Fig. 3

MiTF in B cells. In the normal bone marrow microenvironment, MiTF is highly expressed in naive B cells, where it acts as a repressor of IRF4. After B cell activation, MiTF is downregulated following the inhibition of the E2A factor and the upregulation of miR-148, leading to an increase in IRF4, which is essential for B cell terminal differentiation in antibody-secreting plasma cells. The decreased number of B cells and B cell precursors observed in mi/mi mice can be attributed to both direct and indirect effects of MiTF deficiency in these cells. The lack of MiTF in immature B cells causes an increase in IRF4 expression, leading to diminished proliferative capacity and spontaneous plasma cell differentiation in the absence of external stimuli. Moreover, mi/mi mice are characterized by an osteopetrotic microenvironment, which indirectly leads to the depletion of B cell precursors. In particular, osteoblasts and stromal cells secrete abnormal levels of RANKL to counteract osteoclast dysfunction, thereby activating RANK-expressing cells, which in turn secrete higher levels of IFN-β, which is known to induce cytotoxicity in B cell precursors