B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis.

Myasthenia gravis (MG), primarily caused by acetylcholine receptor (AChR) autoantibodies, is a chronic autoimmune disorder causing severe muscle weakness and fatigability. In particular, seronegative MG constitutes 10%-15% of MG cases and presents diagnostic challenges especially in early-onset female patients who often show severe disease and resistance to immunosuppressive therapy. Furthermore, the immunopathology of seronegative MG remains unclear. Thus, in this study, we aimed to elucidate the pathogenic mechanism of seronegative MG using scRNA-seq analysis and plasma proteome analysis; in particular, we investigated the relationship between immune dysregulation status and disease severity in refractory seronegative MG. Employing single-cell RNA-sequencing and plasma proteome analyses, we analyzed peripheral blood samples from 30 women divided into three groups: 10 healthy controls, 10 early-onset AChR-positive MG, and 10 refractory early-onset seronegative MG patients, both before and after intravenous immunoglobulin treatment. The disease severity was evaluated using the MG-Activities of Daily Living (ADL), MG composite (MGC), and revised 15-item MG-Quality of Life (QOL) scales. We observed numerical abnormalities in multiple immune cells, particularly B cells, in patients with refractory seronegative MG, correlating with disease activity. Notably, severe MG cases had fewer regulatory T cells without functional abnormalities. Memory B cells were found to be enriched in peripheral blood cells compared with naïve B cells. Moreover, plasma proteome analysis indicated significantly lower plasma protein levels of soluble CD22, expressed in the lineage of B-cell maturation (including mature B cells and memory B cells), in refractory seronegative MG patients than in healthy donors or patients with AChR-positive MG. Soluble CD22 levels were correlated with disease severity, B-cell frequency, and RNA expression levels of CD22. In summary, this study elucidates the immunopathology of refractory seronegative MG, highlighting immune disorders centered on B cells and diminished soluble CD22 levels. These insights pave the way for novel MG treatment strategies focused on B-cell biology.

Endoscopic-assisted Surgical Removal of Infected Interosseous Wires 40 Years After Mandibular Surgery.

We demonstrate a highly reliable minimally invasive treatment for removal of residual wire from the mandible. The patient was a 55-year-old Japanese man who was referred to our department for a fistula in his submental area. The patient had undergone open reduction and fixation with wires for mandibular fractures (left parasymphysis, right angle fracture) more than 40 years prior and mandibular tooth extraction and drainage 6 months prior. Minimally invasive endoscopy-assisted wire removal surgery was performed under general anesthesia with good visualization in a narrow surgical field. Bone resection was minimized using an ultrasonic cutting instrument with a wide choice of tip shapes. The use of endoscopy with ultrasonic cutting tools makes it possible to effectively utilize narrow surgical fields with a small skin incision and minimal bone cutting. The advantages and disadvantages of the newer endoscopic systems in oral and maxillofacial surgical units are discussed.

Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis.

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)-mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.

Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50=0.10µM, cell-based mammalian two-hybrid [M2H] assay IC50=0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies.

Effects of TAK-802, a novel acetylcholinesterase inhibitor, and tamsulosin, an alpha1-adrenoceptor antagonist, and their synergistic effects on the urodynamic characteristics in a guinea-pig model of functional bladder outlet obstruction.

OBJECTIVE: To investigate the effects of TAK-802, a potent acetylcholinesterase inhibitor, and tamsulosin, an alpha1-adrenoceptor antagonist, and their concomitant administration on the urodynamic characteristics in a guinea-pig model of functional bladder outlet obstruction. MATERIALS AND METHODS: Cystometry was performed in urethane-anaesthetized guinea pigs, and various urodynamic variables, including the maximum flow rate (Qmax), voiding efficiency, maximum intravesical pressure (Pvesmax) and intravesical pressure at Qmax (PvesQmax), were measured before and after administration of the drugs in combination and alone. RESULTS: Continuous intravenous infusion of phenylephrine, an alpha1-adrenoceptor agonist (1-6 microg/animal/min), dose-dependently decreased the Qmax and voiding efficiency, and increased the Pvesmax and PvesQmax, possibly by constricting urethral smooth muscle. In this functional urethral constriction model, both TAK-802 at 1 and 10 microg/kg and tamsulosin at 3 and 10 microg/kg (intravenously) caused increasing effects on the Qmax and voiding efficiency. The effects were more apparent with combined exposure. Although the Pvesmax was dose-dependently increased by TAK-802 alone, the effects were completely abolished by concomitant treatment with tamsulosin. CONCLUSION: These results suggest that TAK-802 and tamsulosin have synergistic effects in increasing the Qmax and voiding efficiency, and TAK-802 does not inhibit the decreasing effect of tamsulosin on urethral resistance. That TAK-802 increased Pves when administered alone implies that monotherapy using an acetylcholinesterase inhibitor should be withheld in patients with voiding dysfunction caused by obvious bladder outlet obstruction with benign prostatic hyperplasia, to avoid disorders of the upper urinary tracts, and it should be used with an alpha1-adrenoceptor antagonist. Whether TAK-802 combined with an alpha1-adrenoceptor antagonist confers additional clinical benefit is not yet known.