115 results
Search Results
2. Differences in the dynamics of the <scp>tandem‐SH2</scp> modules of the Syk and <scp>ZAP</scp> ‐70 tyrosine kinases
- Author
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Neel H. Shah, Christine L. Gee, John Kuriyan, Jean M. Badroos, Helen T. Hobbs, and Susan Marqusee
- Subjects
Protein Conformation, alpha-Helical ,Conformational change ,Full‐Length Papers ,T-Lymphocytes ,Genetic Vectors ,Gene Expression ,Syk ,chemical and pharmacologic phenomena ,Adaptive Immunity ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,SH2 domain ,Biochemistry ,Full‐Length Paper ,evolution ,Immunoreceptor tyrosine-based activation motif ,Escherichia coli ,Animals ,Humans ,Syk Kinase ,Protein Interaction Domains and Motifs ,Cloning, Molecular ,Tyrosine ,Molecular Biology ,B-Lymphocytes ,Binding Sites ,ZAP-70 Protein-Tyrosine Kinase ,Chemistry ,conformational landscape ,hydrogen–deuterium exchange mass spectrometry ,tyrosine kinase signaling ,Deuterium Exchange Measurement ,hemic and immune systems ,Biological Evolution ,Recombinant Proteins ,Protein kinase domain ,protein dynamics ,Biophysics ,Phosphorylation ,Protein Conformation, beta-Strand ,Tyrosine kinase ,Protein Binding ,Signal Transduction - Abstract
The catalytic activity of Syk‐family tyrosine kinases is regulated by a tandem Src homology 2 module (tSH2 module). In the autoinhibited state, this module adopts a conformation that stabilizes an inactive conformation of the kinase domain. The binding of the tSH2 module to phosphorylated immunoreceptor tyrosine‐based activation motifs necessitates a conformational change, thereby relieving kinase inhibition and promoting activation. We determined the crystal structure of the isolated tSH2 module of Syk and find, in contrast to ZAP‐70, that its conformation more closely resembles that of the peptide‐bound state, rather than the autoinhibited state. Hydrogen–deuterium exchange by mass spectrometry, as well as molecular dynamics simulations, reveal that the dynamics of the tSH2 modules of Syk and ZAP‐70 differ, with most of these differences occurring in the C‐terminal SH2 domain. Our data suggest that the conformational landscapes of the tSH2 modules in Syk and ZAP‐70 have been tuned differently, such that the autoinhibited conformation of the Syk tSH2 module is less stable. This feature of Syk likely contributes to its ability to more readily escape autoinhibition when compared to ZAP‐70, consistent with tighter control of downstream signaling pathways in T cells., PDB Code(s): 7SA7
- Published
- 2021
3. Altered expression of genes related to innate antifungal immunity in the absence of galectin-3
- Author
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André Moreira Pessoni, Patrícia Kellen Martins Oliveira Brito, Gustavo H. Goldman, Caroline Patini Rezende, Thiago Aparecido da Silva, and Fausto Almeida
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Microbiology (medical) ,Antifungal ,Antifungal Agents ,animal structures ,medicine.drug_class ,Galectin 3 ,Galectins ,Immunology ,Infectious and parasitic diseases ,RC109-216 ,Adaptive Immunity ,Biology ,Microbiology ,gene knockout ,Mice ,03 medical and health sciences ,Immunity ,galectin-3 ,Gene expression ,otorhinolaryngologic diseases ,medicine ,Animals ,Gene ,Gene knockout ,030304 developmental biology ,Galectin ,0303 health sciences ,Innate immune system ,030306 microbiology ,EXPRESSÃO GÊNICA ,Immunity, Innate ,Cell biology ,stomatognathic diseases ,Infectious Diseases ,Galectin-3 ,innate immune response ,gene expression ,Parasitology ,antifungal immunity ,Research Article ,Research Paper - Abstract
Galectin-3 (Gal-3) is the most studied member of the animal galectin family, which comprises β-galactoside-binding lectins and participates in several cellular events. Its expression in cells involved in innate and adaptive immunity is related to anti- and proinflammatory functions, signaling an important role in inflammatory, infectious, and tumorigenesis processes. Mice deficient in Gal-3 exhibit important phenotypes, but it is unclear whether these phenotypes reflect an impairment of the functions of this protein. Gal-3 plays an important role in modulating the immune response to different pathogenic microorganisms. However, the role of Gal-3 in immunity to infection is still poorly understood. Therefore, we investigated the effects of Gal-3 deletion on the expression of genes involved in the innate immune response in the lungs, spleens, and brains of Gal-3 KO mice. Gene profiling expression analysis suggested that Gal-3 deletion resulted in differentially modulated expression of the genes encoding beta-glucan, mannose and chitin-responsive pattern recognition receptors, signal transduction, inflammation, and phagocytosis. Our data thus suggest the importance of Gal-3 expression in the host innate immune system.
- Published
- 2021
4. A spontaneous multifunctional hydrogel vaccine amplifies the innate immune response to launch a powerful antitumor adaptive immune response
- Author
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Shunyao Zhu, Miaomiao Zhang, Songlin Gong, Changyang Gong, Tao He, Qinjie Wu, Xinchao Li, Xiuqi Liang, and Lu Li
- Subjects
Ovalbumin ,T-Lymphocytes ,medicine.medical_treatment ,Medicine (miscellaneous) ,chemical and pharmacologic phenomena ,02 engineering and technology ,Adaptive Immunity ,Biology ,Cancer Vaccines ,Mannans ,Mice ,03 medical and health sciences ,Immune system ,Cancer immunotherapy ,Antigen ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Melanoma ,innate immunity ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Schiff Bases ,030304 developmental biology ,Inflammation ,Chitosan ,0303 health sciences ,Ncom Gel vaccine ,cancer immunotherapy ,Innate immune system ,Macrophages ,Hydrogels ,Dendritic Cells ,Immunotherapy ,021001 nanoscience & nanotechnology ,Acquired immune system ,Immunity, Innate ,adaptive immune response ,Tumor antigen ,Mice, Inbred C57BL ,spontaneous multifunctional hydrogel ,Humoral immunity ,Microscopy, Electron, Scanning ,Cancer research ,Female ,Rheology ,0210 nano-technology ,Research Paper - Abstract
Substantial progress has been made with cancer immunotherapeutic strategies in recent years, most of which mainly rely on enhancing the T cell response. However, sufficient tumor antigen information often cannot be presented to T cells, resulting in a failed effector T cell response. The innate immune system can effectively recognize tumor antigens and then initiate an adaptive immune response. Here, we developed a spontaneous multifunctional hydrogel (NOCC-CpG/OX-M, Ncom Gel) vaccine to amplify the innate immune response and harness innate immunity to launch and maintain a powerful adaptive immune response. Methods: Ncom Gel was formed by a Schiff base reaction between CpG-modified carboxymethyl chitosan (NOCC-CpG) and partially oxidized mannan (OX-M). The effects of the Ncom Gel vaccine on DCs and macrophages in vitro and antigen-specific humoral immunity and cellular immunity in vivo were studied. Furthermore, the antitumor immune response of the Ncom Gel vaccine and its effect on the tumor microenvironment were evaluated. Results: The Ncom Gel vaccine enhanced antigen presentation to T cells by facilitating DC uptake and maturation and inducing macrophages to a proinflammatory subtype, further leading to a T cell-mediated adaptive immune response. Moreover, the innate immune response could be amplified via the promotion of antigen-specific antibody production. The Ncom Gel vaccine reversed the tumor immune microenvironment to an inflamed phenotype and showed a significant antitumor response in a melanoma model. Conclusions: Our research implies the potential application of injectable hydrogels as a platform for tumor immunotherapy. The strategy also opens up a new avenue for multilayered cancer immunotherapy.
- Published
- 2021
5. The effect of repetitive exposure to intravenous anesthetic agents on the immunity in mice
- Author
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Liyun Piao, Seong-Hyop Kim, Eun-Hye Seo, Hyun-Jun Park, and Seung Hyun Lee
- Subjects
CD4-Positive T-Lymphocytes ,Male ,medicine.medical_specialty ,Midazolam ,medicine.medical_treatment ,Enzyme-Linked Immunosorbent Assay ,Adaptive Immunity ,Pharmacology ,Kidney ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Dexmedetomidine ,Mice, Inbred BALB C ,propofol ,Cluster of differentiation ,business.industry ,dexmedetomidine ,General Medicine ,Immunohistochemistry ,immunity ,Cytokine ,medicine.anatomical_structure ,Liver ,Anesthetic ,intravenous anesthetic agent ,030211 gastroenterology & hepatology ,Histopathology ,Propofol ,business ,Anesthetics, Intravenous ,Research Paper ,medicine.drug - Abstract
Introduction: This study was designed to assess the effect of repetitive exposure to intravenous anesthetic agents on the immunity in mice. Materials and Methods: The mice were divided into six groups: three intravenous anesthetic agents groups (dexmedetomidine, midazolam and propofol groups), and three corresponding control groups (CD, CM, and CP groups). The intravenous injections were administered once per day for 5 days. The immunity of mice was checked after the last intravenous injection. Histopathology and immunochemistry of liver and kidneys were evaluated. Cytokine levels in the blood was also checked. vs. evaluated with cytokine levels in the blood. Results: Cluster of differentiation (CD)4+ T cells were significantly less expressed in dexmedetomidine and propofol groups, compared with the corresponding control groups [34.08 ± 5.63% in the dexmedetomidine group vs. 59.74 ± 8.64% in the CD group, p < 0.05; 25.28 ± 7.28% in the propofol group vs. 61.12 ± 2.70% in the Cp group, p < 0.05]. Apoptosis of CD4+ T cells was increased significantly in dexmedetomidine and propofol groups, compared with the corresponding control groups. Histopathological findings of liver and kidneys did not show any specific differences of any of three intravenous anesthetic agents groups with their corresponding control groups, although immunohistochemical examination indicated significantly lower expression of Toll-like receptor-4 from liver and kidneys in dexmedetomidine and propofol groups. The cytokine levels were not different between the groups. Conclusion: Repetitive exposure to dexmedetomidine and propofol reduced the expression of CD4+ T cells but did not induce any significant liver or kidney injuries.
- Published
- 2020
6. Novel calreticulin-nanoparticle in combination with focused ultrasound induces immunogenic cell death in melanoma to enhance antitumor immunity
- Author
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Mohit Pratap Singh, P. Jack Hoopes, Jerry R. Malayer, Shitao Li, Sri Nandhini Sethuraman, Steven Fiering, Ashish Ranjan, Girish Patil, and Chandan Guha
- Subjects
0301 basic medicine ,Ultrasonic Therapy ,Population ,Melanoma, Experimental ,Clone (cell biology) ,Medicine (miscellaneous) ,CD47 Antigen ,Immunogenic Cell Death ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,calreticulin ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,Tumor-Associated Macrophages ,melanoma ,Animals ,Humans ,Medicine ,education ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,education.field_of_study ,biology ,business.industry ,nanoparticle ,Melanoma ,Cell Membrane ,medicine.disease ,Combined Modality Therapy ,Xenograft Model Antitumor Assays ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,focused ultrasound ,Cytokines ,Nanoparticles ,Immunogenic cell death ,Lymph Nodes ,business ,Calreticulin ,Spleen ,CD8 ,Research Paper - Abstract
Rationale: Some studies have shown that the local activation of immunogenic cell death (ICD) by upregulating calreticulin (CRT) expression in solid tumors can improve antitumor effects. Although a promising approach, a key current challenge in ICD tumor therapy is the absence of a clinically translatable method for reproducibly inducing the CRT expression. Herein, we report a novel calreticulin-nanoparticle (CRT-NP) that enhances ICD and synergizes with focused ultrasound (FUS) to achieve local and systemic antitumor effects. Methods: Full-length clone DNA of calreticulin was encapsulated in NPs made from DOTAP and cholesterol. Three CRT-NP intratumoral injections of 20 µg each were given 2 days apart, and FUS heating (42-45°C, ~15min) was applied sequentially 24h after each injection to induce ICD. To investigate ICD specific immune effect, the splenocytes of mice vaccinated with CRT-NP (± FUS) treated B16F10 cells were evaluated ex-vivo for TRP-2 antigen specific immunity. Additionally, the long-term protection was evaluated by re-challenging with the melanoma cells in the flank regions of tumor bearing mice. Results: CRT-NP plus FUS (CFUS) upregulated CRT expression, expanded the population of melanoma TRP-2 specific functional CD4+ and CD8+ T cells and tumor-suppressing M1 phenotype, and increased PD-1 and PD-L1 marker expression in the T cells. Therapeutically, CFUS suppressed B16 melanoma growth by >85% vs. that seen in untreated controls, and >~50% vs. CRT-NP or FUS alone, and prevented tumor growth in distal untreated sites. Conclusions: CRT-NP amplifies the FUS and ICD therapeutic outcomes against melanoma, suggesting that the proposed combinatorial methodology may be clinically translatable.
