This is a summary of Afzali, A.M., Nirschl, L., Sie, C. et al. B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4 (2024), which appeared in Nature (2024). https://doi.org/10.1038/s41586-024-07079-8
The challenge
The thymus gland produces white blood cells called T cells, which are crucial for fighting infection. It possesses a sorting mechanism that eliminates T cells that could attack the body: thymus epithelial cells express many molecules found in the body to prevent the cells from attacking these. However, autoimmune diseases can develop if this mechanism fails and faulty T cells are allowed to proliferate. In the case of NMO, T cells target the water channel protein AQP4, which is expressed in astrocytes of the brain and spinal cord. In the peripheral immune system, these AQP4-specific T cells give help to AQP4-specific B cells to develop into antibody-producing cells, and AQP4-specific antibodies eventually induce damage to astrocytes in NMO. Interestingly, alongside T cell precursors, the thymus gland also harbors B cells, the role of which has long puzzled immunologists. Therefore, we studied their role in the development of NMO.
Our approach
We used mouse models to study the significance of thymic B cells in presenting AQP4 to nascent T cells in the thymus. We genetically removed AQP4 from both thymic epithelial cells and B cells to test whether thymic epithelial cells or thymic B cells were most relevant in presenting their endogenous AQP4, and by this means eliminating AQP4-specific thymocytes.
Our findings
Our study shows that B cells licensed in the thymus are pivotal in teaching T cells to avoid AQP4. In the thymus glands of humans and mice, the epithelial cells and the B cells express and present AQP4 to the T cell precursors. When we prevented B cells from expressing AQP4 in our mouse model, the immune system did not learn to ignore AQP4, even when epithelial cells still expressed AQP4, and subsequently, NMO developed. This suggests that B cells in the thymus are crucial for teaching the immune system to tolerate AQP4, preventing autoimmune reactions.
The implications
We believe that issues with how B cells train T cells in the thymus can also cause other autoimmune diseases, such as antiphospholipid syndrome (APS) or certain forms of cerebral amyloid angiopathy since autoantigens associated with these diseases are also expressed in thymic B cells. Studying this interaction in the thymus more closely could help develop treatments tailored to address a series of autoimmune diseases more effectively.
Creating SyNergies
This study was led by Thomas Korn (TUM) in collaboration with Ludger Klein (LMU) and involved SyNergy member Bernhard Hemmer. Our data indicate that immune tolerance against a series of autoantigens that are expressed in CNS border tissues (beyond AQP4) is orchestrated by thymic B cells instead of thymic epithelial cells. Therefore, we will exploit our experimental platforms to test this and – in collaboration with our SyNergy partners – investigate lesion development at CNS borders when tolerance to these autoantigens fails.
