I. Anti–Interferon?Gamma Autoantibodies (Anti?IFN?γ Autoantibodies, AIGA)
Anti?IFN?γ autoantibodies are frequently observed in patients from Taiwan and are commonly associated with nontuberculous mycobacterial (NTM) infections. We first identified a strong association between this disease and specific human leukocyte antigen (HLA) genotypes, DRB116:02 and DQB105:02, indicating a genetic predisposition to anti?IFN?γ autoantibody–associated disease (Chi et al., Blood, 2013).
By expanding patient recruitment to include 145 patients from multiple countries, particularly Southeast Asia, we further demonstrated a strong genetic association between anti?IFN?γ autoantibodies and the HLA genotypes DRB115:02/16:02 and DQB105:01/05:02. The strength of this association suggests that these HLA haplotypes may directly contribute to the induction of anti?IFN?γ autoantibodies (Ku et al., Journal of Allergy and Clinical Immunology, 2016).
The immunodeficiency caused by anti?IFN?γ autoantibodies also predisposes patients to Talaromyces marneffei infection. More than 95% of non?HIV patients with talaromycosis were found to carry anti?IFN?γ autoantibodies. Clinically, this finding explains the geographic distribution of this fungal infection in southern China, while scientifically highlighting the critical role of interferon?γ in controlling fungal infections in humans (Guo et al., Journal of Experimental Medicine, 2020).
Our research further indicates that anti?IFN?γ autoantibodies may be induced by Aspergillus infection through a mechanism of molecular mimicry. Based on this discovery, we developed a novel recombinant interferon?γ variant lacking immunodominant epitopes, enabling it to evade binding by anti?IFN?γ autoantibodies and restore interferon?γ signaling. This strategy represents a potential therapeutic approach for patients suffering from persistent mycobacterial infections (Lin et al., Nature Medicine, 2016).
To better understand the neutralizing mechanisms of anti?IFN?γ autoantibodies, we employed single memory B?cell cloning technology to isolate monoclonal anti?IFN?γ antibodies from patients. Our analysis revealed that these autoantibodies inhibit interferon?γ function through multiple mechanisms, including
1. Blocking ligand?receptor binding,
2. Formation of immune complexes, and
3. Antibody?dependent cell?mediated cytotoxicity (ADCC)
(Shih et al., Journal of Experimental Medicine, 2022).
II. Anti?GM?CSF Autoantibodies
Cryptococcosis, a fungal infection that frequently causes severe meningitis and pneumonia, was historically considered a disease primarily affecting individuals with HIV or overt immunodeficiency. In recent years, however, cryptococcal infections have also been identified in immunocompetent individuals. Our studies revealed that a subset of these patients carry anti?GM?CSF autoantibodies (Kuo et al., Journal of Clinical Immunology, 2017).To further delineate the clinical features associated with these autoantibodies, we expanded our cohort and found that anti?GM?CSF autoantibodies are strongly associated with Cryptococcus gattii infections, particularly involving the central nervous system. Clinically, anti?GM?CSF autoantibodies are also known to be present in pulmonary alveolar proteinosis (PAP), another autoimmune disease.
Using serological comparisons between patients in Taiwan, we observed that although the prevalence of anti?GM?CSF autoantibodies did not differ significantly between cryptococcosis and PAP cohorts, the coexistence of these two diseases was rare. These findings suggest that the pathogenic mechanisms mediated by anti?GM?CSF autoantibodies are more complex than previously understood (Wang et al., Journal of Clinical Immunology, 2022).
Nocardiosis, another infectious disease capable of causing severe meningitis and pneumonia, shares similarities with cryptococcal infection. We identified anti?GM?CSF autoantibodies in immunocompetent patients with nocardial central nervous system infections (Lo et al., Journal of Clinical Immunology, 2024).
Our laboratory continues to investigate the neutralizing mechanisms of anti?GM?CSF autoantibodies to improve understanding of their role in infectious and immune?mediated diseases (Lo et al., manuscript in preparation).