Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL-Faslpr Mice

SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4-CD8- T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases

Vaginal Lymphoma with Immune Thrombocytopenic Purpura: An Unusual Case Report

The female genital tract is rarely the initial site of presentation in lymphoma or leukemia. We report a case of non-Hodgkin's lymphoma (NHL) presenting initially in the vagina. The patient, a 75-year-old woman, had a history of immune thrombocytopenic purpura (ITP). She presented with a chief complaint of genital bleeding and introital pain. On transvaginal ultrasonography, a vaginal tumor with an irregular wall was detected, and the internal echo showed a hypoechoic and echogenic pattern. Ultrasonography and magnetic resonance imaging (MRI) suggested that the vaginal tumor was likely to be a hematoma or a hemorrhagic tumor arising from ITP. Incision and resection for a hematoma or a hemorrhagic tumor were carried out in response to genital bleeding, introital pain, and pathological diagnosis. Postoperative microscopic examination confirmed that the tumor was a vaginal NHL. The final diagnosis using the Ann Arbor staging system was high-stage (stage IV) NHL. The patient received chemotherapy, and she remains in remission for 42 months after treatment

Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores

Aim: Composite population of myofibroblasts (MFs) within myocardial tissue is known to alter impulse propagation, leading to arrhythmias. However, it remains unclear whether and how MFs alter their propagation patterns when contacting cardiomyocytes (CMs) without complex structural insertions in the myocardium. We attempted to unveil the effects of the one-sided, heterocellular CM-MF connection on the impulse propagation of CM monolayers without the spatial insertion of MFs as an electrical or mechanical obstacle.Methods and results: We evaluated fluo8-based spatiotemporal patterns in impulse propagation of neonatal rat CM monolayers cultured on the microporous membrane having 8-μm diameter pores with co-culture of MFs or CMs on the reverse membrane side (CM-MF model or CM-CM model, respectively). During consecutive pacing at 1 or 2 Hz, the CM monolayers exhibited forward impulse propagation from the pacing site with a slower conduction velocity (θ) and a larger coefficient of directional θ variation in the CM-MF model than that in the CM-CM model in a frequency-dependent manner (2 Hz >1 Hz). The localized placement of an MF cluster on the reverse side resulted in an abrupt segmental depression of the impulse propagation of the upper CM layer, causing a spatiotemporally non-uniform pattern. Dye transfer of the calcein loaded in the upper CM layer to the lower MF layer was attenuated by the gap-junction inhibitor heptanol. Immunocytochemistry identified definitive connexin 43 (Cx43) between the CMs and MFs in the membrane pores. MF-selective Cx43 knockdown in the MF layer improved both the velocity and uniformity of propagation in the CM monolayer.Conclusion: Heterocellular Cx43 gap junction coupling of CMs with MFs alters the spatiotemporal patterns of myocardial impulse propagation, even in the absence of spatially interjacent and mechanosensitive modulations by MFs. Moreover, MFs can promote pro-arrhythmogenic impulse propagation when in face-to-face contact with the myocardium that arises in the healing infarct border zone

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice.

BACKGROUND:Neuroinflammation plays an important role in neonatal hypoxic-ischemic encephalopathy (HIE). Although microglia are largely responsible for injury-induced inflammatory response, they play beneficial roles in both normal and disease states. However, the effects of microglial depletion on neonatal HIE remain unclear.METHODS:Tamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ (microglia-depleted model) and Cx3cr1CreER/+Rosa26DTA/- (control) mice at P8 and P9 to assess the effect of microglial depletion. The density of microglia was quantified using Iba-1 staining. Moreover, the proportion of resident microglia after the HI insult was analyzed using flow cytometric analysis. At P10, the HI insult was conducted using the Rice-Vannucci procedure at P10. The infarct size and apoptotic cells were analyzed at P13. Cytokine analyses were performed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at P13.RESULTS:At P10, tamoxifen administration induced > 99% microglial depletion in DTA+ mice. Following HI insult, there was persisted microglial depletion over 97% at P13. Compared to male DTA- mice, male DTA+ mice exhibited significantly larger infarct volumes; however, there were no significant differences among females. Moreover, compared to male DTA- mice, male DTA+ mice had a significantly higher density of TUNEL+ cells in the caudoputamen, cerebral cortex, and thalamus. Moreover, compared to female DTA- mice, female DTA+ mice showed a significantly greater number of TUNEL+ cells in the hippocampus and thalamus. Compared to DTA- mice, ELISA revealed significantly lower IL-10 and TGF-β levels in both male and female DTA+ mice under both normal conditions and after HI (more pronounced).CONCLUSION:We established a microglial depletion model that aggravated neuronal damage and apoptosis after the HI insult, which was predominantly observed in males

Citizen science "Thundercloud Project" -- multi-point radiation measurements of gamma-ray glows from accelerated electrons in thunderstorms

