The Hajdu Cheney Mutation is a Determinant of B Cell Allocation of the Splenic Marginal Zone

5 years ago

The Hajdu Cheney Mutation is a Determinant of B Cell Allocation of the Splenic Marginal Zone

The Notch2 receptor is a determinant of B cell function, and gain-of-NOTCH2–function mutations are associated with Hajdu Cheney Syndrome (HCS), a disease presenting with osteoporosis and acroosteolysis. We generated a mouse model reproducing the HCS mutation (Notch2HCS), and heterozygous global mutant mice displayed gain-of-Notch2 function. In the mutant spleen, the characteristic perifollicular rim marking the marginal zone (MZ), which is the interface between the non-lymphoid red pulp and the lymphoid white pulp, merged with components of the white pulp. As a consequence, the MZ of Notch2HCS mice occupied most of the splenic structure. To explore mechanisms involved, lymphocyte populations from the bone marrow and the spleen were harvested from heterozygous Notch2HCS mice and littermate sex-matched controls, and analyzed by flow cytometry. Notch2HCS mice had ∼5-fold increase in CD21/35^highCD23^- splenic MZ B cells and a proportional decrease in splenic follicular B cells (CD21/35^intCD23⁺) at 1, 2, and 12 months of age. Western blot analysis revealed that the Notch2HCS mutant splenocytes had increased pAKT and pJNK, and gene expression analysis of spleen CD19⁺ B cells demonstrated induction of Hes1 and Hes5 in Notch2HCS mutants. Anti-Notch2 antibodies decreased MZ B cells in control and Notch2HCS mice. In conclusion, Notch2HCS mutant mice have an increase in mature B cells in the MZ of the spleen.

Publisher URL: www.sciencedirect.com/science

DOI: S0002944017306168