Pub Date : 2023-10-09eCollection Date: 2023-01-01DOI: 10.1155/2023/7944102
Elias A Said, Sumaya Al-Dughaishi, Wadha Al-Hatmi, Iman Al-Reesi, Mohammed S Al-Balushi, Atika Al-Bimani, Juma Z Al-Busaidi, Marwa Al-Riyami, Murtadha Al-Khabori, Salam Al-Kindi, Francesco A Procopio, Shadia Al-Sinawi, Aliyaa Al-Ansari, Crystal Y Koh, Khalid Al-Naamani, Ali A Al-Jabri
Midkine (MK) and pleiotrophin (PTN) belong to the same family of cytokines. They have similar sequences and functions. Both have important roles in cellular proliferation, tumors, and diseases. They regulate and are expressed by some immune cells. We have recently demonstrated MK production by some human innate antigen-presenting cells (iAPCs), i.e., monocyte-derived dendritic cells (MDDCs) and macrophages stimulated through Toll-like receptor (TLR)-4, and plasmacytoid dendritic cells (pDCs) stimulated through TLR 7. While PTN production was only documented in tissue macrophages. TLRs 3, 7, 8, and 9 are nucleic acid sensing (NAS) TLRs that detect nucleic acids from cell damage and infection and induce iAPC responses. We investigated whether NAS TLRs can induce MK and PTN production by human iAPCs, namely monocytes, macrophages, MDDCs, myeloid dendritic cells (mDCs), and pDCs. Our results demonstrated for the first time that PTN is produced by all iAPCs upon TLR triggering (p < 0.01). IAPCs produced more PTN than MK (p < 0.01). NAS TLRs and iAPCs had differential abilities to induce the production of MK, which was induced in monocytes and pDCs by all NAS TLRs (p < 0.05) and in MDDCs by TLRs 7/8 (p < 0.05). TLR4 induced a stronger MK production than NAS TLRs (p ≤ 0.05). Monocytes produced higher levels of PTN after differentiation to macrophages and MDDCs (p < 0.05). The production of MK and PTN differs among iAPCs, with a higher production of PTN and a selective induction of MK production by NAS TLR. This highlights the potentially important role of iAPCs in angiogenesis, tumors, infections, and autoimmunity through the differential production of MK and PTN upon TLR triggering.
{"title":"Differential Production of Midkine and Pleiotrophin by Innate APCs upon Stimulation through Nucleic Acid-Sensing TLRs.","authors":"Elias A Said, Sumaya Al-Dughaishi, Wadha Al-Hatmi, Iman Al-Reesi, Mohammed S Al-Balushi, Atika Al-Bimani, Juma Z Al-Busaidi, Marwa Al-Riyami, Murtadha Al-Khabori, Salam Al-Kindi, Francesco A Procopio, Shadia Al-Sinawi, Aliyaa Al-Ansari, Crystal Y Koh, Khalid Al-Naamani, Ali A Al-Jabri","doi":"10.1155/2023/7944102","DOIUrl":"10.1155/2023/7944102","url":null,"abstract":"<p><p>Midkine (MK) and pleiotrophin (PTN) belong to the same family of cytokines. They have similar sequences and functions. Both have important roles in cellular proliferation, tumors, and diseases. They regulate and are expressed by some immune cells. We have recently demonstrated MK production by some human innate antigen-presenting cells (iAPCs), i.e., monocyte-derived dendritic cells (MDDCs) and macrophages stimulated through Toll-like receptor (TLR)-4, and plasmacytoid dendritic cells (pDCs) stimulated through TLR 7. While PTN production was only documented in tissue macrophages. TLRs 3, 7, 8, and 9 are nucleic acid sensing (NAS) TLRs that detect nucleic acids from cell damage and infection and induce iAPC responses. We investigated whether NAS TLRs can induce MK and PTN production by human iAPCs, namely monocytes, macrophages, MDDCs, myeloid dendritic cells (mDCs), and pDCs. Our results demonstrated for the first time that PTN is produced by all iAPCs upon TLR triggering (<i>p</i> < 0.01). IAPCs produced more PTN than MK (<i>p</i> < 0.01). NAS TLRs and iAPCs had differential abilities to induce the production of MK, which was induced in monocytes and pDCs by all NAS TLRs (<i>p</i> < 0.05) and in MDDCs by TLRs 7/8 (<i>p</i> < 0.05). TLR4 induced a stronger MK production than NAS TLRs (<i>p</i> ≤ 0.05). Monocytes produced higher levels of PTN after differentiation to macrophages and MDDCs (<i>p</i> < 0.05). The production of MK and PTN differs among iAPCs, with a higher production of PTN and a selective induction of MK production by NAS TLR. This highlights the potentially important role of iAPCs in angiogenesis, tumors, infections, and autoimmunity through the differential production of MK and PTN upon TLR triggering.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41235902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Macrophage activation syndrome (MAS) is a fatal inflammatory condition, which is often associated with the elevation of multiple proinflammatory cytokines and multiple organ dysfunction. Previous studies have shown that ST2 contributes to T cell overactivation and plays a detrimental role in mouse models of primary hemophagocytic lymphohistiocytosis. The purpose of this study was to investigate the role of the IL-33/ST2 axis in a mouse model of MAS induced by repeated injections of cytosine-phosphate-guanine (CpG).
