Tannemaat, M. R. | Search bioRxiv

bioRxiv2026

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.

immunology↗

bioRxiv2024

Patient-specific therapeutic benefit of MuSK agonist antibody ARGX-119 in MuSK myasthenia gravis passive transfer models

Muscle-specific kinase (MuSK) orchestrates establishment and maintenance of neuromuscular synapses, which enable muscle contraction. Autoantibodies targeting MuSK cause myasthenia gravis (MG), a disease characterized by fatigable skeletal muscle weakness which requires chronic immunosuppressive treatment and ventilatory support at some point in [~]30% of patients. MuSK autoantibodies are predominantly IgG4 and are bispecific, functionally monovalent antibodies due to Fab-arm exchange. Through monovalent binding, MuSK IgG4 autoantibodies act as antagonists on the MuSK signalling pathway, impairing neuromuscular synaptic function. In contrast, bivalent MuSK antibodies act as agonists of the MuSK signalling pathway. Since symptoms in MuSK MG are largely caused by antagonistic monovalent MuSK antibodies, we hypothesized that a bivalent MuSK agonist could rescue MuSK MG, bypassing the need for generalized immunosuppression. In this study, we investigated whether an agonist antibody targeting the Frizzled-like domain of MuSK, ARGX-119, can ameliorate disease in MuSK MG models induced by passive transfer of polyclonal IgG4 from unrelated patients. For each patient material we first established the minimal dose for a progressive MG phenotype based on muscle function tests. ARGX-119 significantly improved survival and muscle weakness in a mouse model induced by one patient material, but not by three others. Mechanistically, this patient-specific efficacy could not be explained by autoantibody epitope specificity, titer or competition for ARGX-119 binding, but rather correlated to the presence of MuSK activating antibodies in some patients. We further provide evidence that an in vitro assay may predict which patients potentially benefit from ARGX-119 and that this treatment, when effective in MuSK MG mice, follows a bell-shaped dose-effect curve. These results provide first proof of concept of a MuSK agonist in a clinically relevant model for MuSK MG. We anticipate this to be a starting point for investigating the therapeutic benefit of ARGX-119 in MuSK MG and other neuromuscular diseases hallmarked by neuromuscular synaptic dysfunction. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/606156v1_figu1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@15c08faorg.highwire.dtl.DTLVardef@1517281org.highwire.dtl.DTLVardef@3498c2org.highwire.dtl.DTLVardef@118e9af_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMuSK agonist ARGX-119 can rescue MuSK MG in a patient-specific manner C_LIO_LIMuSK agonism follows a bell-shaped efficacy curve in this MuSK MG mouse model C_LIO_LIVariation in ARGX-119 efficacy between patient models is not explained by competition for binding on MuSK, but rather appears related to an agonistic fraction of patient antibodies C_LIO_LIAn in vitro assay is potentially predictive for treatment efficacy of the MuSK agonist C_LI

neuroscience↗