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摘要： T cell priming is characterized by an initial activation phase that involves stable interactions with dendritic cells (DCs). How activated T cells receive the paracrine signals required for their differentiation once they have disengaged from DCs and resumed their migration has been unclear. We identified a distinct priming phase that favors CD8 T cells expressing receptors with high affinity for antigen. CXCR3 expression by CD8 T cells was required for their hours-long reengagement with DCs in specific subfollicular niches in lymph nodes. CD4 T cells paused briefly at the sites of CD8 T cell and DC interactions and provided Interleukin-2 (IL-2) before moving to another DC. Our results highlight a previously unappreciated phase of cell-cell interactions during T cell priming and have direct implications for vaccinations and cellular immunotherapies.

关键词： Th2 cytokines   Pulpitis   Biomarkers   Pulpal blood   Diagnostic efficacy   Inflammation markers  

摘要： ObjectiveTo evaluate the diagnostic utility of T-helper type 2 (Th2) cytokines, specifically Interleukin-4 (IL-4), IL-5, IL-10, and IL-13, in distinguishing different stages of pulpitis and their combined performance in clinical *** total of 161 participants were enrolled and categorized into normal pulp (NP, n = 45), reversible pulpitis (RP, n = 75), and symptomatic irreversible pulpitis (IP, n = 41). Th2 cytokine levels in pulpal blood samples were measured using enzyme-linked immunosorbent assays (ELISA).ResultsTh2 cytokine levels (IL-4, IL-5, IL-10, and IL-13) were significantly elevated in pulpitis cases compared to normal pulp, with the highest concentrations observed in symptomatic IP. Diagnostic analysis showed that IL-4 and IL-13 had the highest diagnostic accuracy for distinguishing pulpitis (both RP and IP) from normal pulp, with AUCs of 0.91, and perfect specificity (100%). IL-5 demonstrated the best balance between sensitivity (68%) and specificity (97%) for differentiating IP from NP (AUC = 0.84). IL-13, though less effective overall, provided moderate accuracy (AUC = 0.63) for distinguishing RP from NP. Additionally, the combined diagnostic model of all four cytokines achieved high AUCs, particularly in distinguishing irreversible pulpitis from normal pulp (AUC = 0.94) and irreversible pulpitis from reversible pulpitis (AUC = 0.90).ConclusionsTh2 cytokines, especially IL-4, IL-5, and IL-13, are effective biomarkers for identifying different stages of pulpitis. Their elevated levels, particularly in irreversible pulpitis, provide strong diagnostic accuracy. Combined cytokine analysis enhances diagnostic precision, making Th2 cytokine profiling a valuable tool for assessing pulpitis severity.

关键词： Helicobacter pylori   chronic gastritis   prevalence   gastrointestinal pathologies   histopathology  

摘要： Background/Objectives: Helicobacter pylori (H. pylori) is a significant global health issue causing chronic gastritis, peptic ulcers, and gastric malignancies. Unfortunately, many, particularly in the Middle East, continue to exhibit alarming rates of prevalence. This study aimed to elucidate local epidemiological patterns of H. pylori and examine its histopathological impact on the gastric mucosa. Methods: This retrospective-cross-sectional study included 805 symptomatic adults (329 males, 476 females) who underwent endoscopic evaluation at King Salman Hospital, Ha'il, Saudi Arabia. Biopsies from the antrum and body were processed using routine formalin fixation and paraffin embedding. Staining with hematoxylin-eosin (H&E) and Giemsa permitted assessment of chronic gastritis and detection of H. pylori. Data were evaluated by IBM SPSS (version 23, IBM Corp., Armonk, NY) for associations among infection, histopathology, and patient characteristics. Results: A total of 727 (90.3%) were H. pylori-positive with marginally higher rates in females (91.2%) than males (89.0%). Infection spanned all age groups, reaching 100% in males aged 60-80 years. Overall chronic GI complications were identified in 726 (99.9%), with chronic gastritis being the most profound histopathologically (19.3%). Lymphoid aggregates in 93.0% biopsies reflected a pronounced immune response. Advanced lesions, including metaplasia (0.8%), atrophy (0.3%), and lymphoma (0.1%), were uncommon, though indicative of potential malignant progression. Despite both sexes exhibiting universal symptoms of gastritis, dyspepsia, and heartburn, there were no statistically significant gender-based differences (p > 0.05);specifically, post-H. pylori signs such as vomiting, nausea, weight loss, bleeding or hematemesis occurred equally in all. Histopathology consistently revealed chronic active gastritis with glandular distortion, lymphoplasmacytic infiltration, and occasional mucosal erosions. Giemsa staining further c