Methods: Serum cytokines were determined using the cytometric bead array by flow cytometry. IL-33 and ST2 were detected by immunohistochemistry and real-time quantitative PCR in the liver and spleen of mice. CD3 and F4/80 in the liver were detected by immunohistochemistry. Inflammatory macrophages and effector memory T lymphocytes were detected by flow cytometry.
Result: The CpG-induced MAS model was successfully induced after repeated CpG injections, presenting with hypercytokinemia and hepatosplenomegaly. The numbers of IL-33 positive cells in the liver and spleen decreased significantly, while the expression of ST2 in the liver tended to increase in the mice with MAS. IL-33 and St2 knockout mice showed similar levels of hepatosplenomegaly, peripheral blood count, and cytokine storm when compared with wild-type (WT) mice after induction of MAS. There were also no significant differences in liver pathology (including inflammatory cell infiltration of CD3 and F4/80) and levels of splenic inflammatory macrophages and effector memory T cells between the WT and knockout mice.
Conclusion: These results suggested that IL-33 decreased in the liver and spleen tissues of MAS mice. Further results suggest that IL-33 and St2 knockout mice have no treatment potential in CpG-induced MAS. Thus, the IL-33/ST2 axis has little effect on the prognosis of CpG-induced MAS.
{"title":"The Role of the IL-33/ST2 Axis in CpG-Induced Macrophage Activation Syndrome.","authors":"Yuanji Dong, Rongfen Gao, Kailin He, Jixin Zhong, Lingli Dong","doi":"10.1155/2023/2689360","DOIUrl":"10.1155/2023/2689360","url":null,"abstract":"<p><strong>Background: </strong>Macrophage activation syndrome (MAS) is a fatal inflammatory condition, which is often associated with the elevation of multiple proinflammatory cytokines and multiple organ dysfunction. Previous studies have shown that ST2 contributes to T cell overactivation and plays a detrimental role in mouse models of primary hemophagocytic lymphohistiocytosis. The purpose of this study was to investigate the role of the IL-33/ST2 axis in a mouse model of MAS induced by repeated injections of cytosine-phosphate-guanine (CpG).</p><p><strong>Methods: </strong>Serum cytokines were determined using the cytometric bead array by flow cytometry. IL-33 and ST2 were detected by immunohistochemistry and real-time quantitative PCR in the liver and spleen of mice. CD3 and F4/80 in the liver were detected by immunohistochemistry. Inflammatory macrophages and effector memory T lymphocytes were detected by flow cytometry.</p><p><strong>Result: </strong>The CpG-induced MAS model was successfully induced after repeated CpG injections, presenting with hypercytokinemia and hepatosplenomegaly. The numbers of IL-33 positive cells in the liver and spleen decreased significantly, while the expression of ST2 in the liver tended to increase in the mice with MAS. <i>IL-33</i> and <i>St2</i> knockout mice showed similar levels of hepatosplenomegaly, peripheral blood count, and cytokine storm when compared with wild-type (WT) mice after induction of MAS. There were also no significant differences in liver pathology (including inflammatory cell infiltration of CD3 and F4/80) and levels of splenic inflammatory macrophages and effector memory T cells between the WT and knockout mice.</p><p><strong>Conclusion: </strong>These results suggested that IL-33 decreased in the liver and spleen tissues of MAS mice. Further results suggest that <i>IL-33</i> and <i>St2</i> knockout mice have no treatment potential in CpG-induced MAS. Thus, the IL-33/ST2 axis has little effect on the prognosis of CpG-induced MAS.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41235903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rapid and accurate methods for the diagnosis of tuberculous pleurisy (TP) are urgently needed. Activation markers of tuberculosis (TB)-reactive T cells are considered promising for the diagnosis of active TB (ATB). Different activation indexes may play different roles in the progression of TB, but there are few reports on T cell activation indicators, except for HLA-DR. Hence, we evaluated the expression of early (CD25 and CD69) and late (CD134) activation markers on TB antigen-stimulated CD4+ T cells in populations with different TB infection status and investigated their diagnostic value for ATB, particularly, for TP. Moreover, we compared the differences in the diagnostic efficacy among the indexes from peripheral blood (PB) and pleural fluid (PF) for TP. The expression of each activation marker was significantly increased in TB-infected populations (patients with ATB and latent TB infection vs. healthy individuals; patients with TP vs. non-TP) and was significantly higher in the PF than in the PB of patients with TP. The diagnostic performance of the coexpressed activation markers was superior to that of single expression markers in the differential diagnosis of ATB and non-TB, with CD25+CD134+ showing the best diagnostic efficiency (AUC: 0.93, 95% CI, 0.87-0.99; sensitivity: 86.7%, 95% CI, 72.5%-94.5%; and specificity: 94.0%, 95% CI, 82.5%-98.4%). Except for TB-IGRA, the activation indexes were more accurate than conventional laboratory methods for ATB diagnosis. In addition, the expression of CD25+CD134+ in PB and PF was the best values for differential diagnosis of TP and NTP, with AUCs of 0.87 (95% CI, 0.77-0.96) and 0.95 (95% CI, 0.90-1.00), respectively. Our study provides information on the diagnostic value of different activation markers for TB and shows that the expression of CD25+CD134+ on CD4+ T cells in PF can serve as a potential marker for TP diagnosis.
