The following is a summary of “Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after mRNA vaccination,” published in the March 2024 issue of Allergy & Immunology by Valk, et al.

Immunoglobulin G4 (IgG4) is a noninflammatory antibody associated with tolerance and is uniquely present in humans. Although the mechanisms underlying IgG4 class switching are not fully understood, prolonged antigenic stimulation and IL-4 signaling through the T helper 2 (Th2) pathway are believed to play significant roles. Recent studies have suggested repeated SARS-CoV-2 mRNA vaccination may lead to IgG4 skewing. However, while the effects of commonly used immunosuppressive drugs on humoral responses to SARS-CoV-2 mRNA vaccines have been moderately studied, their impact on IgG4 class switching has not been thoroughly investigated.

The study examined the effects of immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing following repeated SARS-CoV-2 mRNA vaccinations. They measured receptor-binding domain (RBD)-specific antibody responses longitudinally in 600 individuals, including patients with immune-mediated inflammatory diseases receiving TNF inhibitors (TNFi) and/or methotrexate (MTX), patients treated with dupilumab and healthy, untreated controls. The analysis focused on RBD-specific IgG4 antibody level changes and total IgG responses after the third mRNA vaccine dose.

Following the third dose of the SARS-CoV-2 mRNA vaccine, there was a notable increase in the proportion of RBD-specific IgG4 antibodies among healthy, untreated controls, with a median of 21%. The IgG4 skewing was significantly reduced in patients treated with dupilumab, who showed less than 1% IgG4 skewing. Unexpectedly, patients treated with TNFi also displayed a similar suppression of IgG4 skewing (<1%), while MTX treatment led to a modest reduction in IgG4 levels (7%). The levels of RBD-specific total IgG were minimally affected by these immunosuppressive therapies. Additionally, minimal IgG4 skewing was observed in participants who received primary vaccination with an adenoviral vector-based vaccine.

The findings highlighted the crucial roles of IL-4/IL-13 and TNF in IgG4 class switching in vivo. The insights enhanced the understanding of the dynamics of IgG4 class switching and could inform strategies for inducing humoral tolerance, optimizing mRNA vaccine approaches, and treating IgG4-related diseases.

Reference: onlinelibrary.wiley.com/doi/10.1111/all.16089