Return of the Anti-IFN-γ: From Disease Mechanism to Therapeutic Approach｜基因體醫學月會

Описание: 拍攝日期：2025/07/14
主講人：顧正崙（長庚大學分子免疫中心 特聘教授）

[摘要]

Anti–interferon-γ autoantibodies (AIGAs) are key drivers of adult-onset immunodeficiency in Southeast Asia, predisposing individuals to infections such as Talaromyces marneffei and nontuberculous mycobacteria. Using single-cell capture, we cloned 19 monoclonal AIGAs and identified three distinct epitopes on IFN-γ. While all clones exhibited high-affinity binding , only a subset neutralized IFN-γ–STAT1 signaling. Mechanistic studies revealed that epitope group I antibodies block IFN-γ binding to IFN-γR1, whereas group II and III antibodies interfere with IFN-γR1–R2 dimerization even after receptor engagement. Notably, group III antibodies also mediated antibody-dependent cellular cytotoxicity (ADCC), potentially depleting IFN-γ–responsive cells. To therapeutically eliminate these pathogenic antibodies, we developed IFN-γ chimeric autoantibody receptor (CAAR) T cells using an engineered, receptor-nonbinding IFN-γ variant. These CAAR T cells selectively targeted autoreactive B cells from patients, reduced circulating AIGAs in a mouse model, and avoided off-target and Fc-mediated toxicity. This precision approach offers a promising strategy for restoring IFN-γ immunity in affected patients. Meanwhile, due to their potent and specific cytokine-blocking activity, AIGAs are also being repurposed as therapeutic agents for IFN-γ–driven autoimmune diseases such as vitiligo, where IFN-γ contributes to melanocyte destruction. Our work highlights both the pathogenic mechanisms of AIGAs and innovative therapeutic strategies that transform disease insights into clinical applications.

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