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关键词： anti-IL-1 treatment   anakinra   canakinumab   child   neonate   CAPS   pregnancy   paternal-maternal exposure  

摘要： Objectives To determine the effect of paternal and maternal anti-IL-1 treatment exposures on pregnancies and neonatal outcomes in *** A single-centre study consecutive adult CAPS patients and their partners was performed between January 2012 and July 2024. All were screened for pregnancies and anti-IL-1 exposure before conception and/or during pregnancy;teratogenic co-therapies resulted in exclusion. Data included patient characteristics, disease activity, anti-IL-1 treatment, pregnancy complications, neonatal outcomes and child health *** Among 112 patients 11 pregnancies were recorded including eight maternal and three paternal anti-IL-1 exposures. All patients had moderate CAPS, 43% had hearing loss. At conception, all patients received canakinumab. Among the eight maternal exposures, six switched to anakinra, one refused the switch and continued canakinumab, and one had to be switched back to canakinumab due to significant local injection reactions. Pregnancy complications included one miscarriage and one preterm birth, both associated with disease activity. Neonatal outcomes were favorable, with a mean gestational age of 37 + 6 weeks and an average birth weight of 3028 g. No congenital malformations were observed. Neonatal complications included one presumed sepsis (culture negative) requiring IV antibiotics and one mild respiratory syncytial virus infection. CAPS was diagnosed in 5 of 11 offspring, all of whom achieved effective disease control early, with no cases of hearing loss or *** In summary, the benefit risk ratio of maternal and paternal anti-IL-1 exposure during conception and pregnancy in our CAPS patients was favourable. CAPS disease activity may have a significant impact on development of pregnancy complications.

关键词： enterochromaffin cells   IL-18 receptor   intestinal injury   revival stem cells   inflammasomes  

摘要： Upon injury, epithelial-derived IL-18 is released and induces an inflammatory response in underlying IL18R1+ lamina propria cells. Notably, Il18r1 is also predicted to be expressed and functional in intestinal epithelial cells (IECs), since epithelial IL18R1 deficiency contributes to worsened outcomes upon inflammatory challenge. However, the nature of Il18r1+ IECs, and their subsequent role in epithelial-intrinsic IL-18 signaling is poorly characterized. Here, we show that, in the murine small intestine, the IL-18 receptor is expressed by rare IECs that we identified to be a subset of enterochromaffin cells (ECC). While these cells are the major producers of serotonin in the intestine, we found no evidence that IL-18 regulated serotonin metabolism or release. Rather, upon radiation-induced injury, Il18r1+ cells appeared in the crypt base and took on a revival stem cell (revSC) program, marked by mixed expression of YAP/TAZ and enteroendocrine genes signatures. Functionally, irradiated Il18-/- mice display reduced epithelial proliferation and altered differentiation in the small intestine, characterized by increased Paneth cells (PC) and elevated Wnt3 levels, which was partially recapitulated in Il18-/- ileal organoids. In sum, we identified an Il18r1+ population in the epithelium and revealed a role for IEC-intrinsic IL-18 signaling during injury.

关键词： cutaneous leishmaniasis   Leishmania   Staphylococcus aureus   skin infection   microbiota  

摘要： Cutaneous leishmaniasis is a parasitic infection that causes a spectrum of pathology ranging from single, self-healing lesions to disfiguring chronic wounds. In severe disease, uncontrolled inflammation exacerbates tissue damage and delays healing, though the contributing factors are unclear. We previously observed that delayed healing was associated with Staphylococcus aureus in the lesional microbiota of patients with cutaneous leishmaniasis. To investigate how S. aureus impacts immunopathology during leishmania infection, we established a murine model of S. aureus colonization with clinical isolates followed by Leishmania infection. S. aureus triggered early production of interleukin (IL)-1 beta during Leishmania infection, which was critical for neutrophil recruitment and cutaneous inflammation. S. aureus isolates differentially induced IL-1 beta and neutrophil recruitment, and isolates that induced greater neutrophil recruitment were resistant to neutrophil killing and persisted longer. We reveal a mechanism whereby S. aureus mediates immunopathology during cutaneous leishmaniasis, suggesting IL-1 beta as a promising immunomodulatory target for non-healing infections.

关键词： ILC3s   Inflammatory cytokines   Intestinal barrier   MSI2   Ulcerative colitis  

