To establish an immunocompetent TCR repertoire that is useful yet harmless to the body, a de novo thymocyte repertoire generated through the rearrangement of genes that encode TCR is shaped in the ...thymus through positive and negative selection. The affinity between TCRs and self-peptides associated with MHC molecules determines the fate of developing thymocytes. Low-affinity TCR engagement with self-peptide-MHC complexes mediates positive selection, a process that primarily occurs in the thymic cortex. Massive efforts exerted by many laboratories have led to the characterization of peptides that can induce positive selection. Moreover, it is now evident that protein degradation machineries unique to cortical thymic epithelial cells play a crucial role in the production of MHC-associated self-peptides for inducing positive selection. This review summarizes current knowledge on positive selection-inducing self-peptides and Ag processing machineries in cortical thymic epithelial cells. Recent studies on the role of positive selection in the functional tuning of T cells are also discussed.
A repertoire of antigen recognition specificities in mature T cell pool is formed by the selection during T cell development in the thymus. Positive selection is an essential process for the ...development of functionally competent T cells and is dependent on the interaction between T cell antigen receptors (TCRs) that newly generated thymocytes express and self-peptide-associated major histocompatibility complex (pMHC) molecules that cortical thymic epithelial cells (cTECs) express. Characterization of positive-selection-inducing peptides has revealed that the low-affinity TCR engagement by the positive-selection-inducing pMHC complexes initiates intracellular signals that induce the survival of immature thymocytes and their differentiation into mature T cells. Recent studies suggest unique mechanisms of antigen processing in cTECs for the production of positively selecting MHC-bound self-peptides.
To solve a navigation task based on experiences, we need a mechanism to associate places with objects and recall them along the course of action. In a reward-oriented task, if the route to a reward ...location is simulated in mind after experiencing it once, it might be possible that the reward is gained efficiently. One way to solve this is to incorporate a biologically plausible mechanism. In this study, we propose a neural network that stores a sequence of events associated with a reward. The proposed network recalls the reward location by tracing them in its mind in order. We simulated a virtual mouse that explores a figure-eight maze and recalls the route to the reward location. During the learning period, a sequence of events related to firing along a passage was temporarily stored in the heteroassociative network, and the sequence of events is consolidated in the synaptic weight matrix when a reward is fed. For retrieval, an impetus input internally generates the sequential activation of conjunctive cue-place cells toward the reward location. In the figure-eight maze task, the location of the reward was estimated by mind travel, irrespective of whether the reward is in the counterclockwise or distant clockwise route. The mechanism of efficiently reaching the goal by mind travel in the brain based on experiences is beneficial for mobile service robots that perform autonomous navigation.
Interleukin (IL)-17-producing γδT (γδT17) cells mediate inflammatory responses in barrier tissues. Dysregulated γδT17 cell activation can lead to the overproduction of IL-17 and IL-22 and the ...development of inflammatory diseases, including psoriasis. IL-23 and IL-1β are known to synergistically activate γδT17 cells, but the regulatory mechanisms of γδT17 cells have not been fully elucidated. This study aimed to reveal the contribution of the inflammatory cytokine tumor necrosis factor-like ligand 1A (TL1A) to γδT17 cell activation and psoriasis development.
Anti-TL1A antibody was injected into an imiquimod (IMQ)-induced murine psoriasis model. TL1A receptor expression was analyzed in splenic and dermal γδT cells. γδT cells were tested for cytokine production
and
under stimulation with IL-23, IL-1β, and TL1A. TL1A was applied to a psoriasis model induced by intradermal IL-23 injection. Mice deficient in γδT cells were intradermally injected with IL-23 plus TL1A to verify the contribution of TL1A-dependent γδT-cell activation to psoriasis development.
Neutralization of TL1A attenuated γδT17 cell activation in IMQ-treated skin. TL1A induced cytokine production by splenic γδT17 cells in synergy with IL-23. Dermal γδT17 cells constitutively expressed a TL1A receptor at high levels and vigorously produced IL-22 upon intradermal IL-23 and TL1A injection but not IL-23 alone. TL1A exacerbated the dermal symptoms induced by IL-23 injection in wild-type but not in γδT cell-deficient mice.
These findings suggest a novel regulatory mechanism of γδT cells through TL1A and its involvement in psoriasis pathogenesis as a possible therapeutic target.
