Persistent virus-specific and clonally expanded antibody-secreting cells respond to induced self-antigen in the CNS
SUMMARY
B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality. Here, the authors led by Professor Alexander Yermanos (ETH Zurich) and GCIR member Professor Doron Merkler (UNIGE), profiled B cells from the CNS of murine models of intracranial (i.c.) viral infections and autoimmunity. They identified a population of clonally expanded, antibody-secreting cells (ASCs) that had undergone class-switch recombination and extensive somatic hypermutation following i.c. infection with attenuated lymphocytic choriomeningitis virus (rLCMV). Recombinant expression and characterisation of these antibodies revealed specificity to viral antigens (LCMV glycoprotein GP), correlating with ASC persistence in the brain weeks after resolved infection. Furthermore, these virus-specific ASCs upregulated proliferation and expansion programs in response to the conditional and transient induction of the LCMV GP as a neo-self-antigen by astrocytes. This class-switched, clonally expanded, and mutated population persisted and was even more pronounced when peripheral B cells were depleted prior to autoantigen induction in the CNS. In contrast, the most expanded B cell clones in mice with persistent expression of LCMV GP in the CNS did not exhibit neo-self-antigen specificity, potentially a consequence of local tolerance induction. Finally, a comparable population of clonally expanded, class-switched, and proliferating ASCs was detected in the cerebrospinal fluid of relapsing multiple sclerosis (RMS) patients. Taken together, these findings support the existence of B cells that populate the CNS and are capable of responding to locally encountered autoantigens.
Read here the full article published in Acta Neuropathologica: https://doi.org/10.1007/s00401-023-02537-5
Why is it important?
B cells are the main effector cells in autoimmunity through antibody production, antigen presentation and proinflammatory cytokine production. In autoinflammatory diseases of the central nervous system (CNS) such as multiple sclerosis, B cells can penetrate the CNS and contribute to local tissue destruction. However, the exact transcriptional changes, repertoire characteristics and functionality of these B-cell antibodies are still poorly understood.
Here, the authors used mouse models of autoimmunity and infection to uncover phenotypically and functionally diverse CNS B-cell populations. They found, for example, that clonally expanded, virus-specific, IgG-expressing, antibody-secreting cell populations persist in the CNS weeks after viral clearance and can be locally reactivated upon a local antigen re-encounter.
Overall, the study highlights the clonal dynamics of B cells populating the CNS during infection and autoimmunity in experimental models and human disease. The study serves as a starting point to unravel the poorly understood underpinnings of B-cell dysregulation in chronic inflammatory CNS diseases and sheds light on future directions for B-cell modulating therapies in autoimmune diseases.