- Published
- 2020
7. Directs effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on adaptive immunogenesis
- Author
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Galina V. Seledtsova, Ekaterina M. Morozova, Natalja D. Gazatova, Victor I. Seledtsov, M. E. Meniailo, and V. V. Malashchenko
- Subjects
Lipopolysaccharides ,T-Lymphocytes ,030231 tropical medicine ,Immunology ,Adaptive Immunity ,Biology ,Lymphocyte Activation ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,Monocytes macrophages ,030212 general & internal medicine ,Cells, Cultured ,Pharmacology ,Macrophages ,Direct effects ,Granulocyte-Macrophage Colony-Stimulating Factor ,Colony-stimulating factor ,Phenotype ,Granulocyte macrophage colony-stimulating factor ,Cytokines ,Research Paper ,medicine.drug - Abstract
Background: We studied direct effects of human granulocyte-macrophage colony stimulating factor (GM-CSF) on phenotypical characteristics and cytokine-production of non-activated and activated human monocytes/macrophages (Mc/Mphs) and T cells. Methods: Purified Mc/Mphs were activated by bacterial lipopolysaccharide (LPS, 1 μg/ml) for 24 h, while T cells were activated by particles conjugated and antibodies (Abs) against human CD2, CD3, and CD28 for 48 h. Results: GM-CSF treatment (0.01–10 ng/ml) was shown to reduce percentages of CD197 (CCR7)-positive cells in non-activated Mph cultures, without affecting significantly CD14(+) (LPS co-receptor), CD16(+) (FcγRIII, low-affinity Fc-receptor), CD119(+) (interferon-gamma receptor 1), and CD124(+) (IL4 receptor α-subunit) cells. In addition, GM-CSF reduced relative numbers of CD197(+) cells, as well as CD14(+), CD16(+), and CD119(+) cells in activated Mph cultures without affecting CD124(+) cell distribution. GM-CSF at the highest dose of 10 ng/ml enhanced TNF-α and IL-6 (but not IL-1β and IL-10) production in activated Mc/Mphs. In activated T cell cultures, GM-CSF at 0.1–1.0 ng/ml augmented CD38(+) cell numbers in naïve СD45RA(+)/СD197(+) and central memory СD45RA(−)/СD197(+) cell subsets, with no effect on effector СD45RA(−)/СD197(−) and terminally differentiated effector СD45RA(+)/СD197(−) cells. GM-CSF at a low dose (0.01 ng/ml) down-regulated INF-γ production, while at a high dosage (10.0 ng/ml) up-regulated IL-2 and IL-4 production. Conclusion: In general, the results suggest that GM-CSF is able to facilitate the implication of both Mph and T cells in the adaptive immunogenesis.
- Published
- 2019
8. Alteration of Adaptive Immunity in a Colorectal Peritoneal Carcinomatosis Model
- Author
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Hongming Miao, Xia Kang, Wei Xiang, Rongchen Shi, Lili Zhang, Jinping Wang, and Fengtian He
- Subjects
0301 basic medicine ,Colorectal cancer ,business.industry ,peritoneal carcinomatosis ,Intraperitoneal inoculation ,colorectal cancer ,Spleen ,adaptive immunity ,medicine.disease ,Acquired immune system ,Colorectal cancer cell line ,Peritoneal carcinomatosis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,business ,Visceral fat ,CD8 ,Research Paper - Abstract
Colorectal cancer (CRC) usually gives rise to transcoelomic spread and ultimately causes peritoneal carcinomatosis (PC). However, mechanism studies, especially the immunological basis of colorectal PC, are rarely revealed due to lack of a suitable PC model. Here we selected a mouse colorectal cancer cell line MC-38 for intraperitoneal inoculation in the C57BL/6 mice to mimic the development of colorectal PC. We demonstrated that the injected CRC cells preferentially and rapidly migrated and colonized in the visceral fat tissues, but not in other visceral organs. With flow cytometric analysis, we found the proportions of spleen T cells and B cells were not affected by PC progression, while the ratios of blood CD4+ and CD8+ T cells were largely influenced. Especially, the quantity or activity of CD4+ and CD8+ T cells in visceral fats were intimately regulated by PC development. Taken together, we successfully constructed a colorectal PC model in immune-competent mice and revealed the alteration of adaptive immunity in PC development. Our study might potentiate the research and therapy strategies of colorectal PC.
- Published
- 2019
9. RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression
- Author
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Hai-Jiao Yang, Jian Cui, Zhu-Chun Li, Juan Tang, Ming Zheng, Zhen-Yu Liu, Yi-Ming Li, Zhi-Nan Chen, Jian-Li Jiang, Xin-Yu Fan, Jing-Min Yu, and Jian-Chao Wang
- Subjects
0301 basic medicine ,Myeloid ,Carcinogenesis ,Colon ,MAP Kinase Signaling System ,Chemokine CXCL1 ,T-Lymphocytes ,Necroptosis ,T cell ,IBD ,Gene Expression ,necroptosis ,Medicine (miscellaneous) ,Apoptosis ,colorectal cancer ,Adaptive Immunity ,medicine.disease_cause ,Gene Knockout Techniques ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Animals ,Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cell Proliferation ,ulcerative colitis ,Anthracenes ,Tumor microenvironment ,business.industry ,Epithelial Cells ,Colitis ,Mice, Inbred C57BL ,CXCL1 ,030104 developmental biology ,medicine.anatomical_structure ,Tumor progression ,Receptor-Interacting Protein Serine-Threonine Kinases ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Cancer research ,Colorectal Neoplasms ,business ,Signal Transduction ,Research Paper ,RIP3 - Abstract
Rationale: Necroptosis is a programmed form of non-apoptotic cell death that requires receptor-interacting protein 3 (RIP3). RIP3 has been shown to be relevant in multiple tumor types and has differential impact on tumor progression. We investigated whether RIP3 is involved in the progression of colitis-associated cancer (CAC) in mice. Methods: Tissues from colorectal cancer patients were examined for RIP3 expression. CAC was induced using azoxymethane (AOM) injection followed by dextran sodium sulfate (DSS) treatment in RIP3-deficient or wild-type mice. Colon tissues were collected and analyzed by Western blotting and gene expression profile analyses. Immune cell infiltration and CXCL1 expression were examined by flow cytometry and Real-time PCR, respectively. Results: RIP3 expression was upregulated in mouse CAC and human colon cancer. RIP3-deficient mice showed significantly attenuated colitis-associated tumorigenesis. Bone marrow transplantation experiments suggested that RIP3's function in hematopoietic cells primarily contributes to the phenotype. RIP3 supported epithelial proliferation and tumor growth via JNK signaling but had no effect on apoptosis. RIP3 deletion increased T cell accumulation and reduced infiltration by immunosuppressive subsets of myeloid cells during acute colitis and CAC. The immune-suppressive tumor microenvironment was dependent on RIP3-induced expression of the chemokine attractant CXCL1, and administration of recombinant CXCL1 during CAC restored tumorigenesis in Rip3-/- mice. Conclusion: Our results reveal an unexpected function of RIP3 in enhancing the proliferation of premalignant intestinal epithelial cells (IECs) and promoting myeloid cell-induced adaptive immune suppression. These two distinct mechanisms of RIP3-induced JNK and CXCL1 signalling contribute to CAC progression.
- Published
- 2019
10. Correlation Between Stem and Progenitor Cells Number and Immune Response in Patients After Allogeneic Kidney Transplant
- Author
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Maciej Kotowski, Karolina Kędzierska-Kapuza, Marek Ostrowski, K. Tejchman, Edyta Paczkowska, Anna Sobuś, Jerzy Sieńko, Ewa Pilichowska, and Jarosław Piątek
- Subjects
Adult ,Male ,T-Lymphocytes ,medicine.medical_treatment ,CD34 ,Adaptive Immunity ,CD38 ,T-Lymphocytes, Regulatory ,Young Adult ,Immune system ,Humans ,Medicine ,Renal Insufficiency, Chronic ,Progenitor cell ,Kidney transplantation ,Aged ,Original Paper ,B-Lymphocytes ,Transplantation ,business.industry ,Stem Cells ,Immunosuppression ,General Medicine ,Middle Aged ,medicine.disease ,Kidney Transplantation ,Haematopoiesis ,Immunology ,Female ,Stem cell ,business - Abstract
BACKGROUND Stem and progenitor cells are of great interest in all medical procedures involving tissue regeneration. There is a consensus that the use of stem cells after solid organ transplantation may play a role in tissue repair and in immunosuppression. The aim of this study was to determine possible relations between stem cell count and the immune response in a group of patients after kidney transplantation. MATERIAL AND METHODS The study was conducted on a group of 100 patients who underwent kidney transplantation. The following phenotypic markers of the studied cell subpopulations were adopted: Treg cells (CD3+CD4+CD25high), circulating hematopoietic cells (CD34+CD133+CD45+CD38-), and non-hematopoietic cells (Lin-CXCR4+CD133-CD45-). Cell subpopulations were assessed using LSRII flow cytometer (BD Biosciences, San Jose, CA, USA). RESULTS Positive correlation was observed between non-hematopoietic stem cells percentage and recipient's platelets count (P=0.04). Moreover, a higher percentage of non-hematopoietic cells was accompanied by lower numbers of B lymphocytes (P=0.03) and Treg cells (P=0.02). CONCLUSIONS Our study revealed significant associations between the intensity of ongoing immune response processes and tissue damage, and the release of stem and progenitor cells into circulation. These findings suggest their role in the stimulation of protective processes in terms of graft regeneration.
- Published
- 2018
11. Identification of an immune checkpoint gene signature that accurately predicts prognosis and immunotherapy response in endometrial carcinoma
- Author
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Jiayan Chen, Xin Zhang, Chun-Li Dong, Xiuying Xie, Xiaocui Gao, and Shao-Wen Li
- Subjects
Aging ,Epithelial-Mesenchymal Transition ,DNA Repair ,medicine.medical_treatment ,immune checkpoint genes ,BTLA ,endometrial carcinoma ,Biology ,Gene mutation ,Adaptive Immunity ,Antigens, Neoplasm ,Databases, Genetic ,Carcinoma ,medicine ,Humans ,Survival analysis ,Disease Resistance ,TNFRSF18 ,Gene Expression Profiling ,biomarkers ,Cell Biology ,Immunotherapy ,Gene signature ,medicine.disease ,Immune Checkpoint Proteins ,Prognosis ,Survival Analysis ,Immune checkpoint ,Endometrial Neoplasms ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Mutation ,Cancer research ,Female ,immunotherapy ,Research Paper - Abstract
In this study, we performed a bioinformatics analysis to identify immune checkpoint genes (ICGs) associated with prognosis and the immunotherapeutic response in endometrial carcinoma (EC) patients. We classified 47 ICGs into high, medium, and low expression groups by performing RNA-sequencing data analysis of EC patient samples from The Cancer Genome Atlas (n = 521) and GSE77688 (n = 88) datasets. Univariate Cox regression analysis showed that seven ICGs (VTCN1, TNFRSF18, TNFRSF14, TNFRSF4, CD40LG, TMIGD2, and BTLA) were associated with prognosis in EC patients. Spearman correlation analysis showed that prognosis-related ICGs correlated positively with immunotherapy response factors, including tumor mutation burden (TMB), mismatch repair gene mutations, neoantigens, clinical stages, and adaptive immune resistance pathway genes. We identified a prognostic gene signature of four ICGs (IDO1, CD274, CTLA4, and TNFRSF14) that accurately predicted survival outcomes of EC patients. TIMER database and Kaplan-Meier survival analysis showed that OS among EC patients with low TNFRSF14 expression was significantly shorter than among those with high TNFRSF14 expression. In vitro experiments showed that TNFRSF14 silencing increased the migration and invasiveness of EC cells by promoting epithelial-mesenchymal transition (EMT). Collectively, these findings reveal an immune checkpoint gene signature that accurately predicts survival outcomes and immunotherapeutic responses in EC patients.
- Published
- 2021
12. B and T Lymphocyte Densities Remain Stable With Age in Human Cortex
- Author
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Marion S. Buckwalter, Claudia K. Suemoto, Roberta Diehl Rodriguez, Edward D. Plowey, Kacey Berry, Daniela Souza Farias-Itao, Lea T. Grinberg, and Julie A. Schneider
- Subjects
0301 basic medicine ,Adult ,Male ,Aging ,T-Lymphocytes ,brain ,1.1 Normal biological development and functioning ,Inflammation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Cell Count ,Pilot Projects ,Biology ,Adaptive Immunity ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Clinical Research ,Underpinning research ,Cortex (anatomy) ,medicine ,80 and over ,Humans ,human ,Aged ,Aged, 80 and over ,Cerebral Cortex ,Glial activation ,Original Paper ,B-Lymphocytes ,General Neuroscience ,Inflammatory and immune system ,Neurosciences ,T lymphocyte ,adaptive immunity ,Middle Aged ,Acquired immune system ,Brain Disorders ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Neurological ,Female ,Neurology (clinical) ,medicine.symptom ,immune ,030217 neurology & neurosurgery ,Function (biology) ,RC321-571 - Abstract
One hallmark of human aging is increased brain inflammation represented by glial activation. With age, there is also diminished function of the adaptive immune system, and modest decreases in circulating B- and T-lymphocytes. Lymphocytes traffic through the human brain and reside there in small numbers, but it is unknown how this changes with age. Thus we investigated whether B- and T-lymphocyte numbers change with age in the normal human brain. We examined 16 human subjects in a pilot study and then 40 human subjects from a single brain bank, ranging in age from 44–96 years old, using rigorous criteria for defining neuropathological changes due to age alone. We immunostained post-mortem cortical tissue for B- and T-lymphocytes using antibodies to CD20 and CD3, respectively. We quantified cell density and made a qualitative assessment of cell location in cortical brain sections, and reviewed prior studies. We report that density and location of both B- and T-lymphocytes do not change with age in the normal human cortex. Solitary B-lymphocytes were found equally in intravascular, perivascular, and parenchymal locations, while T-lymphocytes appeared primarily in perivascular clusters. Thus, any change in number or location of lymphocytes in an aging brain may indicate disease rather than normal aging.