Objective: Injury to the inferior epigastric artery (IEA) caused by femoral puncture may lead to retroperitoneal hematoma. We report on two cases of IEA injury due to femoral venipuncture for ...neuroendovascular intervention that resulted in hemorrhagic shock and required transcatheter arterial embolization.Case Presentations: A 67-year-old woman and a 71-year-old man receiving dual antiplatelet therapy sustained injury to a branch of the IEA in the process of right femoral venipuncture for neuroendovascular intervention. In both cases, stent placement in the intracranial artery was accomplished as intended with systemic heparinization throughout the procedure; however, the patients became hypotensive during the procedure, and contrast-enhanced CT scans taken after the stenting revealed extravasation of contrast from the IEA and retroperitoneal hematoma. Transcatheter arterial embolization of the bleeding branch of the IEA was performed with the left femoral approach, and subsequent angiography confirmed the disappearance of the extravasation of contrast.Conclusion: Femoral venipuncture for neuroendovascular intervention in patients receiving antithrombotic agents may cause IEA injury requiring transcatheter arterial embolization. The risk of IEA injury may be reduced by using the femoral head as a reference, performing ultrasound-guided puncture, and confirming the course of the IEA by femoral angiography before venipuncture.
Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and cellular infiltration. Studies have shown that disease development depends on proinflammatory cytokines, ...such as interleukin (IL)-23 and IL-17. It has been suggested that IL-23 produced by innate immune cells, such as macrophages, stimulates a subset of helper T cells to release IL-17, promoting neutrophil recruitment and keratinocyte proliferation. However, recent studies have revealed the crucial role of γδT cells in psoriasis pathogenesis as the primary source of dermal IL-17. The nuclear receptors REV-ERBs are ligand-dependent transcription factors recognized as circadian rhythm regulators. REV-ERBs negatively regulate IL-17-producing helper T cells, whereas the involvement of REV-ERBs in regulating IL-17-producing γδT (γδT17) cells remains unclear. Here we revealed the regulatory mechanism involving γδT17 cells through REV-ERBs. γδT17 cell levels were remarkably elevated in the secondary lymphoid organs of mice that lacked an isoform of REV-ERBs. A synthetic REV-ERB agonist, SR9009, suppressed γδT17 cells in vitro and in vivo. Topical application of SR9009 to the skin reduced the inflammatory symptoms of psoriasiform dermatitis in mice. The results of this study provide a novel therapeutic approach for psoriasis targeting REV-ERBs in γδT17 cells.
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•IL-17 production by γδT cells is under the control of REV-ERBs.•Synthetic REV-ERB agonist SR9009 suppresses IL-17 production by γδT cells.•Topical application of SR9009 to the skin ameliorates psoriatic dermatitis in mice.•Targeting REV-ERBs in γδT cells can be a novel therapeutic approach for psoriasis.
Metronidazole induced encephalopathy (MIE), an encephalopathy brought by an antibiotic, is characterized with cerebellar dysfunction, altered mental status and extrapyramidal symptoms. MIE can result ...in an acute manifestation, but MIE has not been reported as a stroke mimic. An 86-year-old patient undergoing metronidazole therapy for Clostridium difficile enteritis presented to our hospital with sudden disoriented status and motor weakness of the left extremities. Computed tomography (CT) was unrevealing of intracranial hemorrhagic change, and CT angiography did not show any apparent major occlusion or stenosis of the intracranial vessels. However, CT perfusion (CTP) revealed a decrease in peripheral blood flow in the right cerebral hemisphere, and tissue plasminogen activator was administrated for a possible acute ischemic stroke. The findings of follow-up magnetic resonance imaging (MRI) were typical for MIE, revealing areas of hyperintensity on fluid attenuated inversion recovery (FLAIR) signal intensity in the dentate nuclei, the splenium of the corpus callosum, and in the dorsal midbrain. The degree of hyperintensity was stronger in the left dentate nucleus than in the right left dentate on FLAIR and the apparent diffusion coefficient map. The asymmetric findings of the left dentate nucleus on MRI were considered to be responsible for the clinical symptoms and the findings of CTP. We report a rare case of MIE mimicking an acute ischemic stroke, and hypothesize the relationship between the findings of CTP and that of MRI based on the anatomical connection of the dentate nucleus and the cerebral hemisphere.
