Distinct transcriptional programs define human IgG4+ memory B cells

Paardekooper, L. M.; van Bokkum, J. M.; Fillie-Grijpma, Y.; Vergoossen, D. L.; Benner, I.; Kissel, T.; Kloet, S. L.; Tannemaat, M. R.; Verschuuren, J. J.; van der Maarel, S. M.; Huijbers, M. G.

doi:10.64898/2026.06.05.728165

bioRxiv · 10.64898/2026.06.05.728165

Distinct transcriptional programs define human IgG4+ memory B cells

Paardekooper, L. M.·van Bokkum, J. M.·Fillie-Grijpma, Y.·Vergoossen, D. L.·Benner, I.·Kissel, T.·Kloet, S. L.·Tannemaat, M. R.·Verschuuren, J. J.·van der Maarel, S. M.·Huijbers, M. G.

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Abstract

Human immunoglobulin G4 (IgG4) shapes both protective and pathogenic immunity, influencing conditions ranging from allergy and autoimmunity to cancer. However, subclass-specific targeting of memory B cells remains challenging due to limited knowledge of their phenotypic and functional heterogeneity. Here, we show that IgG4+ memory B cells are overrepresented in a niche of FCER2+BAFFR+ memory B cells, can be classified in several subtypes, have a distinct transcription factor profile and are the only memory B cell subset to express sterile IGHE transcripts. While IgG4+ B cells display a unique transcriptional profile, only BAFFR, IL5Rb and the B cell receptor were upregulated on protein level on IgG4+ cells. IgG4+ B cells have normal repertoire diversity, but a distinct germline V-gene usage, suggesting IgG4 responses are driven by specific antigens. By labeling autoreactive B cells, we confirmed that MuSK myasthenia gravis (an archetypal IgG4-mediatedautoimmune disease) patients have a normal memory B cell profile and that autoreactive IgG4+ memory B cells are extremely rare. These results highlight the unique features of IgG4+ B cells, provide insight on potential subclass-specific therapeutic targets and point towards an antigen-driven IgG4 response within a largely non-autoreactive memory B cell pool.

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Paardekooper, L. M., van Bokkum, J. M., Fillie-Grijpma, Y., Vergoossen, D. L., Benner, I., Kissel, T., Kloet, S. L., Tannemaat, M. R., Verschuuren, J. J., van der Maarel, S. M., Huijbers, M. G.. 2026-06-09. Distinct transcriptional programs define human IgG4+ memory B cells. https://doi.org/10.64898/2026.06.05.728165

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