- Published
- 2021
13. Differences in C-type lectin receptors and their adaptor molecules in the peritoneal fluid of patients with endometriosis and gynecologic cancers
- Author
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Yong Sung Won, Dong Choon Park, Seung Geun Yeo, and Sang Hoon Kim
- Subjects
Adult ,Genital Neoplasms, Female ,Endometriosis ,Enzyme-Linked Immunosorbent Assay ,Adaptive Immunity ,Immunoglobulin secretion ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,C-type lectin ,Immunoglobulin ,medicine ,Ascitic Fluid ,Humans ,Lectins, C-Type ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Gynecologic cancer ,Receptor ,B cell ,Galectin ,B-Lymphocytes ,030219 obstetrics & reproductive medicine ,business.industry ,Peritoneal fluid ,General Medicine ,Middle Aged ,medicine.disease ,Immunoglobulin A ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Immunoglobulin M ,Immunoglobulin G ,030220 oncology & carcinogenesis ,Cancer research ,Female ,C-type lectin receptors ,business ,Research Paper - Abstract
Endometriosis, although not malignant, has clinically demonstrated properties of invasiveness and metastasis. The pathogenesis of endometriosis, however, has not yet been elucidated. The immunological differences between endometriosis and malignant gynecologic tumors were analyzed by assessing C-type lectin receptors, which are associated with innate immunity, and immunoglobulin secretion, which is associated with B cell adaptive immunity, in the peritoneal fluid of these patients. Peritoneal fluid samples were obtained from 42 patients with benign masses (control group), 38 with endometriosis, and 43 with gynecologic (ovarian, uterine, and cervical) cancers. The levels of expression in these samples of mRNAs encoding the C-type lectin receptors Dectin-1, MR1, MR2, DC-SIGN, Syk, Card 9, Bcl 10, Malt 1, src, Dec 205, Galectin, Tim 3, Trem 1, and DAP 12, were measured by real-time reverse transcription polymerase chain reaction, and the concentrations of IgG, IgA and IgM were measured by enzyme-linked immunosorbent assays (ELISA). Findings in the three groups were compared. The level of galectin mRNA was significantly lower, and the levels of MR2 and DAP 12 mRNAs significantly higher, in the endometriosis than in the control group (p0.05). C-type lectin receptors and immunoglobulins act cooperatively and are closely associated in the pathogenesis of endometriosis. The decreased expression of galectin mRNA in the peritoneal fluid of the endometriosis group suggests that endometriosis and gynecologic cancers have similar immunologic characteristics.
- Published
- 2018
14. CXCL14 Acts as a Specific Carrier of CpG DNA into Dendritic Cells and Activates Toll-like Receptor 9-mediated Adaptive Immunity
- Author
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Rena Takahashi, Naoto Naruse, Rina Iwase, Kohei Tsuji, Akira Shigenaga, Hideko Nuriya, Takahiko Hara, Akira Otaka, and Kosuke Tanegashima
- Subjects
0301 basic medicine ,Endosome ,CpG Oligodeoxynucleotide ,lcsh:Medicine ,chemical and pharmacologic phenomena ,Endosomes ,Adaptive Immunity ,General Biochemistry, Genetics and Molecular Biology ,TLR9 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Animals ,CXCL14 ,lcsh:R5-920 ,CpG DNA ,Interleukin-12 Subunit p40 ,Chemistry ,lcsh:R ,hemic and immune systems ,Dendritic Cells ,General Medicine ,Acquired immune system ,Toll-Like Receptor 9 ,Immunosurveillance ,030104 developmental biology ,Gene Expression Regulation ,Oligodeoxyribonucleotides ,CpG site ,Cancer research ,lcsh:Medicine (General) ,Lysosomes ,Chemokines, CXC ,Research Paper ,030215 immunology - Abstract
CXCL14 is a primordial chemokine that plays multiple roles in tumor suppression, autoimmune arthritis, and obesity-associated insulin resistance. However, the underlying molecular mechanisms are unclear. Here, we show that CXCL14 transports various types of CpG oligodeoxynucleotide (ODN) into the endosomes and lysosomes of bone marrow-derived dendritic cells (DCs), thereby activating Toll-like receptor 9 (TLR9). A combination of CpG ODN (ODN2395) plus CXCL14 induced robust production of IL-12 p40 by wild-type, but not Tlr9-knockout, DCs. Consistent with this, ODN2395-mediated activation of DCs was significantly attenuated in Cxcl14-knockout mice. CXCL14 bound CpG ODN with high affinity at pH 7.5, but not at pH 6.0, thereby enabling efficient delivery of CpG ODN to TLR9 in the endosome/lysosome. Furthermore, the CXCL14-CpG ODN complex specifically bound to high affinity CXCL14 receptors on DCs. Thus, CXCL14 serves as a specific carrier of CpG DNA to sensitize TLR9-mediated immunosurveillance., Highlights • CXCL14 specifically binds CpG DNA with high affinity. • CXCL14/CpG DNA complex is efficiently transported into dendritic cells. • CXCL14/CpG DNA induces cytokine production via Toll-like receptor 9. We discovered that CXCL14 specifically binds CpG DNAs with high affinity and transports them into the endosomes and lysosomes of dendritic cells (DCs). Consequently, Toll-like receptor 9 (Tlr9) in DCs was activated, thereby leading to robust production of IL-12 p40 and IL-6. These activities of CXCL14 were not observed in Tlr9-deficient DCs. Moreover, CpG DNA (ODN2395)-mediated activation of DCs was significantly attenuated in Cxcl14-knockout mice. Therefore, CXCL14 plays an important role in the Tlr9-mediated immunosurveillance against pathogens and cancers. From the clinical point of view, CXCL14/CpG DNA could be useful as a new type of vaccine adjuvant.
- Published
- 2017
15. Global importation and population risk factors for measles in New Zealand: a case study for highly immunized populations
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Nigel P. French, David T. S. Hayman, Tim E. Carpenter, Jonathan C. Marshall, T. Kiedrzynski, and Mick G. Roberts
- Subjects
Adult ,Male ,Adolescent ,Epidemiology ,Population ,Adaptive Immunity ,Measles ,Herd immunity ,Young Adult ,03 medical and health sciences ,Rubella vaccine ,0302 clinical medicine ,Risk Factors ,030225 pediatrics ,Environmental health ,medicine ,Humans ,030212 general & internal medicine ,Risk factor ,Child ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,Vaccination ,Infant, Newborn ,Infant ,Middle Aged ,medicine.disease ,Original Papers ,Infectious Diseases ,Geography ,Child, Preschool ,Immunology ,Regression Analysis ,Pacific islanders ,Female ,Population Risk ,New Zealand ,medicine.drug - Abstract
SUMMARYAs endemic measles is eliminated through immunization, countries must determine the risk factors for the importation of measles into highly immunized populations to target control measures. Despite eliminating endemic measles, New Zealand suffers from outbreaks after introductions from abroad, enabling us to use it as a model for measles introduction risk. We used a generalized linear model to analyze risk factors for 1137 measles cases from 2007 to June 2014, provide estimates of national immunity levels, and model measles importation risk. People of European ethnicity made up the majority of measles cases. Age is a positive risk factor, particularly 0–2-year-olds and 5–17-year-old Europeans, along with increased wealth. Pacific islanders were also at greater risk, but due to 0–2-year-old cases. Despite recent high measles, mumps, and rubella vaccine immunization coverage, overall population immunity against measles remains ~90% and is lower in people born between 1982 and 2005. Greatest measles importation risk is during December, and countries predicted to be sources have historical connections and highest travel rates (Australia and UK), followed by Asian countries with high travel rates and higher measles incidences. Our results suggest measles importation due to travel is seeding measles outbreaks, and immunization levels are insufficient to continue to prevent outbreaks because of heterogeneous immunity in the population, leaving particular age groups at risk.
- Published
- 2017
16. Mathematical modeling based on ordinary differential equations: A promising approach to vaccinology
- Author
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Rodrigo Weber dos Santos, Guilherme Côrtes Fernandes, C. R. B. Bonin, and Marcelo Lobosco
- Subjects
0301 basic medicine ,Pharmacology ,Yellow Fever Vaccine ,Immunology ,Yellow fever vaccine ,Computational biology ,Adaptive Immunity ,Models, Theoretical ,Biology ,Acquired immune system ,Research Papers ,01 natural sciences ,Virology ,03 medical and health sciences ,030104 developmental biology ,Computational immunology ,Ordinary differential equation ,Yellow Fever ,0103 physical sciences ,medicine ,Animals ,Humans ,Immunology and Allergy ,010306 general physics ,medicine.drug - Abstract
New contributions that aim to accelerate the development or to improve the efficacy and safety of vaccines arise from many different areas of research and technology. One of these areas is computational science, which traditionally participates in the initial steps, such as the pre-screening of active substances that have the potential to become a vaccine antigen. In this work, we present another promising way to use computational science in vaccinology: mathematical and computational models of important cell and protein dynamics of the immune system. A system of Ordinary Differential Equations represents different immune system populations, such as B cells and T cells, antigen presenting cells and antibodies. In this way, it is possible to simulate, in silico, the immune response to vaccines under development or under study. Distinct scenarios can be simulated by varying parameters of the mathematical model. As a proof of concept, we developed a model of the immune response to vaccination against the yellow fever. Our simulations have shown consistent results when compared with experimental data available in the literature. The model is generic enough to represent the action of other diseases or vaccines in the human immune system, such as dengue and Zika virus.
- Published
- 2016
17. Thymopentin ameliorates dextran sulfate sodium-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes
- Author
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Chongxiu Yue, Fei Quan, Di Qin, Lutz Birnbaumer, Kun Hao, Yue Wang, Yuan Lu, Xiaoxuan Liu, Yong Yang, Xianjing Li, Hongbao Yang, Zixuan Zhang, Qiuhua Cao, Yanting Lin, Xinghua Gao, and Yanling Zhan
- Subjects
0301 basic medicine ,Male ,lymphocytes ,DSS-INDUCED COLITIS ,medicine.medical_treatment ,Medicine (miscellaneous) ,Adaptive Immunity ,LYMPHOCYTES ,T-Lymphocytes, Regulatory ,Interleukin 22 ,purl.org/becyt/ford/1 [https] ,Feces ,Mice ,0302 clinical medicine ,RAR-related orphan receptor gamma ,IL-22 ,Intestinal Mucosa ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,DSS-induced colitis ,LINFOCITOS ,GUT MICROBIOTA ,TIMOPENTINA ,Dextran Sulfate ,Ulcerative colitis ,3. Good health ,Cytokine ,030220 oncology & carcinogenesis ,CIENCIAS NATURALES Y EXACTAS ,medicine.drug ,COLITIS ,Research Paper ,Colon ,thymopentin ,Peripheral blood mononuclear cell ,Ciencias Biológicas ,THYMOPENTIN ,03 medical and health sciences ,Immune system ,Biología Celular, Microbiología ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Thymopentin ,Colitis ,purl.org/becyt/ford/1.6 [https] ,gut microbiota ,business.industry ,Interleukins ,medicine.disease ,HCT116 Cells ,Immunity, Innate ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,13. Climate action ,Immunology ,TRATAMIENTO MEDICO ,Colitis, Ulcerative ,business ,Spleen - Abstract
Fil: Cao, Qiuhua. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Cao, Qiuhua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Gao, Xinghua. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Gao, Xinghua. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Lin, Yanting. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Lin, Yanting. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Yue, Chongxiu. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yue, Chongxiu. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Wang, Yue. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Wang, Yue. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Quan, Fei. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Quan, Fei. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Zhang, Zixuan. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Zhang, Zixuan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Liu, Xiaoxuan. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Liu, Xiaoxuan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Lu, Yuan.China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Lu, Yuan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Zhan, Yanling. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Zhan, Yanling. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Yang, Hongbao. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yang, Hongbao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Li, Xianjing. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Li, Xianjing. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Fil: Qin, Di. Nanjing sport institute. School of Sports and Health; China Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Laboratory of Neurobiology; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Hao, Kun. China Pharmaceutical University. Key Lab of Drug Metabolism & Pharmacokinetics; China Fil: Yang, Yong. China Pharmaceutical University. State Key Laboratory of Natural Medicines; China Fil: Yang, Yong. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; China Background: Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disease, notoriously challenging to treat. Previous studies have found a positive correlation between thymic atrophy and colitis severity. It was, therefore, worthwhile to investigate the effect of thymopentin (TP5), a synthetic pentapeptide corresponding to the active domain of the thymopoietin, on colitis. Methods: Dextran sulfate sodium (DSS)-induced colitis mice were treated with TP5 by subcutaneous injection. Body weight, colon length, colon weight, immune organ index, disease activity index (DAI) score, and the peripheral blood profile were examined. The immune cells of the spleen and colon were analyzed by flow cytometry. Histology was performed on isolated colon tissues for cytokine analysis. Bacterial DNA was extracted from mouse colonic feces to assess the intestinal microbiota. Intestinal lamina propria mononuclear cells (LPMCs), HCT116, CT26, and splenocytes were cultured and treated with TP5. Results: TP5 treatment increased the body weight and colon length, decreased the DAI score, and restored colon architecture of colitic mice. TP5 also decreased the infiltration of immune cells and expression levels of pro-inflammatory cytokines such as IL-6. Importantly, the damaged thymus and compromised lymphocytes in peripheral blood were significantly restored by TP5. Also, the production of IL-22, both in innate and adaptive lymphoid cells, was triggered by TP5. Given the critical role of IL-22 in mucosal host defense, we tested the effect of TP5 on mucus barrier and gut microbiota and found that the number of goblet cells and the level of Mucin-2 expression were restored, and the composition of the gut microbiome was normalized after TP5 treatment. The critical role of IL-22 in the protective effect of TP5 on colitis was further confirmed by administering the anti-IL-22 antibody (αIL-22), which completely abolished the effect of TP5. Furthermore, TP5 significantly increased the expression level of retinoic acid receptor-related orphan receptor γ (RORγt), a transcription factor for IL-22. Consistent with this, RORγt inhibitor abrogated the upregulation of IL-22 induced by TP5. Conclusion: TP5 exerts a protective effect on DSS-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes. This study delineates TP5 as an immunomodulator that may be a potential drug for the treatment of UC.
