, such as where IgG4 blocks endogenous anti-tumor responses in melanoma patients (Daveau et al, 1977;Huijbers et al, 2018;Karagiannis et al, 2013).…”

“…Recently, a new and growing class of antibody-mediated autoimmune diseases characterized by predominant pathogenic IgG4 responses was described (Huijbers et al, 2018;Huijbers et al, 2015;Koneczny, 2018). IgG4 is a peculiar antibody with unique characteristics.…”