Rooted in Taiwan, Building Regional and International
Partnerships Advancing a Translational Immunology Network for Infection and Anti-Cytokine Autoantibodies
Some adults without a previously recognized congenital or acquired immunodeficiency may develop neutralizing anti-cytokine autoantibodies, which interfere with essential immune signaling pathways and predispose them to severe, recurrent, or unusual infections. These disorders are increasingly recognized as an important cause of adult-onset immunodeficiency.
Among them, anti-interferon-γ autoantibody (AIGA) associated disease is particularly relevant in East and Southeast Asia, where affected patients frequently present with nontuberculous mycobacterial (NTM) infections, Talaromyces marneffei infection, and other opportunistic infections.
The Molecular and Clinical Immunology Center (CMCI) at Chang Gung University has long been dedicated to the study of anti-cytokine autoantibodies and severe infectious diseases in adults. Building upon our clinical and research experience in Taiwan, we aim to connect clinicians and investigators across East and Southeast Asia, while expanding regional and international collaborations, to establish an integrated network encompassing case identification, autoantibody detection, functional characterization, longitudinal clinical follow-up, and mechanistic studies.
Through multinational and multicenter patient recruitment and long-term collaboration, we seek to uncover previously unrecognized immune abnormalities underlying important infectious diseases in the region and translate these discoveries into improved strategies for diagnosis, disease monitoring, and treatment.
We welcome clinicians and researchers with patients presenting with severe, recurrent, or unusual infections suspected to be associated with anti-cytokine autoantibodies to contact our center for potential clinical and research collaboration.
Research Directions and Achievements
I. Anti-Interferon-γ Autoantibodies (AIGA)
- East and Southeast Asian Populations and Associated Infectious Diseases
AIGA-associated disease is particularly prevalent among affected populations in East and Southeast Asia and is frequently associated with disseminated or recurrent NTM infections. Our early studies identified a strong association between AIGA-associated disease and specific human leukocyte antigen (HLA) genotypes, particularly HLA-DRB1*16:02 and HLA-DQB1*05:02 (Chi, Blood, 2013).
By expanding our cohort to include patients from multiple countries, particularly across East and Southeast Asia, we further demonstrated strong genetic associations with HLA-DRB1*15:02, HLA-DRB1*16:02, HLA-DQB1*05:01, and HLA-DQB1*05:02. These striking HLA associations suggest that antigen presentation and subsequent adaptive immune responses may directly contribute to the development of AIGA-associated disease (Ku, J Allergy Clin Immunol, 2016).
Beyond NTM infection, we found that AIGA could be detected in more than 95% of non-HIV patients with Talaromyces marneffei infection in the studied cohort. These findings provided an important immunological explanation for severe adult-onset fungal infection in this region and offered human evidence supporting the critical role of IFN-γ in host defense against T. marneffei (Guo, J Exp Med, 2020).
Together, these studies suggest that AIGA is not merely an isolated autoimmune phenomenon in individual patients, but may arise through interactions among genetic susceptibility, environmental exposure, and infectious triggers in susceptible populations across East and Southeast Asia.
- From Disease Mechanisms to Therapeutic Strategies
We have further investigated why AIGA develops in adults with previously normal immune function. Our studies suggest that the generation of AIGA may be associated with molecular mimicry induced by environmental microbial antigens. Specific fungal antigens share structural similarities with epitopes of human IFN-γ and may trigger cross-reactive immune responses, ultimately leading to the generation of autoantibodies capable of recognizing and neutralizing human IFN-γ.
Based on these findings, we also engineered a modified recombinant IFN-γ with altered antibody-recognition epitopes, thereby reducing its recognition by patient-derived AIGA while preserving biological activity. This strategy partially restored IFN-γ signaling in the presence of autoantibodies and may provide a potential therapeutic approach for persistent or refractory mycobacterial infections (Lin, Nat Med, 2016).
