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关键词： IL-27p28   single positive thymocyte   Th2 bias   IFN-gamma   autoimmune disease  

摘要： The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-gamma production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4(+) T cells from mice harboring dendritic cell (DC)-specific deletion of IL-27p28 display an increased capacity of IFN-gamma production upon TCR stimulation. Here, we demonstrated that similarly altered functionality occurred in CD4SP thymocytes, recent thymic emigrants (RTEs), as well as naive T cells from either Cd11c-p28(f/f) mice or mice deficient in the alpha subunit of IL-27 receptor. Therefore, DC-derived IL-27p28-triggered, IL-27R alpha-mediated signal is critically involved in the establishment of functional bias against IFN-gamma production during their development in the thymus. Epigenetic analyses indicated reduced DNA methylation of the Ifng locus and increased trimethylation of H3K4 at both Ifng and Tbx21 loci in CD4SP thymocytes from Cd11c-p28(f/f) mice. Transcriptome profiling demonstrated that Il27p28 ablation resulted in the coordinated up-regulation of STAT1-activated genes. Concurrently, STAT1 was found to be constitutively activated. Moreover, we observed increased accumulation of STAT1 at the Ifng and Tbx21 loci and a strong correlation between STAT1 binding and H3K4me3 modification of these loci. Of note, Il27p28 deficiency exacerbated the autoimmune phenotype of Aire(-/-) mice. Collectively, this study reveals a novel mechanism underlying the functional bias of newly generated CD4(+) T cells and the potential relevance of such a bias in autoimmunity.

关键词： gamma delta T17 cells   ROR gamma t   -17A   Bmi-1   senescence-associated pathological cardiac hypertrophy  

摘要： New immunosenescence targets for preventing senescence-associated pathological cardiac hypertrophy (SA-PCH) need to be explored. In the present study, with physiologically aged human and mouse samples, the IL-17A level increased with physiological aging, heart failure (HF), and SA-PCH and was negatively correlated with thymic Bmi-1 expression. Bmi-1f/fLckCre+ mice and Bmi-1f/flittermates were generated to determine whether Bmi-1 delayed T cell aging by maintaining thymic T cell development to prevent SA-PCH. As a result, Bmi-1 promoted thymic T cell development by upregulating Notch signaling and prevented DN1 T cells from differentiating into gamma delta T17 cells by downregulating gamma delta T17 cell differentiation signaling. Bmi-1 upregulated Notch signaling by inhibiting p53-mediated Ikzf1 transcription at the-1,863 to-1,849 Ikzf1 promoter region. Bmi-1-RING1B promoted ROR gamma t ubiquitination and degradation byproteas-ome to inhibit the production of IL-17A in gamma delta T17 cells. Bmi-1 also downregulated Rorc transcribed by c-Maf by trimethylating H3K27 at the-1,511 to-1,497 Rorc promoter region. Subsequently, the number of peripheral gamma delta T17 cells infiltrating the heart tissues was reduced, while alleviating IL-17A-dependent cardiac aging, hypertrophy, dysfunction, senescence-associated secretory phenotype (SASP), and macrophage-myofibroblast transition, ultimately improving SA-PCH. The ROR gamma t inhibitor SR1001 and IL-17A neutralizing antibody ixekizumab prevented thymic ROR gamma t-IL-17A-dependent SA-PCH. Furthermore, ROR gamma t bound to Bmi-1 through ARG237 and to RING1B through GLU235, which could be used as a therapeutic strategy for SA-PCH to construct binding peptides promoting Bmi-1-RING1B binding to ROR gamma t and degrading ROR gamma t for inhibiting gamma delta T17 cell differentiation and IL-17A production. Thus, thymic Bmi-1 prevented IL-17A-dependent SA-PCH by decreasing gamma delta T17 cell numbers.

