Adult-onset immunodeficiency (AOID) is associated with persistently elevated autoantibodies to interferon gamma (IFN-γ). As a result, patients frequently develop infections caused by nontuberculous mycobacteria and the fungus Talaromyces marneffei. The condition is more common in individuals of Asian origin, suggesting contributions from both genetic and environmental factors.
Autoantibodies impair IFN-γ signaling through several mechanisms:
- They prevent binding of IFN-γ to its receptors IFN-γR1 and IFN-γR2 on cells, thereby blocking the JAK–STAT1 signaling pathway that drives protective immune responses;
- They promote the destruction of immune cells that express IFN-γR1/2.
These effects may exacerbate mycobacterial infections.
Treatment of AOID includes antibiotics and immunotherapy, including rituximab, a monoclonal antibody that depletes B cells by targeting the CD20 surface molecule. However, in some patients, autoantibody levels remain high even after treatment, suggesting the presence of B-cell populations that are not sensitive to rituximab.
Chinese researchers investigated bone marrow cells producing autoantibodies. They identified 23 autoantibody variants, six of which demonstrated strong neutralizing activity by disrupting the binding of IFN-γ to IFN-γR1 and IFN-γR2.
These autoantibodies suppressed activation and polarization of macrophages — key cells responsible for eliminating intracellular pathogens, including nontuberculous mycobacteria. One antibody, A01BM-03, demonstrated efficacy comparable to that of emapalumab, a clinically used therapeutic agent.
Structural analysis revealed that A01BM-03 binds simultaneously to two regions of the IFN-γ molecule and physically blocks the receptor-binding interface, explaining its strong inhibitory effect.
In addition, analysis of patient cells showed that IFN-γ–specific antibody-producing B cells persist in the bone marrow even after rituximab therapy. These cells are associated with age-related immune remodeling and autoimmune processes.
Persistence and Rebound of Autoantibodies in AOID
Researchers analyzed blood samples from 22 AOID patients. Levels of autoantibodies to IFN-γ were significantly higher than in patients with infectious diseases and in healthy donors.
In one AOID patient with bacterial infection, rituximab therapy initially reduced both autoantibody titers and peripheral B-cell counts, accompanied by clinical improvement. However, autoantibody levels later rebounded to near baseline, and B-cell counts increased despite repeated treatment. No relapse of infection was observed.
Thus, rituximab effectively reduces peripheral B-cell populations but does not eliminate the cells that produce IFN-γ autoantibodies.
Bone Marrow as a Source of Neutralizing Autoantibodies
In the bone marrow of AOID patients, researchers identified antibody-producing cells targeting IFN-γ in both treated and untreated individuals.
Some of these antibodies exhibited strong neutralizing activity, effectively blocking IFN-γ signaling despite having similar binding affinity to other antibodies.
The most potent antibody, A01BM-03, demonstrated the highest neutralizing capacity and binding strength, exceeding that of emapalumab.
Neutralizing antibodies suppressed IFN-γ–dependent activation and polarization of M1 macrophages, potentially impairing the clearance of intracellular pathogens.
Gene expression analysis showed that bone marrow plasma cells in AOID patients exhibit minimal CD20 expression, explaining their resistance to rituximab. At the same time, they display a gene expression profile typical of mature plasma cells.
The subset of cells producing IFN-γ antibodies was characterized by expression of ITGAX and ZEB2 — markers associated with age-related B cells.
Conclusion
In AOID patients, cells producing autoantibodies to IFN-γ are present both during and after rituximab therapy. These antibodies exhibit strong neutralizing activity — blocking receptor interaction and suppressing macrophage activation, which may impair control of intracellular infections.
The primary source of these autoantibodies is CD20-negative bone marrow plasma cells resistant to rituximab. A subset of these cells, characterized by high ITGAX and ZEB2 expression, produces IFN-γ antibodies and is associated with aging and autoimmune diseases.
Targeting this cell population may provide a new therapeutic strategy for AOID and help mitigate the progression of autoimmune disorders.