摘要： Background: Ulcerative colitis (UC) is an inflammatory bowel disease with an unknown cause. Previous studies have shown that Group 3 innate lymphoid cells (ILC3s) are crucial for maintaining intestinal mucosal immune homeostasis by producing key cytokines such as IL-22 and IL-17 A. While the RNA-binding protein Musashi-2 (MSI2) is recognized as essential for promoting intestinal epithelial regeneration post-injury, its impact on immune regulation remains unclear. Therefore, we aim to investigate the protective mechanisms associated with ILC3s-specific MSI2 deletion in a mouse model of ulcerative colitis. Methods: Dextran sulfate sodium (DSS) was used to induce a mouse colitis model. Colitis severity was evaluated through weight loss, diarrhea, fecal traits, colon length, and pathological scoring. Transcriptome sequencing was utilized to identify differentially expressed genes in colon tissues. Flow cytometry was employed to measure the quantity and functionality of ILC3s. Western blot was conducted to analyze protein expression, while real-time polymerase chain reaction and enzyme-linked immunosorbent assay were employed to quantify inflammatory factors. Additionally, immunofluorescence, AB-PAS staining, and immunohistochemistry were employed to evaluate the integrity of the intestinal barrier. Results: Following DSS treatment, colon damage was milder in Msi2 Delta Rorc mice than in Msi2fl/flmice. Transcriptomic analysis revealed the down-regulation of cytokines and pro-inflammatory factors in the colon tissue of Msi2 Delta Rorc mice. Flow cytometry showed that specific deletion of MSI2 reduced the infiltration of ILC3s in the intestinal lamina propria of Msi2 Delta Rorc mice and decreased IL-17 A production. The reduction of IL-17 A-mediated immune responses lessened inflammatory damage to the intestinal barrier, thereby reducing colitis severity. Conclusions: Specific deletion of MSI2 alleviates DSS-induced colitis in mice by reducing ILC3s infiltration and IL-17

关键词： HLA   Streptococcus mutans   Saliva   Caries   Genetics   DRB1*0401  

摘要： Background Genetic factors significantly influence caries development and the colonization of oral bacteria, which could explain why some individuals are more prone or resistant to caries. Human leukocyte antigen (HLA) class II is a component in the adaptive immune system that has been associated with the colonization of oral bacteria such as Streptococcus mutans. This study aimed to investigate the association between specific alleles and genotypes of HLA-DRB1 on subgroup level and the colonization of S. mutans in a group of Swedish children. Methods Blood samples from 357 children were analyzed for HLA using next generation sequencing. Saliva samples were collected and analyzed for S. mutans, after which the subjects were divided into three groups: low, moderate, and high levels of colony forming units (CFU). The frequency of DRB1 alleles and genotypes was compared between the three groups. In addition, colonization levels, including the extremely high and low S. mutans CFU in individuals with alleles DRB1*0401, *0404, and *0301 were compared to the rest of the material. Results Individuals with DRB1*0401 were significantly associated with the extremely high CFU levels, since CFU levels > 100 were observed in 4.3% of individuals with DRB1*0401, compared to none among those without the allele (p = 0.009, Fisher's exact test). No statistical association was noted between the low, moderate, and high S. mutans groups and specific alleles or genotypes. Conclusions The findings suggest a potential relation between HLA class II alleles and the colonization of S. mutans. Specifically, carrying the DRB1*0401 allele may be a predisposing factor for higher levels of colonization.

关键词： 苦参   肿瘤   免疫微环境   免疫细胞   细胞因子   炎症因子  

摘要： 近年来，对肿瘤免疫微环境的研究逐渐成为关注热点。肿瘤免疫微环境是一个复杂的系统，可通过对微环境中肿瘤细胞、免疫细胞、炎症因子等成分进行调节，有效控制肿瘤的生长和转移。苦参是一种药用植物，主要成分为生物碱及黄酮类化合物，具有抗炎、抗菌、抗病毒、抗肿瘤以及免疫调节作用，能作用于肿瘤免疫微环境中免疫细胞、细胞因子、炎症因子等，可通过抑制肿瘤细胞增殖、侵袭和转移、干扰细胞周期、调节肿瘤代谢重编程以及抑制血管生成等发挥抗肿瘤作用。苦参对肿瘤免疫微环境的调节作用为肿瘤的临床治疗提供了新的策略。本文对苦参的生物学特性、抗肿瘤作用和作用机制及其对肿瘤免疫微环境的调节作用进行综述。

关键词： regulatory T cells   Foxp3   type 1 responses   GM-CSF   Treg suppressor function   IL-2   tissue-invading phagocytes   inflammation  

摘要： Regulatory T (T-reg) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. T-reg cell depletion or dysfunction results in fatal multiorgan inflammation linked to unrestrained effector T cell expansion. Here, we combine in vivo gene targeting and fate-mapping with high-dimensional cytometry to identify T-reg cells' steady-state function and suppressive mechanisms that prevent autoimmune inflammation and dissect the T helper (T-H) cell-derived cytokines and responding cells executing tissue damage upon global loss of peripheral tolerance. We unveil that type 1 cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)gamma, but not interleukin (IL)-17A, direct the ensuing immunopathology and mortality. GM-CSF orchestrates tissue invasion by monocytes and granulocytes and enhances their reactive oxygen species production and phagocytic capability. IL-2 modulation by T-reg cells is crucial in restraining pathogenic GM-CSF-producing T-H cells. Our study highlights the critical role of T-reg cells and IL-2 signaling in controlling GM-CSF-producing T-H cells and type 1 responses to curb phagocyte-mediated tissue destruction.

