Identification and characterization of bone marrow plasma cells producing IFN-γ-neutralizing autoantibodies in adult-onset immunodeficiency - PubMed
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- #immunodeficiency
- #autoantibodies
- #bone-marrow
- Adult-onset immunodeficiency (AOID) is linked to anti-interferon (IFN)-γ autoantibodies (AIGAs).
- Rituximab (RTX) reduces circulating B cells but often fails to eliminate AIGAs, suggesting long-lived antibody-secreting cells (ASCs) in immune-privileged sites.
- 23 distinct IFN-γ-specific monoclonal antibodies (mAbs) were identified from bone marrow (BM) ASCs of AOID patients using microwell array chip technology and single-cell RNA sequencing.
- Neutralizing mAbs disrupt IFN-γ engagement with IFN-γR1 or IFN-γR2, impairing JAK-STAT1 signaling.
- Structural analysis of neutralizing mAb A01BM-03 revealed its binding to a quaternary epitope on dimeric IFN-γ, disrupting IFN-γR2 interaction.
- Clonally expanded IFN-γ-specific ASCs were localized within a CD11c+ZEB2+ age-associated B cell (ABC)-like plasma cell cluster in one AOID patient, implicating its role in AOID pathogenesis.
- Findings provide direct evidence for IFN-γ-specific ASCs in the BM despite RTX treatment, supporting targeted ASC therapy to restore immune homeostasis in AOID.