关键词： Gremlin1   白细胞介素-6   慢性肾脏病   预后   预测价值  

摘要： 目的探究血清Gremlin1、白细胞介素-6（IL-6）水平在慢性肾衰竭患者中的表达及不良预后的预测价值。方法随机选取68例慢性肾功能不全患者为试验组，肾功能正常者30例为对照组。试验组慢性肾脏疾病（CKD）分期分为CKD1～2期组（n=35）和CKD3～5期组（n=33），比较试验组、对照组及不同病情严重程度组间血清Gremlin1、IL-6水平；试验组根据随访6个月期间是否进展为终末期肾病分为预后良好组（n=54）及预后不良组（n=14），比较不同预后结果组间血清Gremlin1、IL-6水平，经受试者工作曲线（ROC）评估血清Gremlin1、IL-6水平检测对慢性肾衰竭患者预后早期预测价值。结果试验组WBC、Hb、PLT水平明显低于对照组（P＜0.05）。试验组患者血清Gremlin1、IL-6水平明显高于对照组（P＜0.05）。与CKD1～2期组患者比较，CKD3～5期患者血清Gremlin1、IL-6水平较高（P＜0.05）。预后不良组患者血清Gremlin1、IL-6水平高于预后良好组（P＜0.05）。ROC曲线显示，血清Gremlin1、IL-6水平单独检测及联合检测可作为CKD患者预后的预测指标（P<0.05），其曲线下面积（AUC）分别为0.897、0.745、0.956。结论慢性肾衰竭患者血清Gremlin1、IL-6水平异常升高，二者联合检测对慢性肾衰竭早期预后具有较高的预测价值。

摘要： BACKGROUND:Breast Implant associated anaplastic large cell lymphoma (BIA-ALCL) has affected more than 1700 women. Treatment morbidity is reduced and survival improved by early detection and removal of implant and capsule. OBJECTIVE:To address the need for early detection, we developed a multiplex lateral flow assay (LFA) for soluble IL-10 and CD30 in seromas surrounding implants. METHODS:The range of detection was determined with recombinant CD30 or IL-10 added to a benign seroma to simulate clinical conditions. Then clinical samples from 23 women with BIA-ALCL and 17 benign seromas were analyzed with a multiplex LFA detecting soluble IL-10 and CD30. RESULTS:When recombinant proteins were added to benign seromas, CD30 was detected down to a concentration of 0.5 ng/mL, while IL-10 could be detected to down to 5 ng/mL. Significant differences were found between CD30 and IL-10 test line/control line ratios (TL/CL) of 23 BIA-ALCL and 17 benign seromas. Visual inspection of LFAs resulted in 65% sensitivity improved to 87% using image analysis. CONCLUSIONS:We conclude the multiplex IL-10/CD30 can detect BIA-ALCL with 100% specificity and 65% sensitivity in this group of 40 clinical seromas based on visual assessment of LFA strips. Sensitivity was improved to 87% with image analysis which can provide a screening test for BIA-ALCL. The multiplex LFA demonstrated a perfect positive predictive value (100%), indicating that all positive results correctly identified BIA-ALCL cases. The negative predictive value of 99% can exclude BIA-ALCL.

关键词： ICER   IFNγ   ILC   Leishmania major   NK cell  

摘要： Innate lymphoid cells (ILCs) participate in different skin diseases. Cutaneous leishmaniasis evokes Th1/Tc1-dominated immunity, while in immune-compromised individuals, a Th2/Treg/Th17-immune response dominates. Only few prior studies investigated the role of ILC in leishmaniasis. We show that following physiologic low dose infection with Leishmania major, both lesional NK cell and ILC1 numbers strongly increase. In addition, early lesional IFNγ production derives from type I ILCs. Genetic ablation of both NK cells and ILC1 (NK/ILC1 mice) led to reduced early IFNγ expression with increased pathology, higher parasite burdens and delayed recovery. Furthermore, expression of inducible cAMP early repressor (ICER) is important for disease outcome, as ICER mice exhibited significantly larger lesions. Interestingly, mice that lack ICER specifically in NK cells and ILC1 phenocopied the worsened disease outcome of ICER mice, while ICER deficiency in T cells or macrophages alone failed to do so. In line, ICER deficiency in NK cells/ILC1 resulted in higher lesional parasite burden with fewer IFNγ-positive ILC1 compared to control animals. Thus, our data shows that both NK cells and ILC1 contribute to early parasite control by releasing IFNγ. ICER expression by ILC1 promotes recruitment of IFNγ ILC1 in Leishmania infections important for development of protection against this important pathogen.

