A comprehensive analysis of scRNA-Seq and RNA-Seq unveils B cell immune suppression in the AAV-loaded brain

The use of AAV vectors for in vivo gene therapy has demonstrated the potential to permanently correct genetic diseases by delivering functional gene copies to the nuclei of affected tissues. AAV vectors, as tools for in vivo gene delivery, are particularly appealing and have shown safety and long-term efficacy in numerous organ-targeted experiments. Nevertheless, employing AAV vectors for gene therapy in the brain faces a notable hurdle in the shape of immune responses, chiefly instigated by the brain's resident immune cells, microglia. Additionally, lower levels of AAV vector-neutralizing antibodies have been detected in the cerebrospinal fluid compared to the circulatory system. This research, leveraging transcriptomic and single-cell RNA sequencing (scRNA-seq) data in conjunction with Mendelian randomization analysis, has identified the potential role of the XBP1 protein in mediating B-cell immunosuppression in the brain via the MDK-NCL ligand-receptor pair and associated genes. Furthermore, it paves the way for further investigation into the regulatory factors and pathways within the immune modulation network, as well as their prospective beneficial implications in immunotherapeutic treatments. By employing various innovative approaches, the study seeks to recreate the immune environment generated by AAV in the brain and preliminarily explore the immune suppression mechanisms induced by AAV vectors in the brain.