38th International Cosmic Ray Conference (ICRC2023), 26 July - 3 August, 2023, Nagoya, JapanIt has been a long-standing question whether cosmic rays promote the triggering of lightning and how cosmic-ray air showers interact with the electric field of thunderclouds. The strong electric field in the thunderclouds accelerates electrons to the relativistic regime, of which seed electrons are thought to be supplied from cosmic-ray air shower. Such relativistic electrons emit bremsstrahlung photons in gamma rays, which have been detected by on-ground measurements called gamma-ray glows. Low-altitude winter thunderstorm in Japan provides an ideal environment for observations of gamma-ray glows. We newly launched the citizen science ``Thundercloud Project" to construct a multi-point radiation mapping campaign for glows from winter thunderstorms around Kanazawa, Japan. We developed a new handy radiation monitor and shipped about 60 detectors to citizen supporters. The radiation data are stored in the microSD cards in the detectors, and a part of them is remotely sent to the web server so that researchers and supporters can watch the real-time data. In addition, an automatic alert is sent to public Twitter from the server when a glow is detected. The purpose of this project is (1) to characterize the methodological condition of electron acceleration, (2) to investigate whether accelerated relativistic electrons can enhance the chance of the initiation of lightning discharges, and (3) to find a new way of the citizen science to join in the cutting edge science in the physics field. Here we report this growing citizen science project and examples of successful gamma-ray glow observations. Our first scientific result from this citizen science project was published in Tsurumi et al., GRL 2023, where we reported lightning discharges started in or near the electron acceleration site of a gamma-ray glow

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases

妊娠を契機に血小板減少を来たし，子宮内胎児死亡に至った全身性エリテマトーデス及び抗リン脂質抗体症候群の一例

　抗リン脂質抗体症候群は，抗リン脂質抗体が産生されることで血栓症を主体とする病態を引き起こす自己免疫疾患である．動静脈血栓症に加え，習慣性流産，早産，妊娠高血圧症候群，胎児発育遅延，胎児機能不全などの妊娠合併症を高率に引き起こすとされている．また患者のうち約半数は全身性エリテマトーデスが併存していると言われている．我々は妊娠を契機に血小板減少を来たし，子宮内胎児死亡に至った全身性エリテマトーデス及び抗リン脂質抗体症候群の症例を経験した．　患者は20歳代女性，未経妊未経産．５年前に全身性エリテマトーデス及び抗リン脂質抗体症候群と診断された．プレドニゾロンとタクロリムス，アザチオプリンによる免疫抑制療法及び低用量アスピリン療法を開始され，数年間に渡りプレドニゾロン５mg/ 日＋タクロリムス３mg/ 日＋アザチオプリン50mg/ 日で病態は安定していた．妊娠を契機にプレドニゾロン10mg/ 日の単独治療に切り替えたが，徐々に血小板減少が進行してきたため入院し，プレドニゾロン30mg/ 日への増量及びタクロリムス３mg/ 日を再開した．また血栓予防治療として，低用量アスピリンに加えヘパリン療法を開始した．しかし妊娠16週５日で子宮内胎児死亡が判明したため，血栓予防治療を中止し児の娩出に至った．　抗リン脂質抗体症候群合併妊娠は，周産期管理に慎重を要する例も存在することを念頭に置き，特にハイリスク症例に対しては妊娠成立前から産婦人科と連携して治療にあたる必要がある．　Antiphospholipid syndrome is an autoimmune disease characterized by episodes of recurrent thrombosis. This syndrome is associated with not only recurrent arteriovenous thrombosis but also recurrent pregnancy loss, premature birth, pregnancyinduced hypertension, and fetal growth restriction. It has been reported that systemic lupus erythematosus coexists with antiphospholipid syndrome in as many as about 50% of patients. We report a case of intrauterine fetal death (IUFD) following thrombocytopenia in a patient with systemic lupus erythematosus and antiphospholipid syndrome. A woman in her 20s had difficulty conceiving and had been diagnosed as having systemic lupus erythematosus and antiphospholipid syndrome 5 years earlier. She was started on immunosuppressive therapy with prednisolone 5 mg/day, tacrolimus 3 mg/day, and azathioprine 50 mg/day, with low-dose aspirin therapy. Her disease was stable for several years. Thrombopenia gradually developed after treatment was changed to prednisolone 10 mg/day during pregnancy. She was admitted to hospital and treatment was started with prednisolone 30 mg/day, tacrolimus 3 mg/day, and heparin therapy in addition to low-dose aspirin therapy. However, IUFD was detected at a gestational age of 16 weeks 5 days, so we discontinued thromboprophylaxis treatment and administered a therapeutic abortion. In patients with antiphospholipid syndrome who need meticulous perinatal management, it is important to consult with the obstetrics and gynecology specialists before proceeding with a potentially high-risk pregnancy