摘要： Cutaneous T-cell Lymphoma (CTCL) is a multistage disease characterized by rapid dissemination of malignant T lymphocytes from skin lesions to visceral organs and bone marrow. The cytokine IL-9 and its receptor (IL-9R) are aberrantly overexpressed in CTCL lesions and function to enhance tumor cell survival. Here, we uncovered a critical new role for IL-9 as a potent inducer of migration of malignant T-cells. Stimulation of IL-9R-expressing T-cell lymphoma cells with IL-9 induced a pseudohypoxic cellular state by elevating downstream levels of the pro-migratory and oxygen-sensing transcription factor, hypoxia inducible factor (HIF)-1α. High-throughput quantitative proteomics analyses of pseudohypoxic malignant T-cells identified the actin-modulating protein, Cofilin-1, as a pro-migratory CTCL-intrinsic target downstream of IL-9-HIF-1α signaling. Consistently, multicolor immunofluorescence staining revealed marked co-expression of Cofilin-1 with HIF-1α in both IL-9-treated human lymphoma cell lines and in patient CTCL skin biopsies compared to normal controls. Genetic knockdown of IL-9R or HIF-1α in human T-cell lymphoma lines by RNA interference significantly reduced both HIF-1α and Cofilin-1 co-expression and reversed IL-9-induced migration. Finally, pharmacological antagonism of HIF-1α activity using the FDA-designated orphan drug, echinomycin, significantly abrogated IL-9-triggered migration of both malignant T-cell lines as well as patient-derived T-cell lymphoma cells from CTCL biospecimens. Implications: Our results uncover a CTCL-intrinsic IL-9-HIF-1α-Cofilin-1 axis as a critical promoter of malignant T-cell migration. They further identify HIF-1α and Cofilin-1 as promising therapeutic targets to mitigate IL-9-induced CTCL dissemination.

关键词： neuropathic pain   pro-inflammatory cytokine   TNF-alpha   nerve injury   immunotherapy  

摘要： TNF-alpha is a pro-inflammatory cytokine that plays a pivotal role in the regulation of immune responses. It is predominantly produced by activated macrophages, although other cell types, such as T lymphocytes and NK cells, also contribute to its secretion. TNF-alpha participates in various physiological processes, including cell proliferation and differentiation. Moreover, TNF-alpha has been implicated in the pathogenesis of numerous inflammatory and autoimmune disorders. Recent studies have highlighted the important role of TNF-alpha in neuropathic pain, a complex and frequently disabling condition caused by nerve injury or dysfunction. Increased TNF-alpha levels in the nervous system have been associated with the onset of neuropathic pain, contributing to neuronal sensitization and alterations in pain signaling pathways. This study supports the idea that TNF-alpha connects the immune system with the nervous system, thereby supporting our understanding of the neuroimmune interface of pain and bringing a potential treatment against neuropathic pain: targeting TNF-alpha. Anti-TNF-alpha antibody administration reduces pain behaviors and neuroinflammation in preclinical animal models. Simultaneously, clinical trials are evaluating the safety and efficacy of anti-TNF-alpha treatments, with preliminary results indicating promising outcomes in patients experiencing neuropathic pain. Here, targeting TNF-alpha goes beyond its conventional spectrum of inflammatory pathologies and initiates a new mechanism-based approach to defining neuropathic pain, thereby improving the quality of life of the individuals affected and bringing together an area of colossal unmet clinical need.

关键词： Acute myeloid leukemia   Myelodysplastic syndrome   Bexmarilimab   CLEVER-1   Stabilin-1   Immunotherapy  

摘要： Treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) requires new therapy options, especially for patients uneligible for intense chemotherapy or with relapsed or refractory disease. CLEVER-1 is a myeloid checkpoint protein, which can be targeted with a therapeutic function blocking antibody, bexmarilimab. Bexmarilimab has shown clinical efficacy in different solid tumors. Here, we show preclinical data demonstrating expression of CLEVER-1 on immature malignant myeloid cells and their derivates in MDS and AML bone marrow samples and AML cell lines. Highest CLEVER-1 levels were observed in AML with monocytic differentiation. Ex vivo treatment of AML/MDS bone marrow samples with bexmarilimab led to an increase in antigen-presenting human leukocyte antigen DR isotype (HLA-DR) molecule expression. Combination of bexmarilimab with current standard-of-care (SoC) drugs, azacitidine and venetoclax, showed potential for HLA-DR induction and enhanced killing of leukemic cells, respectively. Our non-clinical findings support the feasibility of CLEVER-1 inhibition in AML/MDS to induce antigen presentating molecule expression and potentially, an anti-leukemic effect together with SoC. Therapeutic targeting of CLEVER-1 with bexmarilimab is currently undergoing clinical investigation in the BEXMAB trial (NCT05428969).

关键词： rheumatoid arthritis   anti-TNF   Nrf2   reverse signaling   biotherapy   monoclonal antibodies   monocytes   prediction  

摘要： (1) Background: TNF inhibitors (TNFis) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30-40% of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFis have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces "Reverse Signaling" (RS) in cells. We previously showed that certolizumab, a Fab' TNFi, activates RS in human primary monocytes, at least in part through the transcription factor Nrf2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) Methods: Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of six genes induced by Nrf2 following tmTNF RS in fresh monocytes. (3) Results: We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3% accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) Conclusions: We have developed a rather simple, short-term test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine.