Distinct transcriptional programs define human IgG4 ⁺ memory B cells

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.