To further dissect the pathogenic mechanisms of AIGA, we used single memory B-cell cloning to isolate IFN-γ-specific monoclonal antibodies from patients. We found that different AIGA clones can disrupt IFN-γ function through multiple mechanisms, including:
1. directly interfering with the interaction between IFN-γ and its receptor
2. forming immune complexes
3. affecting IFN-γ-regulated immune responses through mechanisms including antibody-dependent cellular cytotoxicity (ADCC)
These findings demonstrate that even among patients classified as having AIGA-associated disease, the composition and pathogenic potential of their autoantibodies may differ substantially (Shih, J Exp Med, 2022).
Accordingly, our current research has moved beyond simply determining whether an autoantibody is present. We are now integrating autoantibody levels, epitope specificity, neutralizing activity, clinical manifestations, and longitudinal changes in disease status to better understand disease heterogeneity and identify biomarkers relevant to clinical monitoring and therapeutic response.
II. Anti-GM-CSF Autoantibodies
GM-CSF plays an essential role in the differentiation and function of alveolar macrophages and other myeloid cells. In addition to their well-established association with pulmonary alveolar proteinosis (PAP), anti-GM-CSF autoantibodies have increasingly been implicated in susceptibility to specific infectious diseases.
- Cryptococcosis and Anti-GM-CSF Autoantibodies
Cryptococcosis can cause severe pulmonary and central nervous system infections and has traditionally been associated with HIV infection or other immunocompromised states. However, severe cryptococcal infections can also occur in adults without a previously recognized immunodeficiency.
We found that a subset of these patients harbored anti-GM-CSF autoantibodies, suggesting that acquired disruption of GM-CSF-mediated immunity may contribute to their susceptibility to infection (Kuo, J Clin Immunol, 2017). With expanded patient recruitment, we further identified a particularly notable association between anti-GM-CSF autoantibodies and Cryptococcus gattii infection, frequently involving the central nervous system.
Anti-GM-CSF autoantibodies are also a major pathogenic factor in autoimmune PAP. Interestingly, however, patients with apparently similar autoantibodies do not necessarily develop both PAP and cryptococcosis. By comparing serum and antibody characteristics among different patient groups in Taiwan, we found that the mere presence of anti-GM-CSF autoantibodies is insufficient to fully explain the differences in clinical manifestations. These observations suggest that autoantibody function, host factors, tissue microenvironment, and additional immune determinants may collectively shape disease phenotypes (Wang, J Clin Immunol, 2022).
- Nocardiosis and Anti-GM-CSF Autoantibodies
Nocardia infection can likewise cause severe pulmonary and central nervous system disease. We identified anti-GM-CSF autoantibodies in patients with cerebral nocardiosis who had no previously recognized immunodeficiency, further supporting an important role for GM-CSF-mediated immunity in human defense against specific pathogens. (Lo, J Clin Immunol, 2024).
We are continuing to characterize the antibody profiles, neutralizing capacity, and clinical manifestations of anti-GM-CSF autoantibodies in different patient populations, with the goal of understanding why apparently similar autoantibodies can result in distinct disease phenotypes and which antibody characteristics are truly pathogenic (Lo, manuscript in preparation).
Through collaboration with clinical and research teams in Taiwan, across Asia, and internationally, we hope to establish a more comprehensive landscape of adult-onset infectious immunodeficiencies, identify immune abnormalities that remain underdiagnosed, and translate mechanistic understanding into better clinical care.
Information for Patients and the Public
If you have experienced recurrent, severe, or unusual infections and have been advised by a physician that an underlying immune abnormality or anti-cytokine autoantibody-associated disorder may be suspected, we recommend seeking a comprehensive clinical evaluation by an infectious disease specialist, allergist/immunologist, rheumatologist, or another appropriate specialist.
The diagnosis and interpretation of anti-cytokine autoantibody-associated disorders require integration of the patient’s infectious history, microbiological findings, autoantibody testing, functional antibody assays, and other immunological and clinical information. These disorders cannot be diagnosed on the basis of symptoms or a single autoantibody test alone.
Patients with relevant concerns may seek evaluation through the appropriate clinical departments within the Chang Gung Memorial Hospital system. The treating physician can then determine whether further testing or subsequent clinical and research collaboration with our center may be appropriate.