Talaromyces marneffei causes life-threatening opportunistic infections, mainly in Southeast Asia and South China. T. marneffei mainly infects patients with human immunodeficiency virus (HIV) but also infects individuals without known immunosuppression. Here we investigated the involvement of anti–IFN-γ autoantibodies in severe T. marneffei infections in HIV-negative patients. We enrolled 58 HIV-negative adults with severe T. marneffei infections who were otherwise healthy. We found a high prevalence of neutralizing anti–IFN-γ autoantibodies (94.8%) in this cohort. The presence of anti–IFN-γ autoantibodies was strongly associated with HLA-DRB1*16:02 and -DQB1*05:02 alleles in these patients. We demonstrated that adult-onset acquired immunodeficiency due to autoantibodies against IFN-γ is the major cause of severe T. marneffei infections in HIV-negative patients in regions where this fungus is endemic. The high prevalence of anti–IFN-γ autoantibody–associated HLA class II DRB1*16:02 and DQB1*05:02 alleles may account for severe T. marneffei infections in Southeast Asia. Our findings clarify the pathogenesis of T. marneffei infection and pave the way for developing novel treatments.

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These findings suggest that sex, serum CRP concentration and spun urine WBC count can be used to accurately predict SBI in febrile infants aged less than 3 months of age.

Anti-interferon (IFN)–γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. 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.