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IgG4 antibodies are unique to humans. IgG4 is associated with tolerance during immunotherapy in allergy, but also with pathology, as in pemphigus vulgaris and IgG4-related disease. Its induction is largely restricted to non-microbial antigens, and requires repeated or prolonged antigenic stimulation, for reasons poorly understood.An important aspect in generating high-affinity IgG antibodies is chemokine receptormediated migration of B cells into appropriate niches, such as germinal centers.Here, we show that compared to IgG1 B cells, circulating IgG4 B cells express lower levels of CXCR3, CXCR4, CXCR5, CCR6, and CXCR7, chemokine receptors involved in germinal center reactions and generation of long-lived plasma cells. This phenotype was recapitulated by in vitro priming of naive B cells with an IgG4inducing combination of T FH /T H2 cytokines. Consistent with these observations, we found a low abundance of IgG4 B cells in secondary lymphoid tissues in vivo, and the IgG4 antibody response is substantially more short-lived compared to other IgG subclasses in patient groups undergoing CD20 + B cell depletion therapy with rituximab. These results prompt the hypothesis that factors needed to form IgG4 B This article is protected by copyright. All rights reserved. cells restrain at the same time the induction of a robust migratory phenotype that could support a long-lived IgG4 antibody response. IgG4 B cells express fewer chemokine receptors involved in germinal center reactions and generation of long-lived plasma cells.This might restrain induction of a robust migratory phenotype that could support a long-lived IgG4 antibody response.

No abstract