Anti-interferon-γ autoantibodies: immunopathogenesis, diagnostic innovation, and emerging therapeutic strategies in an adult-onset immunodeficiency
- 1Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University , ,
- 2Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine , ,
- 3Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine , , ,
Abstract
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 ¹ ⁸ F-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.
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BibTeX
@article{tsai2026antiinterferonγ,
title = {{Anti-interferon-γ autoantibodies: immunopathogenesis, diagnostic innovation, and emerging therapeutic strategies in an adult-onset immunodeficiency}},
author = {Chin-Shiang Tsai and Aristine Cheng and Farha Naz},
journal = {Frontiers in immunology},
year = {2026},
month = sep,
doi = {10.3389/fimmu.2026.1964087},
url = {https://europepmc.org/article/PMC/PMC13661404},
note = {CC BY},
}
RIS
TY - JOUR
TI - Anti-interferon-γ autoantibodies: immunopathogenesis, diagnostic innovation, and emerging therapeutic strategies in an adult-onset immunodeficiency
AU - Chin-Shiang Tsai
AU - Aristine Cheng
AU - Farha Naz
PY - 2026
DA - 2026/09/30
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1964087
UR - https://europepmc.org/article/PMC/PMC13661404
AB - 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 ¹ ⁸ F-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.
SN - 1664-3224
ER -