{"title":"Diagnostic Value of CD25, CD69, and CD134 on Tuberculosis-Specific Antigen-Stimulated CD4+ T Cells for Tuberculous Pleurisy.","authors":"Hanlu Shi, Liping Yang, Fujie Zhang, Yu Zhou, Yonglie Zhou","doi":"10.1155/2023/5309816","DOIUrl":"10.1155/2023/5309816","url":null,"abstract":"<p><p>Rapid and accurate methods for the diagnosis of tuberculous pleurisy (TP) are urgently needed. Activation markers of tuberculosis (TB)-reactive T cells are considered promising for the diagnosis of active TB (ATB). Different activation indexes may play different roles in the progression of TB, but there are few reports on T cell activation indicators, except for HLA-DR. Hence, we evaluated the expression of early (CD25 and CD69) and late (CD134) activation markers on TB antigen-stimulated CD4+ T cells in populations with different TB infection status and investigated their diagnostic value for ATB, particularly, for TP. Moreover, we compared the differences in the diagnostic efficacy among the indexes from peripheral blood (PB) and pleural fluid (PF) for TP. The expression of each activation marker was significantly increased in TB-infected populations (patients with ATB and latent TB infection vs. healthy individuals; patients with TP vs. non-TP) and was significantly higher in the PF than in the PB of patients with TP. The diagnostic performance of the coexpressed activation markers was superior to that of single expression markers in the differential diagnosis of ATB and non-TB, with CD25+CD134+ showing the best diagnostic efficiency (AUC: 0.93, 95% CI, 0.87-0.99; sensitivity: 86.7%, 95% CI, 72.5%-94.5%; and specificity: 94.0%, 95% CI, 82.5%-98.4%). Except for TB-IGRA, the activation indexes were more accurate than conventional laboratory methods for ATB diagnosis. In addition, the expression of CD25+CD134+ in PB and PF was the best values for differential diagnosis of TP and NTP, with AUCs of 0.87 (95% CI, 0.77-0.96) and 0.95 (95% CI, 0.90-1.00), respectively. Our study provides information on the diagnostic value of different activation markers for TB and shows that the expression of CD25+CD134+ on CD4+ T cells in PF can serve as a potential marker for TP diagnosis.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10551431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-21eCollection Date: 2023-01-01DOI: 10.1155/2023/5577850
Zhaoyao Qi, Xinxin Qi, Yuanhui Xu, Hongguang Sun, Dengfeng Li, Jincun Liu, Meili Cong, Tao Liu
There remains a lack of standard models that have all the characteristics of human diseases. Especially in immunological hepatic fibrosis, the bovine serum albumin (BSA)-induced liver fibrosis models have the same developmental mechanisms as human liver fibrosis models, but have received little attention. We standardized a BSA-induced liver fibrosis model in rats and thoroughly assessed its pathological characteristics. We also used 16S sequencing to assess homeostasis of the intestinal microflora of rats with BSA-induced liver fibrosis and detected various differential metabolites in the serum of these rats using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). We observed stable and unambiguous histological changes in liver tissue morphology and remarkably high concentrations of inflammatory markers in the serum of BSA-induced liver fibrosis rats. In keeping with the fact that BSA induction can cause gut microbiota disorders in rats. UHPLC-MS/MS analysis of rat serum samples in positive-ion mode and negative-ion mode revealed 17 and 25 differential metabolites, respectively. Network analysis revealed that phenylalanine or tyrosine metabolites (e.g., PAGln) were the predominant metabolites in the sera of BSA-induced liver fibrosis rats. Taken together, our results suggest that disorders of amino acid metabolism caused by the gut microbiota may play an important role in the progression of immunological hepatic fibrosis.
