Maturation of Marginal Zone and Follicular B Cells Requires B Cell Activating Factor of the Tumor Necrosis Factor Family and Is Independent of B Cell Maturation Antigen

B cells undergo a complex series of maturation and selection steps in the bone marrow and spleen during differentiation into mature immune effector cells. The tumor necrosis factor (TNF) family member B cell activating factor of the TNF family (BAFF) (BLyS/TALL-1) plays an important role in B cell homeostasis. BAFF and its close homologue a proliferation-inducing ligand (APRIL) have both been shown to interact with at least two receptors, B cell maturation antigen (BCMA) and transmembrane activator and cyclophilin ligand interactor (TACI), however their relative contribution in transducing BAFF signals in vivo remains unclear. To functionally inactivate both BAFF and APRIL, mice transgenic for a soluble form of TACI were generated. They display a developmental block of B cell maturation in the periphery, leading to a severe depletion of marginal zone and follicular B2 B cells, but not of peritoneal B1 B cells. In contrast, mice transgenic for a soluble form of BCMA, which binds APRIL, have no detectable B cell phenotype. This demonstrates a crucial role for BAFF in B cell maturation and strongly suggests that it signals via a BCMA-independent pathway and in an APRIL-dispensable way

Detection and Morphological Analysis of Micro-Ruptured Cortical Arteries in Subdural Hematoma: Three-Dimensional Visualization Using the Tissue-Clearing Clear, Unobstructed, Brain/Body Imaging Cocktails and Computational Analysis Method

One of the causes of bleeding in subdural hematoma is cortical artery rupture, which is difficult to detect at autopsy. Therefore, reports of autopsy cases with this condition are limited and hence, the pathogenesis of subdural hematoma remains unclear. Herein, for the detection and morphological analysis of cortical artery ruptures as the bleeding sources of subdural hematoma, we used the tissue-clearing CUBIC (clear, unobstructed, brain/body imaging cocktails and computational analysis) method with light-sheet fluorescence microscopy and reconstructed the two-dimensional and three-dimensional images. Using the CUBIC method, we could clearly visualize and detect cortical artery ruptures that were missed by conventional methods. Indeed, the CUBIC method enables three-dimensional morphological analysis of cortical arteries including the ruptured area, and the creation of cross-sectional two-dimensional images in any direction, which are similar to histopathological images. This highlights the effectiveness of the CUBIC method for subdural hematoma analysis

A Palindromic CpG-Containing Phosphodiester Oligodeoxynucleotide as a Mucosal Adjuvant Stimulates Plasmacytoid Dendritic Cell-Mediated T_H1 Immunity

<div><p>Background</p><p>CpG oligodeoxynucleotides (ODNs), resembling bacterial DNA, are currently tested in clinical trials as vaccine adjuvants. They have the nuclease-resistant phosphorothioate bond; the immune responses elicited differ according to the CpG ODN sequence and vaccination method. To develop a CpG ODN that can induce plasmacytoid dendritic cell (pDC)-mediated T_H1 immunity through the mucosa, we constructed phosphodiester G9.1 comprising one palindromic CpG motif with unique polyguanosine-runs that allows degradation similar to naturally occurring bacterial DNA.</p><p>Methods</p><p>T_H1 and T_H2 immunity activation was evaluated by cytokine production pattern and <i>T-bet/GATA-3</i> ratio in human peripheral blood mononuclear cells and mouse bone marrow cells. Adjuvanticity was evaluated in mice administered G9.1 with diphtheria toxoid (DT) through nasal vaccination.</p><p>Results</p><p>G9.1 exhibited stronger IFN-α-inducing activity than A-class CpG ODN2216 and increased <i>T-bet/GATA-3</i> ratio by enhancing <i>T-bet</i> expression. Nasally administered G9.1 plus DT induced DT-specific mucosal IgA and serum IgG, but not IgE, responses with antitoxin activity in C57BL/6 and BALB/c mice, possibly due to IFN/BAFF production. Induction of T_H1, but not T_H2, -type Abs depended completely on pDCs, the first <i>in vivo</i> demonstration by CpG ODNs.</p><p>Conclusions</p><p>G9.1 is a promising mucosal adjuvant for induction of pDC-mediated T_H1 immunity.</p></div