- Published
- 2019
18. Role of the immune system in the peritoneal tumor spread of high grade serous ovarian cancer
- Author
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C. Grimm, Dietmar Pils, Reinhard Horvat, Katharina Auer, Samuel M. Meier, Klaus G. Schmetterer, Anna Bachmayr-Heyda, Christopher Gerner, Nyamdelger Sukhbaatar, and Stefanie Aust
- Subjects
epithelial ovarian cancer ,0301 basic medicine ,Pathology ,Lymphocyte ,Cell Separation ,Adaptive Immunity ,T-Lymphocytes, Regulatory ,Monocytes ,0302 clinical medicine ,PD-1 ,Ascites ,Tumor Microenvironment ,Medicine ,Peritoneal Neoplasms ,Immunoassay ,Ovarian Neoplasms ,next generation sequencing ,B-Lymphocytes ,Immunohistochemistry ,humanities ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,medicine.symptom ,Research Paper ,medicine.medical_specialty ,Down-Regulation ,Inflammation ,03 medical and health sciences ,Immune system ,Antigens, Neoplasm ,Humans ,Metabolomics ,peritoneal tumor spread ,Innate immune system ,Sequence Analysis, RNA ,business.industry ,Macrophages ,flow cytometry ,Monocyte ,Cancer ,medicine.disease ,Immunity, Innate ,030104 developmental biology ,business - Abstract
// Katharina Auer 1 , Anna Bachmayr-Heyda 1 , Nyamdelger Sukhbaatar 1 , Stefanie Aust 1 , Klaus G. Schmetterer 2 , Samuel M. Meier 3 , Christopher Gerner 3 , Christoph Grimm 1 , Reinhard Horvat 4 , Dietmar Pils 1 1 Department of Obstetrics and Gynecology, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria 2 Department for Laboratory Medicine, Medical University of Vienna, Vienna, Austria 3 Department of Analytical Chemistry, University of Vienna, Vienna, Austria 4 Department of Pathology, Medical University of Vienna, Vienna, Austria Correspondence to: Dietmar Pils, email: dietmar.pils@univie.ac.at Keywords: epithelial ovarian cancer, peritoneal tumor spread, flow cytometry, PD-1, next generation sequencing Received: May 05, 2016 Accepted: July 14, 2016 Published: August 03, 2016 ABSTRACT The immune system plays a critical role in cancer progression and overall survival. Still, it is unclear if differences in the immune response are associated with different patterns of tumor spread apparent in high grade serous ovarian cancer patients and previously described by us. In this study we aimed to assess the role of the immune system in miliary (widespread, millet-sized lesions) and non-miliary (bigger, exophytically growing implants) tumor spread. To achieve this we comprehensively analyzed tumor tissues, blood, and ascites from 41 patients using immunofluorescence, flow cytometry, RNA sequencing, multiplexed immunoassays, and immunohistochemistry. Results showed that inflammation markers were systemically higher in miliary. In contrast, in non-miliary lymphocyte and monocyte/macrophage infiltration into the ascites was higher as well as the levels of PD-1 expression in tumor associated cytotoxic T-lymphocytes and PD-L1 expression in tumor cells. Furthermore, in ascites of miliary patients more epithelial tumor cells were present compared to non-miliary, possibly due to the active down-regulation of anti-tumor responses by B-cells and regulatory T-cells. Summarizing, adaptive immune responses prevailed in patients with non-miliary spread, whereas in patients with miliary spread a higher involvement of the innate immune system was apparent while adaptive responses were counteracted by immune suppressive cells and factors.
- Published
- 2016
19. Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity
- Author
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Dong Park, Ronit Mazor, Ira Pastan, Laiman Xiang, Jingli Zhang, Selamawit Addissie, Masanori Onda, and Raffit Hassan
- Subjects
Mesothelioma ,0301 basic medicine ,Lung Neoplasms ,pancreatic cancer ,Immunoglobulin Variable Region ,Epitopes, T-Lymphocyte ,immunogenicity ,Adaptive Immunity ,Protein Engineering ,Epitope ,Mice ,0302 clinical medicine ,Immunotoxin ,Medicine ,Cytotoxic T cell ,Molecular Targeted Therapy ,epitope ,biology ,Immunotoxins ,Immunogenicity ,Antibodies, Monoclonal ,T-Lymphocytes, Helper-Inducer ,Oncology ,Mesothelin ,030220 oncology & carcinogenesis ,Epitopes, B-Lymphocyte ,Female ,Immunotherapy ,Antigenicity ,Recombinant Fusion Proteins ,Bacterial Toxins ,rational design ,Exotoxins ,Mice, Nude ,GPI-Linked Proteins ,03 medical and health sciences ,Cell Line, Tumor ,Pancreatic cancer ,Animals ,Humans ,business.industry ,Mesothelioma, Malignant ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Mutation ,Immunology ,Cancer research ,biology.protein ,business ,Priority Research Paper - Abstract
// Ronit Mazor 1 , Masanori Onda 1 , Dong Park 1,3 , Selamawit Addissie 1 , Laiman Xiang 1,* , Jingli Zhang 2 , Raffit Hassan 2 and Ira Pastan 1 1 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA 2 Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA 3 New Business Development Department, Medytox Inc., Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea * Retired Correspondence to: Ira Pastan, email: // Keywords : epitope, immunogenicity, rational design, mesothelioma, pancreatic cancer Received : March 22, 2016 Accepted : April 22, 2016 Published : May 04, 2016 Abstract Recombinant immunotoxins (RITs) are genetically engineered proteins being developed to treat cancer. They are composed of an Fv that targets a cancer antigen and a portion of a protein toxin. Their clinical success is limited by their immunogenicity. Our goal is to produce a new RIT that targets mesothelin and is non-immunogenic by combining mutations that decrease B- and T-cell epitopes. Starting with an immunotoxin that has B-cell epitopes suppressed, we added mutations step-wise that suppress T-cell epitopes. The final protein (LMB-T14) has greatly reduced antigenicity as assessed by binding to human anti-sera and a greatly decreased ability to activate helper T-cells evaluated in a T-cell activation assay. It is very cytotoxic to mesothelioma cells from patients , and to cancer cell lines. LMB-T14 produces complete remissions of a mesothelin expressing cancer (A431/H9) xenograft. The approach used here can be used to de-immunize other therapeutic foreign proteins.
- Published
- 2016
20. Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice
- Author
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Venugopal Reddy Venna, Rodney M. Ritzel, Kendra Maas, Joshua Crapser, Anita Patel, Anjali Chauhan, Rajkumar Verma, Edward C. Koellhoffer, Joerg Graf, Fudong Liu, Austin Ricker, and Louise D. McCullough
- Subjects
0301 basic medicine ,Aging ,middle cerebral artery occlusion ,Inflammation ,Adaptive Immunity ,Biology ,Permeability ,Brain Ischemia ,Sepsis ,Brain ischemia ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Gastric mucosa ,medicine ,Animals ,Risk factor ,Stroke ,Cell Biology ,Hypothermia ,medicine.disease ,Acquired immune system ,infection ,Immunity, Innate ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,inflammation ,Gastric Mucosa ,Bacterial Translocation ,030220 oncology & carcinogenesis ,Immunology ,medicine.symptom ,experimental stroke ,Research Paper - Abstract
Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of gut-derived bacteria following stroke. Furthermore, sickness parameters and components of innate and adaptive immunity were examined. We found that while stroke induced gut permeability and bacterial translocation in both young and aged mice, only young mice were able to resolve infection. Bacterial species seeding peripheral organs also differed between young (Escherichia) and aged (Enterobacter) mice. Consequently, aged mice developed a septic response marked by persistent and exacerbated hypothermia, weight loss, and immune dysfunction compared to young mice following stroke.
- Published
- 2016
21. Immunoglobulin G-dependent enhancement of the infection with Coxsackievirus B4 in a murine system
- Author
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Didier Hober, Mehdi A. Benkahla, Leila Aguech-Oueslati, Hela Jaïdane, Firas Elmastour, Mahjoub Aouni, Famara Sane, and Jawhar Gharbi
- Subjects
0301 basic medicine ,Microbiology (medical) ,030106 microbiology ,Immunology ,Spleen ,Adaptive Immunity ,Microbiology ,Virus ,Immunoglobulin G ,03 medical and health sciences ,Immune system ,In vivo ,Enterovirus Infections ,medicine ,Splenocyte ,Humans ,Antibody-dependent enhancement ,biology ,Virology ,Titer ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,biology.protein ,Parasitology ,Research Paper - Abstract
It was demonstrated that specific IgG can enhance the infection with CV-B4, in vitro, in the human system. This enhancement could be involved in the pathophysiology of CV-B4 induced diseases. To investigate further the role of enhancing IgG in the infection with CV-B4 E2 in vivo, animal models are needed. Therefore, it was decided to assess whether inoculation of CV-B4 E2 to mice results in the appearance of IgG able to enhance the infection with this virus. Swiss albino mice were inoculated with CV-B4 E2 intraperitoneally. Serum samples were obtained from tail vein blood collected from day 0 to day 80 p.i. IgG were isolated by Protein G affinity chromatography. Seroneutralisation assays were carried out. In total murine spleen cells cultures inoculated with CV-B4 E2 mixed with various dilutions of serum or IgG samples, the enhancing activity was assayed through i) the antiviral activity titer of supernatants ii) the detection of intracellular viral RNA by RT-PCR iii) the level of infectious particles in supernatants. In most serum samples (76/105), neutralizing and enhancing activities were detected peaking between days 14 and 30 p.i and were higher in sera from mice inoculated with 2.10(6) TCID50 units than with lower doses. The enhancing activity was due to the IgG-enriched fraction of serum from CV-B4 E2 infected animals but not from control animals. These data show that IgG from immune mice can enhance the infection of splenocytes with CV-B4 E2 in vitro and open the way to explore whether such an enhancing activity can play a role in vivo.
- Published
- 2016
22. The Toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism
- Author
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Hans E. Grossniklaus, Craig M. Brackett, Vanessa M. Morales-Tirado, Edmund K. Waller, Qing Zhang, Wayne Harris, Lyudmila G. Burdelya, Matthew W. Wilson, Camille A Benjamin, Zezhong Li, Andrei V. Gudkov, and Hua Yang
- Subjects
Uveal Neoplasms ,0301 basic medicine ,Agonist ,medicine.drug_class ,medicine.medical_treatment ,Ocular Melanoma ,Melanoma, Experimental ,Antineoplastic Agents ,Adaptive Immunity ,entolimod ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Cytotoxic T cell ,Melanoma ,TLR5 ,business.industry ,Liver Neoplasms ,Transcription Factor RelA ,Immunotherapy ,medicine.disease ,Acquired immune system ,Immunity, Innate ,3. Good health ,Killer Cells, Natural ,Mice, Inbred C57BL ,Disease Models, Animal ,Toll-Like Receptor 5 ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Hepatocytes ,Cancer research ,uveal melanoma ,Peptides ,business ,liver metastases ,Research Paper ,Entolimod - Abstract
Uveal melanoma (UM) is the most common primary cancer of the eye in adults and progresses to metastatic disease predominantly of the liver in ∼50% of patients. In these cases, life expectancy averages just 9 months due to the lack of effective treatment options. The Toll-like receptor 5 (TLR5) agonist entolimod (former name CBLB502) rapidly activates TLR5-NF-κB signaling in hepatocytes and suppresses growth of both TLR5-expressing and non-expressing tumors in the liver through mobilization and activation of innate and adaptive immune mechanisms. The goal of this study was to explore the potential of entolimod as an immunotherapeutic agent against hepatic metastasis of UM using the TLR5-positive B16LS9 mouse model of ocular melanoma. Mice were given seven subcutaneous injections of vehicle or entolimod given 72 h apart started one day before, on the same day or three days after intraocular injection of B16LS9 cells. All tested regimens of entolimod treatment resulted in significantly reduced B16LS9 metastasis to the liver. Entolimod induced mobilization of natural killer (NK) cells to the liver and stimulated their maturation, differentiation and activation. Antibody-mediated depletion of NK cells from mice abrogated entolimod's antimetastatic activity in the liver and eliminated the entolimod-elicited in vitro cytotoxic activity of hepatic lymphocytes against B16LS9 cells. These results provide pre-clinical evidence of entolimod's efficacy against hepatometastasis of UM and support its further development as an anticancer immunotherapeutic drug.