{"title":"Alterations in the \"Gut-Liver Axis\" on Rats with Immunological Hepatic Fibrosis.","authors":"Zhaoyao Qi, Xinxin Qi, Yuanhui Xu, Hongguang Sun, Dengfeng Li, Jincun Liu, Meili Cong, Tao Liu","doi":"10.1155/2023/5577850","DOIUrl":"https://doi.org/10.1155/2023/5577850","url":null,"abstract":"<p><p>There remains a lack of standard models that have all the characteristics of human diseases. Especially in immunological hepatic fibrosis, the bovine serum albumin (BSA)-induced liver fibrosis models have the same developmental mechanisms as human liver fibrosis models, but have received little attention. We standardized a BSA-induced liver fibrosis model in rats and thoroughly assessed its pathological characteristics. We also used 16S sequencing to assess homeostasis of the intestinal microflora of rats with BSA-induced liver fibrosis and detected various differential metabolites in the serum of these rats using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). We observed stable and unambiguous histological changes in liver tissue morphology and remarkably high concentrations of inflammatory markers in the serum of BSA-induced liver fibrosis rats. In keeping with the fact that BSA induction can cause gut microbiota disorders in rats. UHPLC-MS/MS analysis of rat serum samples in positive-ion mode and negative-ion mode revealed 17 and 25 differential metabolites, respectively. Network analysis revealed that phenylalanine or tyrosine metabolites (e.g., PAGln) were the predominant metabolites in the sera of BSA-induced liver fibrosis rats. Taken together, our results suggest that disorders of amino acid metabolism caused by the gut microbiota may play an important role in the progression of immunological hepatic fibrosis.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10539088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41135497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-20eCollection Date: 2023-01-01DOI: 10.1155/2023/4877700
Yatao Bao, Meng Lian, Yong Chen, Xiaotian Gu, Kunyu Cao, Xiaoping Du, Jiyu Ju
Genetic factors play an important role in the pathogenesis of systemic lupus erythematosus (SLE), and abnormal Toll-like receptor (TLR) signaling pathways are closely related to the onset of SLE. In previous studies, we found that the mutant somatic nuclear autoantigenic sperm protein (sNASP) gene in the mouse lupus susceptibility locus Sle2 can promote the development of lupus model mice, but the mechanism is still unclear. Here, we stimulated mouse peritoneal macrophages with different concentrations of lipopolysaccharide. The results showed that sNASP gene mutations can promote the response of the TLR4-TAK1 signaling pathway but have no significant effect on the TLR4-TBK1 signaling pathway. sNASP mutations enhanced TLR4-mediated nuclear factor-κ-gene binding and mitogen-activated protein kinase activation and IL-6, tumor necrosis factor secretion in murine peritoneal macrophages. Collectively, our study revealed the impact of sNASP gene mutation on the sensitivity of TLR4 receptors in mouse peritoneal macrophages and shed light on potential mechanisms underlying inflammation in autoimmune diseases.
{"title":"sNASP Mutation Aggravates to the TLR4-Mediated Inflammation in SLE by TAK1 Pathway.","authors":"Yatao Bao, Meng Lian, Yong Chen, Xiaotian Gu, Kunyu Cao, Xiaoping Du, Jiyu Ju","doi":"10.1155/2023/4877700","DOIUrl":"https://doi.org/10.1155/2023/4877700","url":null,"abstract":"<p><p>Genetic factors play an important role in the pathogenesis of systemic lupus erythematosus (SLE), and abnormal Toll-like receptor (TLR) signaling pathways are closely related to the onset of SLE. In previous studies, we found that the mutant somatic nuclear autoantigenic sperm protein (sNASP) gene in the mouse lupus susceptibility locus <i>Sle2</i> can promote the development of lupus model mice, but the mechanism is still unclear. Here, we stimulated mouse peritoneal macrophages with different concentrations of lipopolysaccharide. The results showed that sNASP gene mutations can promote the response of the TLR4-TAK1 signaling pathway but have no significant effect on the TLR4-TBK1 signaling pathway. sNASP mutations enhanced TLR4-mediated nuclear factor-<i>κ</i>-gene binding and mitogen-activated protein kinase activation and IL-6, tumor necrosis factor secretion in murine peritoneal macrophages. Collectively, our study revealed the impact of sNASP gene mutation on the sensitivity of TLR4 receptors in mouse peritoneal macrophages and shed light on potential mechanisms underlying inflammation in autoimmune diseases.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41129773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL.
