Anti-interferon-γ autoantibodies: immunopathogenesis, diagnostic innovation, and emerging therapeutic strategies in an adult-onset immunodeficiency.

Adult-onset immunodeficiency with anti-interferon-γ autoantibodies (AIGA) is a rare acquired immunodeficiency increasingly recognized in East and Southeast Asia, characterized by disseminated infections with nontuberculous mycobacteria and other intracellular pathogens. Recent studies have refined our understanding of its immunopathogenesis, including HLA-linked susceptibility, epitope-specific neutralization of IFN-γ, and molecular mimicry, while highlighting persistent gaps in diagnosis and treatment. This Perspective synthesizes emerging evidence into a clinically oriented framework spanning diagnosis, monitoring, and immunomodulatory therapy. We discuss functional confirmation of AIGA, repurposing of the QuantiFERON-TB platform as an accessible screening strategy, and quantitative titers and ¹8F-FDG PET as complementary biomarkers of disease activity and treatment response. We propose a clinical decision pathway in which refractory or progressive infection, rather than a fixed titer threshold, triggers immunomodulation, with rituximab and cyclophosphamide as the best-supported induction strategies, daratumumab reserved for refractory cases, and emerging AIGA-specific evidence supporting azathioprine for maintenance. Recognizing heterogeneous access to specialized testing and biologics across AIGA-endemic regions, we propose a resource-stratified approach integrating widely available markers with referral-based testing and resource-adapted treatment. We also highlight emerging antigen-specific strategies, including chimeric autoantibody receptor T cells engineered to eliminate autoantibody-producing B cells, as a future direction toward durable remission. Finally, we outline priorities for prospective validation and biomarker-guided therapy.