[Pubmed] Single-cell atlas reveals heterogeneous response to FcRn blockade in anti-AChR antibody-positive generalised my

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Clin Transl Med. 2025 Aug;15(8):e70436. doi: 10.1002/ctm2.70436.

ABSTRACT

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease predominantly driven by autoantibodies targeting acetylcholine receptor (AChR), resulting in muscle weakness. Efgartigimod, a neonatal Fc receptor (FcRn) blocker, reduces pathogenic immunoglobulin G in anti-AChR antibody-positive generalised MG (gMG). This study aimed to identify immune mechanisms underlying MG pathology and response to efgartigimod.

METHODS: We constructed a single-cell atlas of peripheral immune cells from treatment-naïve and efgartigimod-treated patients with gMG. Comprehensive immunophenotyping was performed to compare the clonal diversity of B- and T-cell populations, alongside experimental validation to assess the activation of Th17-related pathways before and after FcRn blockade.

RESULTS: B cells in patients with gMG exhibit heightened activation and differentiation, while T cells display distinct pro-inflammatory phenotypes. Enhanced intercellular signalling contributed to the pathogenicity associated with gMG. Efgartigimod mitigated upregulated antigen processing and presentation pathways in MG. Additionally, B-cell clonal diversity and IGHG1-bearing B-cell receptors increased. Transcriptional factor alterations were noted in suboptimal responders. Regulation of T-cell activity, particularly within Th17-related pathways, was associated with remission rates.

CONCLUSIONS: These findings underscore immune heterogeneity and dynamics during efgartigimod treatment, providing mechanistic insights into therapeutic response in gMG.

KEY POINTS: Aberrant B cells and pro-inflammatory T cells contribute critically to generalised myasthenia gravis (gMG) pathogenesis. Neonatal Fc receptor (FcRn) blockade induces immunoglobulin G (IgG) depletion feedback, reflected by increased class-switched BCRs. Th17 cell proliferation is attenuated following FcRn blockade. Antigen processing and presentation pathways are downregulated after FcRn blockade in gMG.

PMID:40770830 | DOI:10.1002/ctm2.70436


Source: https://pubmed.ncbi.nlm.nih.gov/4077083 ... t9+e462414