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Vortrag von Cheng-Lung Ku

Vortragstitel: "The monoclonal resolution of the pathogenic mechanism of anti-interferon-γ autoantibodies in adult-onset immunodeficiency"
Anlass: SFB - Seminar
Beginn: 16.05.2024 - 16:15 Uhr
Ort: CellNanOs, 38/201

Über den Vortragenden: Prof. Dr. Cheng-Lung Ku forscht am Center for Molecular and Clinical Immunology der Chang Gung University in Taiwan.

Inhalt des Vortrags:

Anti-interferon (IFN)–γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs are almost exclusively found in the population from Southeast Asia and South China, and the number of affected individuals is largely underestimated. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ–reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD < 10−9 M) binding to IFN-γ, but only eight neutralized IFN-γ–STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I–III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1–IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody–IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ–responsive cells.