- Published
- 2015
23. Bioinformatic evidence of widespread priming in type I and II CRISPR-Cas systems
- Author
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Simon A. Jackson, Raymond H.J. Staals, Peter C. Fineran, Chris M. Brown, Thomas J. Nicholson, and Bradley I. Croft
- Subjects
Prophages ,Priming (immunology) ,Computational biology ,adaptation ,Genome, Viral ,Biology ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,Plasmid ,Microbiologie ,CRISPR ,CRISPR-Cas ,priming ,Molecular Biology ,Gene ,Prophage ,030304 developmental biology ,VLAG ,0303 health sciences ,primed ,Computational Biology ,Cell Biology ,Archaeal Viruses ,adaptive immunity ,Acquired immune system ,Adaptation, Physiological ,030220 oncology & carcinogenesis ,CRISPR Loci ,spacer acquisition ,CRISPR-Cas Systems ,Research Paper - Abstract
CRISPR-Cas systems provide bacteria and archaea with adaptive immunity against invading genetic elements, such as plasmids, bacteriophages and archaeal viruses. They consist of cas genes and CRISPR loci, which store genetic memories of previously encountered invaders as short sequences termed spacers. Spacers determine the specificity of CRISPR-Cas defence and immunity can be gained or updated by the addition of new spacers into CRISPR loci. There are two main routes to spacer acquisition, which are known as naïve and primed CRISPR adaptation. Naïve CRISPR adaptation involves the de novo formation of immunity, independent of pre-existing spacers. In contrast, primed CRISPR adaptation (priming) uses existing spacers to enhance the acquisition of new spacers. Priming typically results in spacer acquisition from locations near the site of target recognition by the existing (priming) spacer. Primed CRISPR adaptation has been observed in several type I CRISPR-Cas systems and it is potentially widespread. However, experimental evidence is unavailable for some subtypes, and for most systems, priming has only been shown in a small number of hosts. There is also no current evidence of priming by other CRISPR-Cas types. Here, we used a bioinformatic approach to search for evidence of priming in diverse CRISPR-Cas systems. By analysing the clustering of spacers acquired from phages, prophages and archaeal viruses, including strand and directional biases between subsequently acquired spacers, we demonstrate that two patterns of primed CRISPR adaptation dominate in type I systems. In addition, we find evidence of a priming-like pathway in type II CRISPR-Cas systems.
- Published
- 2018
24. The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity
- Author
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Valentina Folgiero, Heinz Jungbluth, Daniela T. Pilz, Franco Locatelli, Evangelos Axiotis, Chiara Farroni, Stefania Petrini, Valerio D’Alicandro, Carlo Dionisi-Vici, Ulrike Schara, E. Piano Mortari, Rita Carsetti, Diego Martinelli, Chiara Bocci, Paolo Romania, Valentina Marcellini, Rosalba Carrozzo, and Emanuele Bellacchio
- Subjects
0301 basic medicine ,Research Paper - Basic Science ,Medizin ,Vesicular Transport Proteins ,Autophagy-Related Proteins ,Endosomes ,Biology ,Adaptive Immunity ,Cataract ,Cell Line ,03 medical and health sciences ,TLR9 ,Immune system ,medicine ,memory B cells ,Autophagy ,Humans ,Vici syndrome ,Molecular Biology ,B-Lymphocytes ,Lysosome-Associated Membrane Glycoproteins ,Proteins ,Biological Transport ,Cell Biology ,DNA ,Acquired immune system ,medicine.disease ,Immunity, Innate ,Cell biology ,EPG5 ,030104 developmental biology ,Endosomal trafficking ,CpG site ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Toll-Like Receptor 9 ,epg5 ,tlr9 ,vici syndrome ,endosomal trafficking ,memory b cells ,Mutation ,Nucleic acid ,RNA ,Agenesis of Corpus Callosum ,Lysosomes ,Intracellular - Abstract
Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity.
- Published
- 2017
25. A correlation of measles specific antibodies and the number of plasmacytoid dendritic cells is observed after measles vaccination in 9 month old infants
- Author
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Lino Eduardo Cardiel-Marmolejo, Laura C. Bonifaz, Brenda Hernández-Pérez, Miguel L. García-León, Rosa María Wong-Chew, José Ignacio Santos-Preciado, and Bogart Espinosa-Torres
- Subjects
Adult ,Male ,T-Lymphocytes ,Measles Vaccine ,Immunology ,Population ,Cell Count ,Viral Plaque Assay ,Adaptive Immunity ,Biology ,Antibodies, Viral ,Measles ,Measles virus ,Immune system ,medicine ,Humans ,Immunology and Allergy ,education ,Mexico ,Pharmacology ,education.field_of_study ,Innate immune system ,Vaccination ,Age Factors ,Infant ,hemic and immune systems ,Dendritic Cells ,Acquired immune system ,biology.organism_classification ,medicine.disease ,Antibodies, Neutralizing ,Virology ,Immunity, Innate ,Immunity, Humoral ,Female ,Measles vaccine ,Research Paper - Abstract
Measles virus (MeV) represents one of the main causes of death among young children, particularly in developing countries. Upon infection, MeV controls both interferon induction (IFN) and the interferon signaling pathway which results in a severe host immunosuppression that can persists for up to 6 mo after infection. Despite the global biology of MeV infection is well studied, the role of the plasmacytoid dendritic cells (pDCs) during the host innate immune response after measles vaccination remains largely uncharacterized. Here we investigated the role of pDCs, the major producers of interferon in response to viral infections, in the development of adaptive immune response against MeV vaccine. We report that there is a strong correlation between pDCs population and the humoral immune response to Edmonston Zagreb (EZ) measles vaccination in 9-month-old mexican infants. Five infants were further evaluated after vaccination, showing a clear increase in pDCs at baseline, one week and 3 months after immunization. Three months postvaccination they showed increase in memory T-cells and pDCs populations, high induction of adaptive immunity and also observed a correlation between pDCs number and the humoral immune response. These findings suggest that the development and magnitude of the adaptive immune response following measles immunization is directly dependent on the number of pDCs of the innate immune response.
- Published
- 2015
26. Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration
- Author
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Timothy J. Zumwalt, Ajay Goel, C. Richard Boland, and Mildred Arnold
- Subjects
Male ,Chemokine ,Immune Cell ,Cell Communication ,Adaptive Immunity ,Granzymes ,CCL5 ,GZMB ,Lymphocytes, Tumor-Infiltrating ,Immune system ,Tumor Microenvironment ,Humans ,Cytotoxic T cell ,Neoplasm Invasiveness ,Chemokine CCL5 ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Tumor microenvironment ,biology ,Cytotoxic T-Lymphocyte ,Gene Expression Profiling ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,Flow Cytometry ,Acquired immune system ,Colorectal cancer ,Chemokine CXCL10 ,Gene Expression Regulation, Neoplastic ,Chemotaxis, Leukocyte ,Phenotype ,Oncology ,Granzyme ,biology.protein ,Cancer research ,Female ,Tumor Escape ,Colorectal Neoplasms ,Helper T-cell ,T-Lymphocytes, Cytotoxic ,Research Paper - Abstract
Transcriptional expression of CXCR3 and CCR5 cognate chemokines correlate with CD8+ T-cell infiltration and prolonged survival in colorectal cancer (CRC). These findings were derived mainly from paraffin embedded tissues; thus little is known about the secretion pattern of CD8+ T-cell targeting chemokines from CRCs. Therefore, we developed and introduced a novel platform that assesses the immune mediators that are secreted from live excised tissues. Transcriptional profiling and unsupervised hierarchical clustering of 43 CRCs based on expression of genes that represent the adaptive immune response were used to predict tumors that are strong secretors of T-cell targeting chemokines. Secretion of these mediators were corroborated using flow cytometric analysis of T-cell lineage markers: CD4, CD8, IFN-γ, and GzmB. We demonstrate that stronger secretion of CXCL10 (CXCR3 ligand) and CCL5 (CCR5 ligand) and infiltration of GzmB+CD8+ cytotoxic T-lymphocytes (CTLs) and IFN-γ+CD4+ helper T-cells can be predicted by transcriptional profiling, and that CRCs with stronger T-cell immunity were proportionally skewed towards early TNM stages and lacked distant organ metastasis. Our study represents the first functional analysis of secreted immune mediators from CRCs beyond immunohistochemistry and real-time PCR, and observed active physiological interactions between the tumor cells and the immune cells in the tumor microenvironment.
- Published
- 2014
27. Comparison of adaptive and innate immune responses induced by licensed vaccines for human papillomavirus
- Author
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Uzma N. Sarwar, Douglas M Herrin, Barney S. Graham, LaSonji A. Holman, Richard A. Koup, Yuanji Pan, Robert A. Seder, Pamela Costner, Ligia A. Pinto, Martha Nason, Troy J. Kemp, Kapil K Saharia, Galina Yamshchikov, John T. Schiller, Emily E. Coates, Yuk Ying S. Pang, and Julie E. Ledgerwood
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Adolescent ,viruses ,medicine.medical_treatment ,Immunology ,Adaptive Immunity ,Human papillomavirus vaccine ,Biology ,Antibodies, Viral ,Young Adult ,Papillomavirus Vaccines ,Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 ,Antigen ,medicine ,Humans ,Immunology and Allergy ,Human papillomavirus ,Pharmacology ,Innate immune system ,virus diseases ,Acquired immune system ,Virology ,Immunity, Innate ,female genital diseases and pregnancy complications ,Cytokines ,Female ,HPV/Research Papers ,Chemokines ,Adjuvant - Abstract
Two HPV virus-like particle (VLP) vaccines, HPV-16/18 (GlaxoSmithKline, Cervarix®) and HPV-6/11/16/18 (Merck, Gardasil®), are currently licensed in the United States. Given the similar antigenic content but different adjuvant formulations in the 2 vaccines, they provide an efficient method for evaluating adjuvants and comparing the kinetics of the innate and adaptive immune responses. We randomized women to receive either Cervarix® or Gardasil®, followed 6 month vaccination delivery schedules per manufacturer's recommendations, and analyzed the humoral immune response, T cell response, and circulating plasma cytokine levels in response to vaccination. Cervarix® recipients had higher anti-HPV-16 antibody and neutralization titers at month 7, and elevated anti-HPV-18 antibody and neutralization titers at months 7 and 12. Antibody avidity was similar for the 2 vaccines. HPV-31 was the only phylogenetically related non-vaccine HPV type, for which there is evidence of cross-protection, to be cross-neutralized and only in response to Cervarix®. Comparing CD4+ T cell cytokine responses at month 12, there was a trend of increased levels of IL-2 and TNF-α in the Cervarix® groups versus the Gardasil® groups that was consistent across all 4 tested HPV types (16/18/33/45). Elevated levels of circulating plasma cytokine/chemokines were observed post first vaccination in Gardasil® recipients and proinflammatory cytokines were elevated following 1st and 3rd Cervarix® vaccinations. Cervarix® and Gardasil® are both highly immunogenic vaccines. Higher antibody levels and CD4 T cell responses were achieved with Cervarix® after 3 doses, although similar affinity maturation was measured for the 2 vaccines. The clinical implications of the differences in immune responses are unknown.
- Published
- 2014
28. What makes a blood cell based miRNA expression pattern disease specific? - A miRNome analysis of blood cell subsets in lung cancer patients and healthy controls
- Author
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Eckart Meese, Indra N. Dahmke, Hanno Huwer, Andreas Keller, Christina Backes, Valentina Galata, Robert Bals, Petra Leidinger, and Ingo Stehle
- Subjects
Adult ,Male ,Lung Neoplasms ,leukocytes ,T-Lymphocytes ,Adaptive Immunity ,Biology ,Monocytes ,Blood cell ,Immune system ,microRNA ,Biomarkers, Tumor ,medicine ,Humans ,Lung cancer ,Oligonucleotide Array Sequence Analysis ,B-Lymphocytes ,Gene Expression Profiling ,Cancer ,Middle Aged ,Oncomir ,Flow Cytometry ,medicine.disease ,Acquired immune system ,Immunity, Innate ,Microvesicles ,Gene Expression Regulation, Neoplastic ,Killer Cells, Natural ,lung cancer ,MicroRNAs ,medicine.anatomical_structure ,Oncology ,cell separation ,Immunology ,Female ,microarray ,Research Paper ,Granulocytes - Abstract
There is evidence of blood-borne miRNA signatures for various human diseases. To dissect the origin of disease-specific miRNA expression in human blood, we separately analyzed the miRNome of different immune cell subtypes, each in lung cancer patients and healthy individuals. Each immune cell type revealed a specific miRNA expression pattern also dependinging on the cell origin, line of defense, and function. The overall expression pattern of each leukocyte subtype showed great similarities between patients and controls. However, for each cell subtype we identified miRNAs that were deregulated in lung cancer patients including hsa-miR-21, a well-known oncomiR associated with poor lung cancer prognosis that was up-regulated in all leukocyte subtype comparisons of cancer versus controls. While the miRNome of cells of the adaptive immune system allowed only a weak separation between patients and controls, cells of the innate immune system allowed perfect or nearly perfect classification. Leukocytes of lung cancer patients show a cancer-specific miRNA expression profile. Our data also show that cancer specific miRNA expression pattern of whole blood samples are not determined by a single cell type. The data indicate that additional blood components, like erythrocytes, platelets, or exosomes might contribute to the disease specificity of a miRNA signature.