摘要： High-dose posttransplantation cyclophosphamide (HD-PTCy), given at 50 mg/kg/day on days +3/+4, is a standard-of-care graft-versus-host disease (GVHD) prophylaxis for allogeneic hematopoietic cell transplantation (HCT). Our murine MHC-haploidentical HCT studies suggested intermediate-dose PTCy produces superior GVHD control compared with HD-PTCy and PTCy is maximally effective on day +4. We conducted a single-institutional prospective phase 1/2 trial to reduce PTCy dosing to 25 mg/kg/day on days +3/+4 or on day +4 only for myeloablative HLA-haploidentical bone marrow HCT using PTCy, sirolimus, and mycophenolate mofetil. Among 35 patients, 89% were ethnic/racial minorities, 46% had high/very-high-risk disease, and median comorbidity score was 3. The phase 1 dose-limiting-toxicity, grade III-IV acute GVHD, was not observed after either reduced-PTCy dose level. PTCy 25 mg/kg/day on days +3/+4 (intermediate-dose (ID)-PTCy;n = 23), the phase 2 dose, resulted in no grade II-IV acute GVHD;2-year cumulative incidences of chronic GVHD requiring systemic immunosuppression, nonrelapse mortality, and relapse were 13%, 17%, and 22%, and 2-year overall survival, disease-free survival, and GVHD-free/relapse-free survival were 61%, 61%, and 52%. In exploratory analysis compared with HD-PTCy (n = 5), ID-PTCy resulted in significantly faster engraftment and T-cell reconstitution, fewer transfusions, less mucositis, and reduced severity of BK-virus-associated cystitis/urethritis;area-under-the-curve exposure of 4-hydroxycyclophosphamide (4HCY), a key cyclophosphamide metabolite, correlated with these outcomes but not with chronic GVHD occurrence. Ideal-body-weight-based PTCy dosing best approximated 4HCY exposure. ID-PTCy is effective and has apparent clinical benefits compared with HD-PTCy. Before broader implementation, further studies are needed to confirm these findings and define optimal PTCy dosing across various donor/graft types. This trial was registered at www. clinicaltrials

关键词： Epstein-Barr virus-associated NK-cell lympho-proliferative diseases   Long non-coding RNA   LINC02446   Hemophagocytic lymphohistiocytosis   IL-10   KLRs  

摘要： Introduction: Refractory Epstein-Barr virus-associated NK-cell lymphoproliferative diseases (EBV-NK-LPDs) are prone to hemophagocytic lymphohistiocytosis (HLH) with short survival and poor prognosis. Although various therapies have been used to relieve the symptoms, hematopoietic stem cell transplantation is considered the only potentially therapeutic approach. There is an urgent need to explore the pathogenesis of EBV-NK-LPDs and develop an effective better treatment. Methods: Here, we investigated long non-coding RNA (lncRNA) profile using high-throughput RNA sequencing data (n = 6, healthy donors;n = 5, infectious mononucleosis;n = 10, chronic active Epstein-Barr virus disease (CAEBV)-NK;n = 7, CAEBV-T) and screened out LINC02446, whose upregulation was further validated by quantitative real-time polymerase chain reaction in EBV-NK-LPDs. We further explored the correlation between LINC02446 and the clinical characteristics of patients with EBV-NK-LPDs. Then, based on sequencing data, we performed in vitro experiments to investigate the function and mechanism of LINC02446 in EBV-NK-LPDs. Results: LINC02446 was specifically highly expressed in NK cells of EBV-NK-LPDs patients. EBV-NK-LPDs patients with high expression of LINC02446 showed higher EBV-DNA copy number and ferritin levels, as well as a higher incidence of HLH. LINC02446 was closely related to the KLRs family and LINC02446 could regulate the expression of KLRs genes. In addition, LINC02446 positively regulated the expression of IL-10 in EBV-NK-LPDs cell lines, which revealed that LINC02446 may promote HLH by upregulating IL-10 in EBV-NK-LPDs. Conclusions: This is the first study that LINC02446 regulates the expression of KLRs family and IL-10 in EBV-NKLPDs, resulting in lymphoma progression and HLH occurrence, showing its potential as a therapeutic target for EBV-NK-LPDs.

关键词： common genes   such as SNAP25   AQP4   SV2B   KCND3   ABCA2   CD163   CD14  

摘要： Tumor necrosis factor receptor-associated factors (TRAFs) are crucial intracellular signaling proteins in bone homeostasis. TRAFs mediate pathways associated with bone remodeling, particularly in response to inflammatory stimuli, influencing osteoclast differentiation and function. Dysregulation of TRAF-mediated signaling contributes significantly to osteoporosis, a condition marked by increased bone resorption and fragility. Natural products, with their anti-inflammatory and antioxidant properties, offer promising therapeutic potential by targeting TRAF-associated pathways to inhibit excessive osteoclast activity and promote bone formation. This review explores the mechanisms by which natural compounds modulate TRAF signaling in osteoclastogenesis and osteoblastogenesis, providing insights into their potential for osteoporosis treatment.