Bleomycin (BLM) has been reported to induce lung inflammation and fibrosis in human and mice and showed genetic susceptibility. Interestingly, the C57BL/6 (B6) mice had prominent mediastinal ...fat-associated lymphoid cluster (MFALCs) under healthy condition, and showed susceptibility to development of lung fibrosis following BLM administration. However, the pathogenesis of lung lesion progression, and their correlation with MFALC morphologies, remain to be clarified. To investigate the correlations between MFALC structures and lung injuries in B6 mice, histopathological examination of mediastinal fat tissues and lungs was examined at 7 and 21 days (d) following a single 50 μL intranasal (i.n.) instillation of either BLM sulfate (5 mg/kg) (BLM group) or phosphate-buffered saline (control group). The lung fibrosis was examined by Masson's trichrome (MT) stain of paraffin sections and mRNA expression levels of Col1a1, Col3a1, and Acta2 in different frozen lung samples. Furthermore, immunohistochemistry for CD3, B220, Iba1, Gr1, BrdU, LYVE-1, and peripheral node addressin (PNAd) was performed to detect T- and B-cells, macrophages, granulocytes, proliferating cells, lymph vessels (LVs), and high endothelial venules (HEVs). We found that MFALCs were more abundant in the BLM group as compared to the control group. The lung of BLM group developed pneumonitis with severe cellular infiltrations at 7 days and significant collagen deposition (MT) and higher expression of Col1a1, and Col3a1 at 21 days post-administration. Numerous immune cells, proliferating cells, HEVs, and LVs were observed in both MFALCs and lungs of the BLM group. Interestingly, PNAd + HEVs were observed in the lungs of the BLM group, but not the control group. Moreover, numerous Gr1 + polymorphonuclear and mononuclear-like ring cells were found in the MFALCs and lungs of the BLM group. Interestingly, flow cytometric analysis revealed a significant increase of B-cell populations within the MFALCs of BLM group suggesting a potential proliferative induction of B-cells following inflammation. Furthermore, significant positive correlations were observed between quantitative parameters of these immune cells in both the lungs and MFALCs. Thus, we suggest a potentially important role for MFALCs and HEVs in the progression of lung disease, especially in inflammatory lung disease.
Objectives
Thrombi in cerebral large vessel occlusion associated with active cancer are often fibrin and platelet-rich white thrombi. However, evaluating the thrombus composition in a short time ...before thrombectomy is often ineffective. We sought to determine factors related to white thrombi in acute ischemic stroke due to large vessel occlusion in cancer patients.
Methods
Consecutive cancer patients undergoing thrombectomy for acute ischemic stroke due to large vessel occlusion between January 2018 and May 2022 were retrospectively reviewed. The patients were classified into white thrombus and red thrombus groups on the basis of the pathological findings of retrieved thrombi. Patient characteristics and laboratory findings were compared between the two groups.
Results
There were 12 patients in the white thrombus group and 11 patients in the red thrombus group. Active cancer was significantly more in the white thrombus group than in the red thrombus group (91.7% vs. 36.3%, p = 0.0094). Internal carotid artery occlusion was significantly less in the white thrombus group than in the red thrombus group (0% vs. 36.4%, p = 0.037). Among laboratory findings, D-dimer levels were an independent factor associated with white thrombi (odds ratio 8.97 95% confidence interval 1.71–368.99, p < 0.0001). The cutoff value of D-dimer levels for predicting white thrombi was 3.5 μg/mL (83.3% sensitivity and 100% specificity).
Conclusions
In acute ischemic stroke in cancer patients, active cancer, no internal carotid artery occlusion, and higher D-dimer levels (≥3.5 μg/mL) may be associated with occlusion with fibrin and platelet-rich white thrombi.
The reproductive strategies of vertebrates are diverse. Seahorses (Pisces: Syngnathidae) possess the unique characteristic of male pregnancy; i.e., males, not females, incubate embryos in a ...specialized structure called a 'brood pouch'. The brood pouch is formed along the ventral midline of the tail. The lumen of the brood pouch is surrounded by loose connective tissue, called pseudoplacenta, and dermis.
We visualized and evaluated the morphology of brood pouch formation in
to gain generalizable insights into this process in seahorses. First, we employed several staining methods to characterize the pseudoplacenta and dermis of the brood pouch of mature male seahorses. The pseudoplacenta is composed mainly of reticular fibers, while the dermis is composed mainly of collagenous fibers. Further observations showed that pouch formation is initiated by linear projections of epithelia on both ventrolateral sides of the body. These projections elongated toward the ventral midline, eventually fused together, and then formed a baggy structure composed of a single dermis layer with neither smooth muscle nor pseudoplacenta. Finally, the pseudoplacenta was formed, together with two layers of dermis and smooth muscle. Thus, a fully developed brood pouch was established. The morphology of the luminal epithelium also changed during pouch formation. We analyzed the localization of C-type lectins as markers; haCTL II was localized in both the outer and luminal epithelia of the brood pouch throughout development in the male seahorse, whereas haCTL IV, which was not detected in the early stage of seahorse development, became localized only in the luminal epithelium as development proceeded.
We categorized the processes of brood pouch formation during male seahorse development into three stages: (1) the early stage, characterized by formation of a baggy structure from the primordium; (2) the middle stage, characterized by the differentiation and establishment of brood pouch-specific tissues; and (3) the late stage, characterized by a fully formed pouch with developing blood vessels and a pouch fold ultimately capable of carrying and incubating embryos.
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