摘要： Acquired aplastic anemia (AA) is an immune-mediated bone marrow failure caused by autoreactive cytotoxic T lymphocytes targeting hematopoietic stem progenitor cells (HSPCs). Approximately 30% of AA patients exhibit leukocytes lacking HLA class I alleles (HLA[-]). In addition to this direct immune assault, the pathogenesis of AA is thought to involve indirect suppression mediated by the proinflammatory cytokine interferon-gamma (IFN-gamma). Using HSPCs derived from induced pluripotent stem cells (iPSCs) with different HLA genotypes, HLA(-) HSPCs were found to be resistant to the suppressive effects of IFN-gamma, whereas IFN-gamma effectively suppressed the growth and development of HSPCs expressing HLA class I molecules. Further analysis showed that, in contrast to HLA(-) HSPCs, WT HSPCs showed enhanced CD119 expression in response to IFN-gamma, activating downstream signaling pathways that promote apoptosis, suggesting that transcription factors involved in the apoptotic pathway following IFN-gamma stimulation are differentially expressed between WT and HLA(-) HSPCs. Notably, IFN-gamma stimulation reduced the expression of pSTAT3, a key regulator of apoptosis, in WT HSPCs, whereas its expression was elevated in HLA(-) HSPCs. In conclusion, this study showed that the selective hematopoietic inhibition of HSPCs by IFN-gamma likely facilitates clonal hematopoiesis and contributes to the persistence of HLA(-) HSPCs in patients with AA.

摘要： The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFN gamma secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8+ T cells. Inhibiting lipid uptake by activated B cells impaired CD8+ T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.

摘要： Resistance to DNA damage is one of the primary mechanisms by which tumor cells evade the effects of standard chemotherapeutic agents and radiotherapy. Dynamic and complex interactions between the tumor microenvironment (TME) and tumor cells critically influence the DNA damage response. Interleukin-33 (IL-33) is a multifunctional cytokine secreted at high levels in response to cellular damage and stress. Recently, increasing evidence has suggested that IL-33 plays a key role in promoting the therapeutic resistance of tumors. However, the actual source of IL-33 during cancer therapy and how IL-33 contributes to a resistant TME remain incompletely understood. In this study, we found that both cancer-associated fibroblasts (CAFs) and tumor cells treated with DNA damage-inducing agents expressed and secreted high levels of IL-33, subsequently leading to enhanced DNA damage repair efficacy. Mechanistically, nuclear IL-33 primarily functions as a transcriptional co-activator of homologous recombination repair (HRR) genes, whereas the active form of IL-33 can drive the non-homologous end joining (NHEJ) pathway via the canonical IL-33/ST2 axis. Overall, we demonstrated that IL-33 plays a key role in mediating a DNA damage-resistant TME, which could represent a potential therapeutic vulnerability in chemoresistant cancer cells.

关键词： Cellular crosstalk   Chronic kidney diseases   Local interstitial acidosis   Local inflammation   IL-6 effects   p38-signaling  

摘要： Background Local interstitial acidosis in chronic kidney disease (CKD) induces inflammatory responses and dedifferentiation of proximal tubule cells (PTCs), disrupting cellular crosstalk through cytokine and COX-2 metabolite secretion. This promotes a switch to an inflammatory fibroblast phenotype, further exacerbating inflammation and PTC dedifferentiation. p38-signaling and downstream transcription factors, including P-CREB and c-fos, contribute to these responses. This study investigates the impact of acidosis on inflammatory responses in PTCs and fibroblasts, focusing on cellular crosstalk and the role of p38-signaling. Methods HK-2 (human PTCs) and CCD-1092Sk (human fibroblasts) were exposed to acidic or control media in mono- and coculture for 30 min, 3 h, or 48 h. Protein expression of IL-6, phosphorylated (P-) and total CREB, P- and total SRF, c-fos, and P- and total p38 was analyzed by western blot. IL-6 secretion was measured using ELISA. The impact of p38 and IL-6 receptor activity was assessed by pharmacological intervention. Results In coculture, acidosis initially caused a transient decrease in IL-6 secretion but significantly increased IL-6 levels after 48 h. Acidosis induced intracellular IL-6 expression in HK-2 cells within 3 h independent of culture conditions, with sustained IL-6 protein increase after 48 h only in coculture. Acidosis also enhanced P-CREB and c-fos expression in coculture during the first 3 h. Regardless of culture conditions, acidosis increased IL-6, c-fos, and P-SRF expression in CCDSK cells after 48 h. P-CREB and COX-2 expression were elevated in CCDSK in coculture. Acidosis-mediated effects on IL-6, P-CREB, and P-SRF expression were p38-dependent in both cell lines. Finally, we assessed the pH-dependency of IL-6 action and found that IL-6 addition increased COX-2 expression via the IL-6 receptor in acidic but not control media. Thus, acidosis enhances IL-6 secretion and potentiates its receptor-mediated biological effects. Con

摘要： We report the initial case of EBV-positive classic Hodgkin lymphoma (cHL) after guselkumab therapy for psoriasis. High-plex spatial proteomic analysis showed a Th2-polarized immunosuppressive tumor microenvironment, indicating immune reprogramming from IL-23 inhibition might have triggered the onset of EBV-positive cHL.