Methods: In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo.
Results: As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells.
Conclusion: Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients.
{"title":"Super Enhancer Regulatory Gene FYB1 Promotes the Progression of T Cell Acute Lymphoblastic Leukemia by Activating IGLL1.","authors":"Kunlong Zhang, Jun Lu, Fang Fang, Yongping Zhang, Juanjuan Yu, Yanfang Tao, Wenyuan Liu, Lihui Lu, Zimu Zhang, Xinran Chu, Jianwei Wang, Xiaolu Li, Yuanyuan Tian, Zhiheng Li, Qian Li, Xu Sang, Li Ma, Ningling Wang, Jian Pan, Shaoyan Hu","doi":"10.1155/2023/3804605","DOIUrl":"https://doi.org/10.1155/2023/3804605","url":null,"abstract":"<p><strong>Background: </strong>Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL.</p><p><strong>Methods: </strong>In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated <i>in vitro</i> and/or <i>in vivo</i>.</p><p><strong>Results: </strong>As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. <i>In vitro</i>, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. <i>In vivo</i>, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells.</p><p><strong>Conclusion: </strong>Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41147173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-15eCollection Date: 2023-01-01DOI: 10.1155/2023/4027701
Antonella Loperfido, Andrea Ciofalo, Carlo Cavaliere, Elona Begvarfaj, Francesca Cascone, Giacomo Alfonzo, Rosalba Cadeddu, Stefano Millarelli, Gianluca Bellocchi, Antonio Greco, Marco de Vincentiis, Simonetta Masieri
Background: Dupilumab represents the first approved biological for severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP).
Objective: Aim of this paper is to provide a multicentric real-life study about treatment with dupilumab for CRSwNP with a special focus on blood parameters and IgE, IgG, and IgA.
Method: A retrospective data collection was jointly conducted at the Otolaryngology departments of San Camillo Forlanini Hospital and University of Rome "La Sapienza" from December 2020 to January 2023.
Results: A total of 130 patients were included in the study. Monitoring our patients for 18 months, we observed a reduction in nasal polyposis and an improvement in symptoms and their impact on quality of life. Regarding blood tests, a transient increase in blood eosinophils was found in most cases. Total IgE showed a gradual decrease in values. IgG and IgA also showed a slight reduction of values, while remaining within normal ranges.
Conclusion: To the best of our knowledge, this is the first study to evaluate the impact of dupilumab on several blood parameters in patients receiving treatment for CRswNP. Further studies are needed to confirm our results and to understand the underlying immunological mechanisms.
{"title":"Dupilumab's Impact on Blood Parameters in Nasal Polyposis: 18-Month Follow-Up in Real Life.","authors":"Antonella Loperfido, Andrea Ciofalo, Carlo Cavaliere, Elona Begvarfaj, Francesca Cascone, Giacomo Alfonzo, Rosalba Cadeddu, Stefano Millarelli, Gianluca Bellocchi, Antonio Greco, Marco de Vincentiis, Simonetta Masieri","doi":"10.1155/2023/4027701","DOIUrl":"https://doi.org/10.1155/2023/4027701","url":null,"abstract":"<p><strong>Background: </strong>Dupilumab represents the first approved biological for severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP).</p><p><strong>Objective: </strong>Aim of this paper is to provide a multicentric real-life study about treatment with dupilumab for CRSwNP with a special focus on blood parameters and IgE, IgG, and IgA.</p><p><strong>Method: </strong>A retrospective data collection was jointly conducted at the Otolaryngology departments of San Camillo Forlanini Hospital and University of Rome \"La Sapienza\" from December 2020 to January 2023.</p><p><strong>Results: </strong>A total of 130 patients were included in the study. Monitoring our patients for 18 months, we observed a reduction in nasal polyposis and an improvement in symptoms and their impact on quality of life. Regarding blood tests, a transient increase in blood eosinophils was found in most cases. Total IgE showed a gradual decrease in values. IgG and IgA also showed a slight reduction of values, while remaining within normal ranges.</p><p><strong>Conclusion: </strong>To the best of our knowledge, this is the first study to evaluate the impact of dupilumab on several blood parameters in patients receiving treatment for CRswNP. Further studies are needed to confirm our results and to understand the underlying immunological mechanisms.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41132761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-25eCollection Date: 2023-01-01DOI: 10.1155/2023/5221658
Szabina Erdő-Bonyár, Diána Simon, Anna Bajnok, Jasper Nörenberg, Tímea Serény-Litvai, Ákos Várnagy, Kálmán Kovács, Eszter Hantosi, Emese Mezősi, Tímea Berki