- Published
- 2014
29. Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine-activated human aortic endothelial cells – Novel qualification markers for chronic disease risk factors and conditional DAMPs
- Author
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Candice Johnson, Ruijing Zhang, Xiaohua Jiang, Yifan Lu, Jun Yu, Fatma Saaoud, Hong Wang, Daohai Yu, Xiaofeng Yang, Charles Drummer, Gayani Nanayakkara, Yu Sun, Ying Shao, Xinyuan Li, William Y. Yang, and Eric T. Choi
- Subjects
0301 basic medicine ,Clinical Biochemistry ,Inflammation ,Adaptive Immunity ,Biology ,Models, Biological ,Biochemistry ,Histones ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Risk Factors ,medicine ,Humans ,lcsh:QH301-705.5 ,Transcription factor ,Aorta ,chemistry.chemical_classification ,lcsh:R5-920 ,Genes, Essential ,Effector ,Organic Chemistry ,Endothelial Cells ,Lysophosphatidylcholines ,Acetylation ,Atherosclerosis ,Cell biology ,030104 developmental biology ,Enzyme ,Histone ,Lysophosphatidylcholine ,Gene Expression Regulation ,lcsh:Biology (General) ,chemistry ,Chronic Disease ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Disease Susceptibility ,medicine.symptom ,lcsh:Medicine (General) ,Biomarkers ,Metabolic Networks and Pathways ,030217 neurology & neurosurgery ,Research Paper ,Signal Transduction - Abstract
To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245). Keywords: Trained immunity, Human aortic endothelial cell activation, Proatherogenic lipids lysophosphatidycholine (LPC), RNA-Seq, Chromatin long range interaction
- Published
- 2019
30. Comprehensive Transcriptome Profiling and Functional Analysis of the Frog (Bombina maxima) Immune System
- Author
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Yun Zhang, Wen-Hui Lee, Xuan Wang, Yang Yang, Chao Yan, Guangyin Wang, Feng Zhao, and Yang Xiang
- Subjects
Adaptive Immunity ,Biology ,Genome ,Transcriptome ,Immune system ,Genetics ,Animals ,Coding region ,KEGG ,Molecular Biology ,Gene ,Sequence Analysis, RNA ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,General Medicine ,Full Papers ,tissue-specific genes ,Acquired immune system ,Immunity, Innate ,Protein Structure, Tertiary ,frog ,Gene expression profiling ,immune system ,non-coding RNAs ,Anura - Abstract
Amphibians occupy a key phylogenetic position in vertebrates and evolution of the immune system. But, the resources of its transcriptome or genome are still little now. Bombina maxima possess strong ability to survival in very harsh environment with a more mature immune system. We obtained a comprehensive transcriptome by RNA-sequencing technology. 14.3% of transcripts were identified to be skin-specific genes, most of which were not isolated from skin secretion in previous works or novel non-coding RNAs. 27.9% of transcripts were mapped into 242 predicted KEGG pathways and 6.16% of transcripts related to human disease and cancer. Of 39 448 transcripts with the coding sequence, at least 1501 transcripts (570 genes) related to the immune system process. The molecules of immune signalling pathway were almost presented, several transcripts with high expression in skin and stomach. Experiments showed that lipopolysaccharide or bacteria challenge stimulated pro-inflammatory cytokine production and activation of pro-inflammatory caspase-1. These frog's data can remarkably expand the existing genome or transcriptome resources of amphibians, especially immunity data. The entity of the data provides a valuable platform for further investigation on more detailed immune response in B. maxima and a comparative study with other amphibians.
- Published
- 2013
31. CRISPR-Cas systems preferentially target the leading regions of MOBFconjugative plasmids
- Author
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Søren Høgh, Peter C. Fineran, Sarah Neumann, Fernando de la Cruz, Gerrit Gort, Raymond H.J. Staals, Edze R. Westra, Stan J. J. Brouns, Netherlands Organization for Scientific Research, Royal Society of New Zealand, Nederlandse Stichting Zuivel voor Voeding en Gezondheid, Ministerio de Ciencia e Innovación (España), and European Commission
- Subjects
medicine.disease_cause ,Wiskundige en Statistische Methoden - Biometris ,Plasmid ,Microbiologie ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,streptococcus-thermophilus ,Genetics ,0303 health sciences ,adaptive immune-systems ,horizontal gene-transfer ,adaptive immunity ,Acquired immune system ,humanities ,Conjugation, Genetic ,embryonic structures ,Horizontal gene transfer ,antiviral defense ,Research Paper ,conjugation ,DNA, Single-Stranded ,microbial communities ,in-vitro ,Biology ,Microbiology ,acquired-resistance ,F Factor ,03 medical and health sciences ,Acquired resistance ,plasmid mobilization ,Bacterial Proteins ,host-range ,medicine ,Mathematical and Statistical Methods - Biometris ,Molecular Biology ,Escherichia coli ,VLAG ,030304 developmental biology ,Base Sequence ,Escherichia coli K12 ,030306 microbiology ,mobile genetic element ,Cell Biology ,eye diseases ,escherichia-coli ,protospacer distribution ,protein h-ns ,CRISPR-Cas Systems ,Mobile genetic elements ,human activities - Abstract
Most prokaryotes contain CRISPR-Cas immune systems that provide protection against mobile genetic elements. We have focused on the ability of CRISPR-Cas to block plasmid conjugation, and analyzed the position of target sequences (protospacers) on conjugative plasmids. The analysis reveals that protospacers are non-uniformly distributed over plasmid regions in a pattern that is determined by the plasmid's mobilization type (MOB). While MOBP plasmids are most frequently targeted in the region entering the recipient cell last (lagging region), MOBF plasmids are mostly targeted in the region entering the recipient cell first (leading region). To explain this protospacer distribution bias, we propose two mutually non-exclusive hypotheses: (1) spacers are acquired more frequently from either the leading or lagging region depending on the MOB type (2) CRISPR-interference is more efficient when spacers target these preferred regions. To test the latter hypothesis, we analyzed Type I-E CRISPR-interference against MOBF prototype plasmid F in Escherichia coli. Our results show that plasmid conjugation is effectively inhibited, but the level of immunity is not affected by targeting the plasmid in the leading or lagging region. Moreover, CRISPR-immunity levels do not depend on whether the incoming single-stranded plasmid DNA, or the DNA strand synthesized in the recipient is targeted. Our findings indicate that single-stranded DNA may not be a target for Type I-E CRISPR-Cas systems, and suggest that the protospacer distribution bias might be due to spacer acquisition preferences. © 2013 Landes Bioscience., This work was financially supported by an NWO Vidi grant to SJJB (864.11.005). PCF was supported by a Rutherford Discovery Fellowship from the Royal Society of NZ and the VLAG (Voeding, Levensmiddelentechnologie, Agrobiotechnologie en Gezondheid). Work in the FdlC group was supported by grants BFU2011-26608 from Ministerio de Ciencia e Innovación (Spain), and grant no 282004/FP7-HEALTH.2011.2.3.1-2 from the European VII Framework Program.
- Published
- 2013
32. Responses to hepatitis B vaccine in isolated anti-HBc positive adults
- Author
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Wen Ren, Yongdi Chen, Jingjing Ren, Zhenggang Jiang, Ying Liu, Jun Yao, Huan Shan, Lingzhi Shen, Xuewei Dai, Yan Qiu, and Jing Li
- Subjects
Adult ,Male ,medicine.medical_specialty ,HBsAg ,China ,Hepatitis B vaccine ,Immunology ,Adaptive Immunity ,medicine.disease_cause ,Gastroenterology ,Serology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,Hepatitis B Vaccines ,030212 general & internal medicine ,Young adult ,Hepatitis B Antibodies ,Pharmacology ,Hepatitis B virus ,Hepatitis B Surface Antigens ,business.industry ,virus diseases ,Middle Aged ,Hepatitis B Core Antigens ,Research Papers ,digestive system diseases ,Vaccination ,Cohort ,030211 gastroenterology & hepatology ,Female ,business - Abstract
Immune responses of isolated anti-HBc subjects are not well characterized in populations in China. This study aimed to evaluate immune responses to hepatitis B vaccination in isolated anti-HBc positive subjects. A cohort of 608 subjects were selected and separated into isolated anti-HBc (negative for HBsAg and anti-HBs, positive for anti-HBc) and control (negative for HBsAg, anti-HBs, and anti-HBc) groups, who were matched by age and sex. All subjects received 3 doses of hepatitis B vaccine (20μg) at months 0, 1, and 3, followed by testing for serological responses 1 month after the third vaccination. The positive seroprotection rate and geometric mean titer (GMT) for hepatitis B surface antibody (anti-HBs) of isolated anti-HBc subjects were significantly lower than those in the control group(86.2% vs.92.1%, P = 0.02; 47.26 vs.97.81 mIU/mL, P < 0.001). When stratified by age, positive seroprotection rate in the isolated anti-HBc group were 92%, 88.5% and 79.4% in the 20-34, 35-49, and 50-60 y old subgroups, respectively (χ2 = 5.919, P = 0.04). Additionally, the GMT level for anti-HBs in the isolated anti-HBc group for different age subgroups were 104.43, 47.87 and 31.79 mIU/mL respectively (χ2 = 19.44, P < 0.001). The GMT level for anti-HBc before vaccination were negatively correlated with GMT for anti-HBs after 3 doses of hepatitis B vaccine (r = -0.165, P < 0.001). In conclusion, isolated anti-HBc positive subjects can achieve good immune responses after hepatitis B vaccination, and the positive seroprotection rate and GMT level for anti-HBs were lower than the control group. Better responses could be observed in young adults, and significant negative correlations were found between GMT of anti-HBc before vaccination and GMT of anti-HBs after vaccination.
- Published
- 2016
33. The DNA methylation profile of activated human natural killer cells
- Author
-
E. Andres Houseman, Karl T. Kelsey, Melissa Eliot, Derick Siegel, Rondi A. Butler, Manuel A. Sepulveda, George Hsuang, Stephanie Kim, and John K. Wiencke
- Subjects
0301 basic medicine ,Cancer Research ,Differentially methylated regions ,Blood Donors ,NK cells ,Medical Biochemistry and Metabolomics ,Adaptive Immunity ,Lymphocyte Activation ,Epigenesis, Genetic ,0302 clinical medicine ,Basic Helix-Loop-Helix Transcription Factors ,Killer Cells ,2.1 Biological and endogenous factors ,Aetiology ,Promoter Regions, Genetic ,innate immunity ,B-Lymphocytes ,DNA methylation ,digital PCR ,Methylation ,Acquired immune system ,Killer Cells, Natural ,medicine.anatomical_structure ,CpG site ,Natural ,Reprogramming ,Research Paper ,T cell ,Biology ,Promoter Regions ,03 medical and health sciences ,Genetic ,medicine ,Genetics ,Humans ,Molecular Biology ,Homeodomain Proteins ,Innate immune system ,Human Genome ,DNA ,DNA Methylation ,Molecular biology ,NKp46 ,030104 developmental biology ,CpG Islands ,Biochemistry and Cell Biology ,030215 immunology ,Epigenesis ,Developmental Biology ,Genome-Wide Association Study - Abstract
Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in naive NK, T- and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.
- Published
- 2016
34. Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination
- Author
-
Lina Marcela Carmona, David G. Schatz, and Sebastian D. Fugmann
- Subjects
0301 basic medicine ,Transposable element ,animal diseases ,Transposases ,chemical and pharmacologic phenomena ,Biology ,Adaptive Immunity ,DNA-binding protein ,Recombination-activating gene ,Evolution, Molecular ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,RAG2 ,Genetics ,Animals ,Strongylocentrotus purpuratus ,Transposase ,Homeodomain Proteins ,V(D)J recombination ,fungi ,hemic and immune systems ,3T3 Cells ,V(D)J Recombination ,DNA-Binding Proteins ,030104 developmental biology ,chemistry ,embryonic structures ,DNA Transposable Elements ,DNA ,Recombination ,Developmental Biology ,Research Paper - Abstract
The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate V(D)J recombination, the process that assembles the B- and T-lymphocyte antigen receptor genes of jawed vertebrates. RAG1 and RAG2 are thought to have arisen from a transposable element, but the origins of this element are not understood. We show that two ancestral RAG1 proteins, Transib transposase and purple sea urchin RAG1-like, have a latent ability to initiate V(D)J recombination when coexpressed with RAG2 and that in vitro transposition by Transib transposase is stimulated by RAG2. Conversely, we report low levels of V(D)J recombination by RAG1 in the absence of RAG2. Recombination by RAG1 alone differs from canonical V(D)J recombination in having lost the requirement for asymmetric DNA substrates, implicating RAG2 in the origins of the “12/23 rule,” a fundamental regulatory feature of the reaction. We propose that evolution of RAG1/RAG2 began with a Transib transposon whose intrinsic recombination activity was enhanced by capture of an ancestral RAG2, allowing for the development of adaptive immunity.
