10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID)

X mutation is novel and causes a substitution of an amino acid conserved among multiple species. Objectives: It is unclear whether and how the PSMB9 X mutation contributes to the manifestations of the patients. In order to clarify this issue, we have generated and analyzed mutant mice carrying the mutation. Methods: The mice carrying the Psmb9 X mutation were generated with CRISPR/Cas9 technology. Homozygous Psmb9 X mutant mice died within 6 months old. Therefore, the heterozygous Psmb9 X mutant mice were mainly analyzed. Not only biochemical but also immunological analyses including histological and flow cytometry analyses were performed. Results: Heterozygous Psmb9 X mutant mice appeared healthy at glance. The 1i subunit becomes mature after processing by the proteasome, but this maturation process was impaired in splenocytes of the heterozygous Psmb9 X mutant mice. In the mutant mice, thymus was small and the cortico-medullary junction was unclear. All thymocytes such as CD4 + , CD8 + , double positive and double negative cells were decreased. In the spleen, B cells as well as CD4 + and CD8 + T cells were decreased. Furthermore, serum levels of immunoglobulins, including IgM, IgGs and IgA, were severely decreased. Dendritic cells (DCs) and all DC subsets were also decreased, although the conventional DC1 subset, defined as CD8 + CD11b -cells, was most severely decreased. Meanwhile, CD11b + cells consisting mainly of neutrophils and monocytes were increased in the bone marrow. These phenotype of the heterozygous Psmb9 X mutant mice were not identical to, but overlapping significantly with the manifestations of the two patients.