T helper type 1 (Th1) and inflammatory cytokines play essential roles in early pregnancy and also in the pathogenesis of Hashimoto's thyroiditis (HT). Changes in the serum level of autoantibodies to cytokines, which may be able to modulate their availability and actions have been described in several autoimmune disorders. Yet, no data are available on anti-cytokine autoantibodies either during early pregnancy or in patients with HT. The aim of the study was to measure autoantibodies to inflammatory-, Th1- and Th22-cytokines in serum samples in healthy pregnancy (HP) and in pregnant women with HT (HTP). As pathological autoantibodies are hallmarks of HT, in addition we also measured anti-B-cell activator factor (BAFF) autoantibodies. The measurement was carried out with a Luminex multiplex assay and the Luminex MAGPIX Instrument, age-matched healthy women (HC) and women with HT (HT) were used as controls. In the first trimester of HP, anti-TNFα, anti-IL-8, and anti-IFNγ autoantibodies were significantly decreased, while autoantibodies to BAFF were significantly elevated compared to the HC. However, these alterations were not present in the HTP. Moreover, the levels of autoantibodies to IL-22 and TNFα were significantly increased in HTP compared to the HP. All differences in the levels of the investigated autoantibodies could be detected in the first trimester of pregnancies except for anti-IL-22 autoantibodies. According to our results we can conclude that alterations in the levels of autoantibodies to inflammatory and Th1 cytokines are physiological in the first trimester of pregnancy and their disturbance can be associated with autoimmune conditions such as HT.
{"title":"Physiological Changes in the Levels of Anti-Cytokine Autoantibodies in Early Pregnancy Are Missing in Pregnant Women with Hashimoto's Thyroiditis.","authors":"Szabina Erdő-Bonyár, Diána Simon, Anna Bajnok, Jasper Nörenberg, Tímea Serény-Litvai, Ákos Várnagy, Kálmán Kovács, Eszter Hantosi, Emese Mezősi, Tímea Berki","doi":"10.1155/2023/5221658","DOIUrl":"10.1155/2023/5221658","url":null,"abstract":"<p><p>T helper type 1 (Th1) and inflammatory cytokines play essential roles in early pregnancy and also in the pathogenesis of Hashimoto's thyroiditis (HT). Changes in the serum level of autoantibodies to cytokines, which may be able to modulate their availability and actions have been described in several autoimmune disorders. Yet, no data are available on anti-cytokine autoantibodies either during early pregnancy or in patients with HT. The aim of the study was to measure autoantibodies to inflammatory-, Th1- and Th22-cytokines in serum samples in healthy pregnancy (HP) and in pregnant women with HT (HTP). As pathological autoantibodies are hallmarks of HT, in addition we also measured anti-B-cell activator factor (BAFF) autoantibodies. The measurement was carried out with a Luminex multiplex assay and the Luminex MAGPIX Instrument, age-matched healthy women (HC) and women with HT (HT) were used as controls. In the first trimester of HP, anti-TNF<i>α</i>, anti-IL-8, and anti-IFN<i>γ</i> autoantibodies were significantly decreased, while autoantibodies to BAFF were significantly elevated compared to the HC. However, these alterations were not present in the HTP. Moreover, the levels of autoantibodies to IL-22 and TNF<i>α</i> were significantly increased in HTP compared to the HP. All differences in the levels of the investigated autoantibodies could be detected in the first trimester of pregnancies except for anti-IL-22 autoantibodies. According to our results we can conclude that alterations in the levels of autoantibodies to inflammatory and Th1 cytokines are physiological in the first trimester of pregnancy and their disturbance can be associated with autoimmune conditions such as HT.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10154715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
There is controversial literature about the effects of the interleukin-2 (IL-2) cytokine family in COVID-19 pathogenesis and immunity. So we aimed to identify the potential in the role of the IL-2 family in COVID-19. A narrative review search was done through online databases, including PubMed, Scopus, and Web of Science. The search deadline was up to December 2022. We applied no time limits for the searching strategy. After retrieving articles from the databases, the authors summarized the data into two data extraction tables. The first data extraction table described the changes in the IL-2 cytokine family in COVID-19 and the second table described the therapeutic interventions targeting IL-2 family cytokines. The results of the literature on the role of the IL-2 cytokine family do not show a singular rule. IL-2 cytokine family can change during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some studies suggest that IL-2 cytokine family rise during the infection and cause severe inflammatory response and cytokine storm. These cytokines are shown to be increased in immunocompromised patients and worsen their prognosis. In individuals without underlying disease, the upregulation of the IL-2 family shows the clinical outcome of the disease and rises with disease severity. However, some other studies show that these cytokines do not significantly change. IL-2 cytokine family is mostly upregulated in healthy individuals who had vaccination, but immunocompromised patients did not show significant changes after a single dose of vaccines, which shows that these patients need booster doses for efficient immunity. IL-2 cytokine family can also be used as immunotherapy agents in COVID-19.
