Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after mRNA vaccination.

BACKGROUND: The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated. METHODS: Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination. RESULTS: We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based. CONCLUSIONS: Our results imply a critical role for IL-4/IL-13 as well as TNF in vivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization.

BAFF, IL-4 and IL-21 separably program germinal center-like phenotype acquisition, BCL6 expression, proliferation and survival of CD40L-activated B cells in vitro.

A B cell culture system using BAFF, IL-4 and IL-21 was recently developed that generates B cells with phenotypic and functional characteristics of in vivo-generated germinal center (GC) B cells. Here, we observe discrete influences of each exogenous signal on the expansion and differentiation of a CD40L-activated B cell pool. IL-4 was expressly necessary, but neither BAFF nor IL-21 was required for B cell acquisition of the GC B cell phenotypes of peanut agglutinin binding and loss of CD38 and IgD expression. Both IL-4 and IL-21 enhanced cell cycle entry upon initial activation dose-dependently, and did so additively. Importantly, while both cytokines acted in concert to increase overall BCL6 expression amounts, IL-21 exposure uniquely caused a small proportion of cells to attain a higher level of BCL6 expression, reminiscent of in vivo GC B cells. In contrast, BAFF supported survival of a fraction of memory-like B cells in extended cultures after removal of surrogate T cell-help signals. Thus, by separably programming proliferation, survival and GC phenotype acquisition, IL-4, BAFF and IL-21 drive distinct components of activated B cell fate.