Scientists discovered that haploinsufficiency in the Pax5 gene affects antiviral responses. The research team led by Prof. Dr. Aleksandra Pandyra from the Institute of Clinical Chemistry and Clinical Pharmacology at the University Hospital Bonn in collaboration with Prof. Dr. Arndt Borkhardt, Clinic Director at the Pediatric Oncology at the University Hospital Düsseldorf analyzed how PAX5 deficiency leads to impaired antibody production, resulting in a more severe disease outcome after viral infection. Intriguingly, researchers demonstrated that immune training, a process in which the innate immune system develops a more effective response to future infections after the initial exposure to certain stimuli, effectively improved the disease outcome. The findings were published in the latest edition of EMBO Molecular Medicine.
PAX5 is a transcription factor that is exclusively expressed in B lymphoid lineage cells and is crucial for B cell development. In recent years, it was shown that PAX5 dysregulation supports the development of acute lymphoblastic leukemia (B-ALL), a disease characterized by overproduction of abnormal B lymphocytes in the bone marrow. The cells accumulate in the bone marrow and blood and block the traffic of healthy blood cells. This results in impaired function of the immune system making it easier for infections to thrive.
Despite the risk for developing B-ALL, Pax5 mutation affect B cell differentiation, as it limits the production of B cells. So far, no increased risk of infection or autoimmunity has been reported as a result of this. Nonetheless, studies investigating the long-term effects after viral stimulation and the changes in the bone marrow environment are lacking. “Our team investigated the effects of long-term chronic viral infection in haploinsufficient Pax5 hosts.” explains Prof. Dr. Aleksandra Pandyra. The research team analyzed viral infection using different strains of the non-cytopathic Lymphocytic Choriomeningitis Virus (LCMV), whose clearance is dependent on T cell activity. “Can the immune system clear the virus? How does it affect the bone marrow environment milieu? And how does it impact the survival? These are the questions we aimed to answer in our study,” adds Prof. Dr. Aleksandra Pandyra.
The study shows that the long-term antiviral immune response in the heterozygous Pax5 hosts against chronic LCMV infection was indeed severely affected. The ability to produce late-stage LCMV-neutralizing antibodies was impaired, subsequently the chronic LCMV infection could not be properly cleared.
Immune training with b-glucan improves disease outcome
The term “trained immunity” defines the ability of the innate immune system to develop a long-term enhanced response to infections or other stimuli after the initial exposure. Trained immunity involves epigenetic and metabolic reprogramming of innate immune cells, such as monocytes, macrophages, and natural killer (NK) cells that allows them to respond more effectively to subsequent challenges, even if the stimulus is different from the initial one. b-glucan is a compound used in the context of trained immunity and has been studied in cancer, autoimmune disease, and neuroinflammation models for its promising therapeutic benefits.
In the current study, the prophylactic pre-treatment with the b-glucan immune trainer had a positive effect on the disease outcome after LCMV infection. The viral clearance was enhanced, the cytotoxic T lymphocyte (CTL) responses strengthened, and the neutralizing antibody production was increased. Simultaneously, the monocyte-mediated immunosuppression was reduced across multiple LCMV-infected host organs. “The b-glucan immune training restored host immunity after chronic viral infection and effectively improved disease outcome. Our team will further investigate trained immunity in individuals with genetic predispositions for its potential benefits in the prophylactic and also interventional setting.” says Prof. Dr. Aleksandra Pandyra.
Funding
The study was supported by the Deutsches Zentrum für Infektionsforschung (DZIF, TTU 07-711), BMBF 01KD2410A (EDI-4-ALL), and the Deutsche José Carreras Leukämie-Stiftung (DJCLS 18R/2021, 07/19).
Publication
Zhe Lu, Olivia Stencel et al. Immune training enhances anti-viral responses and improves outcomes in Pax5-/+ mice susceptible to chronic infection, EMBO Molecular Medicine (2025), DOI: https://doi.org/10.1038/s44321-025-00208-4
Contact
Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn
Cluster Of Excellence ImmunoSensation2
E-Mail: apandyr1@uni-bonn.de