关于白细胞介素-2(IL-2)细胞因子家族在新冠肺炎发病机制和免疫中的作用,有争议的文献。因此,我们旨在确定IL-2家族在新冠肺炎中的潜在作用。通过PubMed、Scopus和Web of Science等在线数据库进行叙述性综述搜索。搜索截止日期为2022年12月。我们对搜索策略没有时间限制。从数据库中检索文章后,作者将数据汇总为两个数据提取表。第一个数据提取表描述了新冠肺炎中IL-2细胞因子家族的变化,第二个表描述了针对IL-2家族细胞因子的治疗干预。关于IL-2细胞因子家族作用的文献结果没有显示出单一的规则。IL-2细胞因子家族在严重急性呼吸综合征冠状病毒2型感染期间可能发生变化。一些研究表明,IL-2细胞因子家族在感染期间升高,并引起严重的炎症反应和细胞因子风暴。这些细胞因子在免疫功能受损的患者中增加,并恶化他们的预后。在没有潜在疾病的个体中,IL-2家族的上调显示了疾病的临床结果,并随着疾病的严重程度而升高。然而,其他一些研究表明,这些细胞因子没有显著变化。IL-2细胞因子家族在接种疫苗的健康个体中大多上调,但免疫功能低下的患者在单剂疫苗接种后没有表现出显著变化,这表明这些患者需要加强剂量才能获得有效免疫。IL-2细胞因子家族也可作为新冠肺炎的免疫疗法药物。
{"title":"The Important Role of Interleukin-2 in COVID-19.","authors":"Leila Ghanbari Naeini, Laleh Abbasi, Farzaneh Karimi, Pajman Kokabian, Fahimeh Abdi Abyaneh, Delaram Naderi","doi":"10.1155/2023/7097329","DOIUrl":"10.1155/2023/7097329","url":null,"abstract":"<p><p>There is controversial literature about the effects of the interleukin-2 (IL-2) cytokine family in COVID-19 pathogenesis and immunity. So we aimed to identify the potential in the role of the IL-2 family in COVID-19. A narrative review search was done through online databases, including PubMed, Scopus, and Web of Science. The search deadline was up to December 2022. We applied no time limits for the searching strategy. After retrieving articles from the databases, the authors summarized the data into two data extraction tables. The first data extraction table described the changes in the IL-2 cytokine family in COVID-19 and the second table described the therapeutic interventions targeting IL-2 family cytokines. The results of the literature on the role of the IL-2 cytokine family do not show a singular rule. IL-2 cytokine family can change during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some studies suggest that IL-2 cytokine family rise during the infection and cause severe inflammatory response and cytokine storm. These cytokines are shown to be increased in immunocompromised patients and worsen their prognosis. In individuals without underlying disease, the upregulation of the IL-2 family shows the clinical outcome of the disease and rises with disease severity. However, some other studies show that these cytokines do not significantly change. IL-2 cytokine family is mostly upregulated in healthy individuals who had vaccination, but immunocompromised patients did not show significant changes after a single dose of vaccines, which shows that these patients need booster doses for efficient immunity. IL-2 cytokine family can also be used as immunotherapy agents in COVID-19.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10465260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10118749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-19eCollection Date: 2023-01-01DOI: 10.1155/2023/5149306
Liu Yang, Yajun Zhang, Xuefei Yu, Danni Li, Na Liu, Xindong Xue, Jianhua Fu
White matter damage (WMD) is a primary cause of cerebral palsy and cognitive impairment in preterm infants, and no effective treatments are available. Microglia are a major component of the innate immune system. When activated, they form typical pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes and regulate myelin development and synapse formation. Therefore, they may play a pivotal role in hypoxic-ischemic (HI) WMD. Herein, we investigated neural inflammation and long-term microglia phenotypic polarization in a neonatal rat model of hypoxia-ischemia-induced WMD and elucidated the underlying pathophysiological processes. We exposed 3-day-old (P3) Sprague-Dawley rats to hypoxia (8% oxygen) for 2.5 hr after unilateral common carotid artery ligation. The activation of NLRP3 inflammatory bodies, microglia M1/M2 polarization, myelination, and synaptic development in our model were monitored 7, 14, and 21 days after birth. In addition, the Morris water maze test was performed on postnatal Day 28. We confirmed myelination disturbance in the periventricular white matter, abnormal synaptic development, and behavioral changes in the periventricular area during the development of HI WMD. In addition, we found an association between the occurrence and development of HI WMD and activation of the NLRP3 inflammasome, microglial M1/M2 polarization, and the release of inflammatory factors. NLRP3 inhibition can play an anti-inflammatory role by inhibiting the differentiation of microglia into the M1 phenotype, thereby improving myelination and synapse formation. In conclusion, microglia are key mediators of the inflammatory response and exhibit continuous phenotypic polarization 7-21 days after HI-induced WMD. This finding can potentially lead to a new treatment regimen targeting the phenotypic polarization of microglia early after HI-induced brain injury.