- Published
- 2016
35. SOX9 indirectly regulates CEACAM1 expression and immune resistance in melanoma cells
- Author
-
Gal Markel, Shira Ashkenazi, Rona Ortenberg, Michal J. Besser, and Jacob Schachter
- Subjects
0301 basic medicine ,Sp1 Transcription Factor ,Blotting, Western ,T cells ,Biology ,Adaptive Immunity ,Proto-Oncogene Protein c-ets-1 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,ETS1 ,Antigens, CD ,Cell Line, Tumor ,medicine ,melanoma ,Gene silencing ,Humans ,Immune response ,Promoter Regions, Genetic ,Transcription factor ,CEACAM1 ,Gene knockdown ,Binding Sites ,Melanoma ,Research Paper: Immunology ,Immunity ,SOX9 Transcription Factor ,Acquired immune system ,medicine.disease ,Immune checkpoint ,Cell biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,embryonic structures ,Immunology and Microbiology Section ,RNA Interference ,Cell Adhesion Molecules ,SOX9 ,Protein Binding - Abstract
As melanoma cells are immunogenic, they instigate an adaptive immune response and production of anti-tumor T-cells. A central factor in this interaction is CEACAM1 (carcinoembryonic antigen cell adhesion molecule 1), a transmembrane glycoprotein previously shown in our lab to protect melanoma cells from T cell-mediated killing. In this study, we examine the role of transcription factor SOX9 in the regulation of CEACAM1 expression and immune resistance in melanoma cells. Knockdown of endogenous SOX9 results in CEACAM1 up-regulation, while its overexpression leads to the opposite effect. We show that SOX9 controls CEACAM1 expression at a transcriptional level, but in an indirect manner, as regulation of the CEACAM1 promoter remains intact even when all eight potential SOX9-binding sites are abolished. A series of promoter truncations localizes the SOX9-controlled area to the proximal 200bp of the promoter. Point mutations in putative Sp1 and ETS1 binding sites identify these transcription factors as the primary SOX9-controlled mediators. Co-immunoprecipitation studies show that SOX9 and Sp1 physically interact in melanoma cells, while silencing of SOX9 down-regulates ETS1, but not Sp1, in the same cells. Finally, knockdown of SOX9 indeed renders melanoma cells resistant to T cell-mediated killing, in line with the increased CEACAM1 expression. In conclusion, we show that SOX9 regulates CEACAM1 expression in melanoma cells, and thereby their immune resistance. As CEACAM1 is a pivotal protein in melanoma biology and immune crosstalk, further understanding of its regulation can provide new insights and contribute to the development of novel approaches to therapy.
- Published
- 2015
36. Growing old with the immune system: a study of immunosenescence in the zebra finch (Taeniopygia guttata)
- Author
-
Elin Noreen, Sophie Bourgeon, and Claus Bech
- Subjects
Male ,Aging ,Blood Bactericidal Activity ,Bactericidal competence ,Cellular immunity ,Immunosenescence ,PHA ,Physiology ,Population ,Immunoglobulins ,chemical and pharmacologic phenomena ,Adaptive Immunity ,Biology ,Biochemistry ,Sex Factors ,Age ,Endocrinology ,Immune system ,IgY ,Animals ,Phytohemagglutinins ,education ,Zebra finch ,Ecology, Evolution, Behavior and Systematics ,Immunity, Cellular ,Original Paper ,education.field_of_study ,biochemical phenomena, metabolism, and nutrition ,Acquired immune system ,biology.organism_classification ,Immunology ,Humoral immunity ,bacteria ,Female ,Animal Science and Zoology ,Finches ,Taeniopygia - Abstract
Immunosenescence has not received much attention in birds and the few existing studies indicate that the occurrence of immunosenescence and/or its extent may differ between species. In addition, not much information is available on the immunosenescence patterns of different immune parameters assessed simultaneously in both sexes within a single species. The present study reports the results on immunosenescence in innate immunity and both cellular and humoral acquired immunity of both sexes in a captive population of zebra finch (Taeniopygia guttata) using three age groups (approximately 0.2, 2.5 and 5.1 years). Both male and female finches showed an inverse U-shaped pattern in cellular immune function with age, quantified by a PHA response. Males showed stronger responses than females at all ages. In contrast, an increase with age in humoral immunity, quantified through total plasma immunoglobulin Y levels, was found in both sexes. However, our measurements of innate immunity measured through the bacteria-killing ability against Escherichia coli gave inconclusive results. Still, we conclude that both cellular and humoral acquired immunity are susceptible to immunosenescence, and that the sexes differ in cellular immunity.
- Published
- 2011
37. Restraint Stress Fails to Render C57BL/6 Mice Susceptible to Theiler’s Virus-Induced Demyelination
- Author
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C.J.R. Welsh, Andrew J. Steelman, Colin R. Young, E. Alford, Mary W. Meagher, and Thomas H. Welsh
- Subjects
Central Nervous System ,Restraint, Physical ,C57BL/6 ,Exacerbation ,medicine.medical_treatment ,Immunology ,Inflammation ,Demyelinating Autoimmune Diseases, CNS ,Adaptive Immunity ,Nerve Fibers, Myelinated ,Mice ,Endocrinology ,Degenerative disease ,Theilovirus ,Cardiovirus Infections ,Immune Tolerance ,medicine ,Demyelinating disease ,Animals ,Genetic Predisposition to Disease ,Neurons ,Original Paper ,Movement Disorders ,biology ,Endocrine and Autonomic Systems ,business.industry ,Multiple sclerosis ,Immunosuppression ,Viral Load ,medicine.disease ,biology.organism_classification ,Mice, Inbred C57BL ,Disease Models, Animal ,Neurology ,Female ,Disease Susceptibility ,medicine.symptom ,business ,Viral load ,Stress, Psychological - Abstract
Objectives: Multiple sclerosis is a degenerative disease of the CNS with a pathology consistent with immunological mediation. Although its cause is unknown, multiple factors are thought to influence both the onset and exacerbation of the disease, including both genetic background as well as environmental factors. Methods: We are interested in the effect of psychological stress on the onset and exacerbation of Theiler’s virus-induced demyelinating disease (TVID), a murine model of MS in which viral persistence facilitates demyelination. In the current study, we determined whether chronic restraint stress (RS)-induced immunosuppression could result in the establishment of a persistent CNS infection in the normally TVID-resistant C57BL/6 mouse strain, resulting in demyelination. Results: Our data indicated that RS repeated over the course of 7 days was not sufficient to cause decreases in virus-specific adaptive immunity, and did not significantly alter CNS viral levels. Furthermore, chronic repeated RS lasting until 4 weeks after infection altered neither the development of virus-specific IgG nor motor function determined by Rotarod analysis. In addition, histological analysis of the CNS of stressed mice indicated no inflammation or demyelination on day 193 after infection. Conclusion: These results suggest that stress alone is not sufficient to overcome genetic resistance to TVID in the C57BL/6 mouse strain.
- Published
- 2009
38. Adjuvants may reduce in vivo transfection levels for DNA vaccination in mice leading to reduced antigen-specific CD8+ T cell responses
- Author
-
Peter R. Hoffmann, Pietro Bertino, FuKun W. Hoffmann, Aaron H. Rose, Jared Hara, Stefan Moisyadi, and Johann Urschitz
- Subjects
medicine.medical_treatment ,T cell ,Immunology ,Green Fluorescent Proteins ,Biology ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,Transfection ,DNA vaccination ,Immune system ,Antigen ,Adjuvants, Immunologic ,medicine ,Vaccines, DNA ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Cationic liposome ,Pharmacology ,Mice, Inbred BALB C ,Innate immune system ,Dendritic Cells ,Immunity, Innate ,medicine.anatomical_structure ,Blood ,Female ,Lymph Nodes ,Adjuvant ,Spleen ,Research Paper - Abstract
Adjuvants for DNA vaccination are designed to promote transformation of transgenes into target cells and increase inflammation in the site of injection, with resultant immune cell recruitment. Numerous studies indicated cationic liposomes as effective adjuvants for DNA vaccination due to their ability to promote in vivo transfection and innate immune system activation. Commercial reagents as Adjuplex and in vivo-JetPEI are also intended to facilitate DNA vaccination. Here, we evaluate the adjuvant properties of cationic liposomes, Adjuplex and in vivo-JetPEI compared to injection of DNA without adjuvant. In mice vaccinated with piggyBac pDNA vaccines, we assessed in vivo antigen expression, innate immune responses in draining lymph nodes, and antigen-specific T cell responses in spleens and blood. Surprisingly, vaccination with DNA in PBS emerged as the most efficient in promoting in vivo transfection and consequent antigen expression, while the addition of adjuvant reduced the amount of antigen expressed. On the other hand, we discovered higher numbers of innate immune cells and activated dendritic cells in the lymph nodes of mice injected with adjuvants than those vaccinated in PBS. The analysis of eGFP-specific immune responses revealed that all the different immunizations induced functional antigen-specific T cells in spleens, although only T cells generated by non-adjuvant vaccination and Adjuplex were identified in the blood of vaccinated mice. These results provide insight into the effects of these 3 adjuvants and may facilitate appropriate use off adjuvants by researchers using DNA vaccines in laboratory animals.
- Published
- 2015
39. What infections actually are
- Author
-
Bruce, Beutler and Jules, Hoffmann
- Subjects
Paper ,Toll-Like Receptors ,Humans ,Adaptive Immunity ,Antigens ,Communicable Diseases ,Antibodies ,Immunity, Innate - Published
- 2010
40. MicroRNAs in the key events of systemic lupus erythematosus pathogenesis
- Author
-
Marketa Husakova
- Subjects
0301 basic medicine ,microrna ,T-Lymphocytes ,lcsh:Medicine ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,microRNA ,estrogen ,Genetic predisposition ,medicine ,Animals ,Humans ,Lupus Erythematosus, Systemic ,Genetic Predisposition to Disease ,Epigenetics ,skin and connective tissue diseases ,innate immunity ,B cell ,030203 arthritis & rheumatology ,B-Lymphocytes ,Innate immune system ,sle ,lcsh:R ,Estrogens ,adaptive immunity ,Immune dysregulation ,Acquired immune system ,Immunity, Innate ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,genetic predisposition - Abstract
Background: Small non-coding RNA molecules (miRs) are involved in immune cell maturation and function and might influence immunopathological processes of systemic lupus erythematosus (SLE) pathogenesis. Methods and Results: This paper presents the results of a literature search for publications dealing with the relationship between miRs and pathological factors related to SLE such as genetic background, immune dysregulation and gender-associated differences participating in SLE development. In SLE, distinct miRs are differentially expressed in SLE cells of innate and adaptive immunity. The miR-146a and miR-155 genes, among others, interfere with intracellular signalling pathways downstream of toll-like receptors 7 and 9 (TLR- 7, TLR-9) and influences interferon (IFN)-type I synthesis in plasmacytoid dendritic cells. In T and B cells, miR-126, miR-21, miR-146a, miR-155, miR-1246 and others might influence gene expression by epigenetic modifications, support abnormal cytosine release, differentiation of cell subsets, B cell hyperactivity and autoantibody production. Besides, estrogen might up- and downregulate immunologically active miRs, which are potential mediators of hormonal influences in SLE development. Moreover, SLE genetic basis included some polymorphisms of the miR-146a gene, which varies across populations. Conclusion: Distinct miRs are differentially expressed in both SLE mice models and human patients and promote autoimmune features of immune processes. MiRs are important molecules modulating susceptibility to SLE as well as its onset, clinical diversity and progression.
- Published
- 2016
41. Author Correction: Antibody responses to the RTS,S/AS01E vaccine and Plasmodium falciparum antigens after a booster dose within the phase 3 trial in Mozambique
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Núria Díez-Padrisa, James G. Beeson, Ross L. Coppel, Lina Sánchez, David R. Cavanagh, Gemma Moncunill, Inocencia Cuamba, Sheetij Dutta, Evelina Angov, Chenjerai Jairoce, Carlota Dobaño, Joseph J. Campo, Marta Vidal, Nana Aba Williams, Deepak Gaur, Pedro Aide, Augusto Nhabomba, Itziar Ubillos, and Ruth Aguilar
- Subjects
lcsh:Immunologic diseases. Allergy ,Adaptive immunity ,Immunology ,Booster dose ,lcsh:RC254-282 ,Antigen ,medicine ,Pharmacology (medical) ,Author Correction ,Pharmacology ,Vaccines ,biology ,business.industry ,RTS,S ,Plasmodium falciparum ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Acquired immune system ,medicine.disease ,biology.organism_classification ,Virology ,Malaria ,Infectious Diseases ,Antibody response ,lcsh:RC581-607 ,business - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
42. Modeling Influenza Virus Infection: A Roadmap for Influenza Research
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Dunja Bruder, Van Kinh Nguyen, Kai Schulze, Niharika Sharma, Carlos A. Guzmán, Sabine Stegemann-Koniszewski, Michael Meyer-Hermann, Franklin R. Toapanta, Esteban A. Hernandez-Vargas, Thomas Ebensen, Alessandro Boianelli, Esther Wilk, and BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany.