白质损伤(WMD)是早产儿脑瘫和认知障碍的主要原因,目前尚无有效的治疗方法。小胶质细胞是先天性免疫系统的主要组成部分。当被激活时,它们会形成典型的促炎(M1)和抗炎(M2)表型,并调节髓鞘发育和突触形成。因此,它们可能在缺氧缺血性(HI)WMD 中发挥关键作用。在此,我们研究了缺氧缺血诱导的WMD新生大鼠模型中的神经炎症和长期小胶质细胞表型极化,并阐明了其潜在的病理生理过程。我们将出生 3 天(P3)的 Sprague-Dawley 大鼠置于单侧颈总动脉结扎后的缺氧(8% 氧气)环境中 2.5 小时。在大鼠出生后 7、14 和 21 天,对其 NLRP3 炎性体的激活、小胶质细胞 M1/M2 极化、髓鞘化和突触发育情况进行了监测。此外,还在出生后第28天进行了莫里斯水迷宫试验。我们证实,在 HI WMD 的发育过程中,脑室周围白质的髓鞘化紊乱、突触发育异常以及脑室周围区域的行为发生了变化。此外,我们还发现 HI WMD 的发生和发展与 NLRP3 炎性体的激活、小胶质细胞 M1/M2 极化和炎性因子的释放有关。抑制 NLRP3 可抑制小胶质细胞向 M1 表型分化,从而改善髓鞘形成和突触形成,从而起到抗炎作用。总之,小胶质细胞是炎症反应的关键介质,在 HI 诱导大规模毁灭性脑损伤后 7-21 天表现出持续的表型极化。这一发现有可能导致针对 HI 诱导的脑损伤后早期小胶质细胞表型极化的新治疗方案。
{"title":"Periventricular Microglia Polarization and Morphological Changes Accompany NLRP3 Inflammasome-Mediated Neuroinflammation after Hypoxic-Ischemic White Matter Damage in Premature Rats.","authors":"Liu Yang, Yajun Zhang, Xuefei Yu, Danni Li, Na Liu, Xindong Xue, Jianhua Fu","doi":"10.1155/2023/5149306","DOIUrl":"10.1155/2023/5149306","url":null,"abstract":"<p><p>White matter damage (WMD) is a primary cause of cerebral palsy and cognitive impairment in preterm infants, and no effective treatments are available. Microglia are a major component of the innate immune system. When activated, they form typical pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes and regulate myelin development and synapse formation. Therefore, they may play a pivotal role in hypoxic-ischemic (HI) WMD. Herein, we investigated neural inflammation and long-term microglia phenotypic polarization in a neonatal rat model of hypoxia-ischemia-induced WMD and elucidated the underlying pathophysiological processes. We exposed 3-day-old (P3) Sprague-Dawley rats to hypoxia (8% oxygen) for 2.5 hr after unilateral common carotid artery ligation. The activation of NLRP3 inflammatory bodies, microglia M1/M2 polarization, myelination, and synaptic development in our model were monitored 7, 14, and 21 days after birth. In addition, the Morris water maze test was performed on postnatal Day 28. We confirmed myelination disturbance in the periventricular white matter, abnormal synaptic development, and behavioral changes in the periventricular area during the development of HI WMD. In addition, we found an association between the occurrence and development of HI WMD and activation of the NLRP3 inflammasome, microglial M1/M2 polarization, and the release of inflammatory factors. NLRP3 inhibition can play an anti-inflammatory role by inhibiting the differentiation of microglia into the M1 phenotype, thereby improving myelination and synapse formation. In conclusion, microglia are key mediators of the inflammatory response and exhibit continuous phenotypic polarization 7-21 days after HI-induced WMD. This finding can potentially lead to a new treatment regimen targeting the phenotypic polarization of microglia early after HI-induced brain injury.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10460280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10220206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}