- Subjects
Orthomyxoviridae ,lcsh:QR1-502 ,Review ,Adaptive Immunity ,Biology ,medicine.disease_cause ,lcsh:Microbiology ,Virology ,parameters estimation ,Influenza, Human ,Pandemic ,Influenza A virus ,medicine ,Animals ,Humans ,Coinfection ,host genetic factors ,aging ,Immunosenescence ,Models, Theoretical ,Pneumonia, Pneumococcal ,Acquired immune system ,Influenza research ,medicine.disease ,biology.organism_classification ,coinfection ,Vaccination ,Disease Models, Animal ,Infectious Diseases ,Host-Pathogen Interactions ,Immunology ,vaccinology ,influenza ,mathematical models - Abstract
Influenza A virus (IAV) infection represents a global threat causing seasonal outbreaks and pandemics. Additionally, secondary bacterial infections, caused mainly by Streptococcus pneumoniae, are one of the main complications and responsible for the enhanced morbidity and mortality associated with IAV infections. In spite of the significant advances in our knowledge of IAV infections, holistic comprehension of the interplay between IAV and the host immune response (IR) remains largely fragmented. During the last decade, mathematical modeling has been instrumental to explain and quantify IAV dynamics. In this paper, we review not only the state of the art of mathematical models of IAV infection but also the methodologies exploited for parameter estimation. We focus on the adaptive IR control of IAV infection and the possible mechanisms that could promote a secondary bacterial coinfection. To exemplify IAV dynamics and identifiability issues, a mathematical model to explain the interactions between adaptive IR and IAV infection is considered. Furthermore, in this paper we propose a roadmap for future influenza research. The development of a mathematical modeling framework with a secondary bacterial coinfection, immunosenescence, host genetic factors and responsiveness to vaccination will be pivotal to advance IAV infection understanding and treatment optimization.
- Published
- 2015
43. The immune response against Candida spp. and Sporothrix schenckii
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Arturo Flores-Carreón, Héctor M. Mora-Montes, Luis A. Pérez-García, and José A. Martínez-Álvarez
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Antigens, Fungal ,Neutrophils ,Adaptive Immunity ,Microbiology ,Immunocompromised Host ,Mice ,Immune system ,Cell Wall ,medicine ,Animals ,Humans ,Sporothrix schenckii ,Candida albicans ,Candida ,Immunity, Cellular ,biology ,Sporotrichosis ,Macrophages ,Sporothrix ,Candidiasis ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,medicine.disease ,Lymphocyte Subsets ,Corpus albicans ,Infectious Diseases ,Host-Pathogen Interactions ,Immunology ,Candida spp ,Systemic candidiasis - Abstract
Candida albicans is the main causative agent of systemic candidiasis, a condition with high mortality rates. The study of the interaction between C. albicans and immune system components has been thoroughly studied and nowadays there is a model for the anti-C. albicans immune response; however, little is known about the sensing of other pathogenic species of the Candida genus. Sporothrix schenckii is the causative agent of sporotrichosis, a subcutaneous mycosis, and thus far there is limited information about its interaction with the immune system. In this paper, we review the most recent information about the immune sensing of species from genus Candida and S. schenckii. Thoroughly searches in scientific journal databases were performed, looking for papers addressing either Candida- or Sporothrix-immune system interactions. There is a significant advance in the knowledge of non-C. albicans species of Candida and Sporothrix immune sensing; however, there are still relevant points to address, such as the specific contribution of pathogen-associated molecular patterns (PAMPs) for sensing by different immune cells and the immune receptors involved in such interactions. This manuscript is part of the series of works presented at the “V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi” (Oaxaca, Mexico, 2012).
- Published
- 2014
44. Neutrophils: Their Role in Innate and Adaptive Immunity
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Eileen Uribe-Querol, Clifford A. Lowell, Carlos Rosales, and Nicolas Demaurex
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lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Article Subject ,Leukotriene B4 ,Neutrophils ,Immunology ,Inflammation ,Adaptive Immunity ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Immunology and Allergy ,Humans ,Innate ,ddc:612 ,NADPH oxidase ,Innate immune system ,biology ,Platelet-activating factor ,Immunity ,Chemotaxis ,General Medicine ,Neutrophil extracellular traps ,Immunity, Innate ,Editorial ,030104 developmental biology ,chemistry ,biology.protein ,medicine.symptom ,lcsh:RC581-607 - Abstract
Polymorphonuclear neutrophils (PMNs) are the most abundant leukocytes in the blood and constitute the first line of host defense against numerous infectious pathogens, including bacteria, fungi, and protozoa. Neutrophils are the first leukocytes to migrate from the blood to injured or infected sites for killing pathogens and removing cellular debris. Neutrophils migrate to sites of inflammation and infection where they recognize and phagocytose invading microorganisms, in order to kill them via different cytotoxic mechanisms. This process involves molecular mechanisms that coordinate cell polarization, delivery of receptors, and activation of integrins at the leading edge of neutrophils migrating toward chemoattractants. Once at sites of infection, neutrophils actively phagocytose microorganisms or form neutrophil extracellular traps (NETs) to trap and kill pathogens. Association of the nicotinamide adenine dinucleotide phosphate (NADPH) reduced oxidase complex at the phagosomal membrane for the production of reactive oxygen species (ROS) and delivery of proteolytic enzymes into the phagosome initiate pathogen killing and removal. In recent years, it has become evident that neutrophils not only have a fundamental role in the acute phase of inflammation when they actively eliminate pathogens, but also are capable of modifying the overall immune response. Neutrophils can do this by exchanging information with macrophages, dendritic cells, and other cells of the adaptive immune system through either soluble mediators or direct cell-cell contact. To illuminate the complex role of neutrophils in infection, inflammation, and immunity, this special issue has gathered original and review articles that will help us expand our knowledge on neutrophil biology. As stated before, any neutrophil response begins with migration of these leukocytes to the site of infection or inflammation. Chemotaxis, the directional movement of the cell guided by extracellular chemoattractant gradients, plays an essential role in the recruitment of neutrophils to sites of inflammation. Chemotaxis is mediated by G protein-coupled receptor (GPCR) signaling pathway. The article by X. Xu and T. Jin describes the novel functions of the PLC/PKC/PKD signaling axis in GPCR-mediated chemotaxis of neutrophils. Similarly, the review by J. Gamara et al. explains how the small monomeric GTPases of the Arf family and their guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) participate in GPCR signaling cascades regulating several neutrophil functional responses. The various cell responses to different chemoattractants are highlighted by the studies of R. Vaivoda et al. and M. A. Hidalgo et al. R. Vaivoda et al. describe how the deficiency of CYP4F18, an enzyme that catalyzes hydroxylation of leukotriene B4 (LTB4), does not alter the chemotactic response to LTB4 but causes a twofold increase response to complement component C5a. M. A. Hidalgo et al. describe that although N-formyl-methionyl-leucyl-phenylalanine (fMLF) and Platelet Activating Factor (PAF) induce similar intracellular signaling profiles, only fMLF induces interleukin-8 (IL-8) release and NADPH oxidase activity in neutrophils. Several microbicidal functions of neutrophils involve the activation of the NADPH oxidase complex for production of reactive oxygen species (ROS) to mediate pathogen killing. The interesting review by R. C. Allen describes the principles of particle physics and quantum mechanics to develop a fundamental explanation of neutrophil microbicidal metabolism based on ROS atomic properties. Myeloperoxidase, the most abundant neutrophil-granule protein, is known to have potent microbicidal properties. But, recently it has become apparent that myeloperoxidase also participates in regulating adaptive immune responses. The review by D. Odobasic et al. presents an overview on how this enzyme has key roles in various functions of neutrophils in innate and adaptive immunity. When neutrophils cannot kill microorganisms by the classical phagocytosis or degranulation mechanisms, they can also form neutrophil extracellular traps (NETs) to kill microbes. NETs are fibers composed of chromatin and neutrophil-granule proteins and are induced by several pathogens and also some pharmacological stimuli. Antigen-antibody complexes can also induce NET formation. The paper by O. R. Aleman et al. explores direct stimulation of individual Fcγ receptors to induce NET formation and finds that only FcγRIIIb cross-linking induced NET formation in a NADPH oxidase-, PKC-, and ERK-dependent fashion. An intriguing observation on the microbicidal function of neutrophils of older women is reported by J. Bartholomeu-Neto et al. They find that phagocytic and oxidative activities of neutrophils of healthy older women that exercise regularly are higher than those of sedentary older women. The physical condition of each individual was a significant predictor of phagocytosis potential. Clearly, regular exercise contributes to a better innate immune system. However, no mechanism for this beneficial effect is known. This should be an interesting line of future neutrophil research. Neutrophils are potent regulators of inflammation via the release of proinflammatory factors and several cytokines. The paper by M. R. Tardif et al. describes an alternative secretion pathway in neutrophils for the release of the S100A8/A9 (calprotectin) and S100A12, proinflammatory mediators. The secretion of these cytoplasmic proteins was dependent on the production of ROS and required K+ exchanges through ATP-sensitive K+ channels. Because neutrophils can also cause tissue damage, their downregulation at the inflammatory site is required for proper resolution of inflammation. The paper by M. A. Sugimoto et al. describes how Annexin A1, an endogenous glucocorticoid-regulated protein, inhibits neutrophil tissue accumulation by reducing leukocyte infiltration and activating neutrophil apoptosis. Annexin A1 also induced macrophage reprogramming toward a resolving phenotype, resulting in reduced production of proinflammatory cytokines and increased release of immunosuppressive and proresolving molecules. Similarly, the paper by M. Cohen-Mazor et al. describes how heparin binds to activated neutrophils and induces apoptosis. These results provide an explanation for the long-known anti-inflammatory effects of heparin. Neutrophils seem to have dual roles in promoting and controlling inflammation. The mechanisms that control the final outcome are not completely described, but these opposite functions must be tightly balanced. During sepsis, neutrophils are responsible for both the release of cytokines and the phagocytosis of pathogens. But, in SIRS (systemic inflammatory response syndrome), neutrophils contribute to maintaining of a whole-body inflammatory state. In the review by H. Fang et al., the role of neutrophils in these two clinical conditions is described and the therapeutic effect of G-CSF in sepsis is discussed in relation to its function of regulating neutrophil blood levels. Moreover, because neutrophil-derived products can regulate the action of other immune cells and can contribute to the development and chronicity of inflammatory diseases, I. Naegelen et al. propose in their article an original strategy based on linear fitting, to analyze the link between cytokine release and degranulation time. This method could find correlations between granule proteins and cytokines secreted to the inflammatory site. The idea is to be able in the future to predict the type of inflammatory response that neutrophils could induce under certain conditions. In addition, C. F. M. Morris et al. describe in their review how two apparent opposite models of inflammation may be compatible in the outcome of inflammation. The two-hit model states that a first injury (i.e., hit) can serve as a priming event which sequential insults can build on, culminating in a disproportioned inflammatory response to injury. On the other hand, the ischemic preconditioning (IPC) model states that a mild ischemic event, either remote or local, can be protective and can actually attenuate the inflammatory response to the following insults. This article tries to reconcile both models and presents evidence that each of them brings its own unique perspective onto the biology of inflammation. Finally, the dual role of neutrophil function during inflammation is emphasized again in the review by E. Uribe-Querol et al., where the protumor or antitumor character of the tumor-associated neutrophils (TANs) is revised. Recent findings on the mechanisms for neutrophil recruitment to the tumor, for neutrophils supporting tumor progression, and for neutrophil activation to enhance their antitumor functions are presented. These articles together represent the fascinating flexible functions of neutrophils not only in fighting infections, but also in shaping the immune response and the consequences this may have to important health issues such as resolution of inflammation, autoimmunity, and cancer. Carlos Rosales Nicolas Demaurex Clifford A. Lowell Eileen Uribe-Querol
- Published
- 2016
45. Cellular Immunity of Patients with Tuberculosis Combined with Diabetes
- Author
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Peng Cheng, Liang Wang, and Wenping Gong
- Subjects
Immunity, Cellular ,Hyperglycemia ,Immunology ,Diabetes Mellitus ,Humans ,Tuberculosis ,Immunology and Allergy ,General Medicine ,Adaptive Immunity - Abstract
Tuberculosis (TB) is one of humanity’s three major infectious diseases. Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia due to impaired insulin secretion or impaired insulin function. It has been reported that DM is a primary risk factor for TB disease. Given the increasing public health threat to people’s health, more and more studies have focused on diabetes complicated by TB. Hyperglycemia can affect the function of human immune cells, promote primary infections and reactivation of TB, and increase the susceptibility and severity of TB. However, the immunological mechanism behind it is still not clear. By reviewing the related articles on tuberculosis complicated with diabetes published in recent years, this paper expounds on the effect of hyperglycemia on innate immunity and adaptive immunity of patients with TB. This review provides new insights for elucidating the immunological mechanism of TB complicated with DM and lays the foundation for finding potential targets for preventing and treating TB combined with DM.
- Published
- 2022
46. The immune response to SARS-CoV-2 and COVID-19 immunopathology – Current perspectives
- Author
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A. Morais, Luís Delgado, Inês Chora, and José Laerte Boechat
- Subjects
PRR, pattern recognition receptor ,Chemokine ,ICs, immune complexes ,viruses ,Review ,Adaptive Immunity ,medicine.disease_cause ,Severity of Illness Index ,IRFs, interferon regulatory factors ,0302 clinical medicine ,S protein, spike protein ,Immunopathology ,Medicine ,030212 general & internal medicine ,SARS-CoV-2, coronavirus-related second severe acute respiratory syndrome ,COVID-19, coronavirus disease 2019 ,Coronavirus ,Innate immunity ,Respiratory Distress Syndrome ,TNF, tumor necrosis factor ,biology ,RBD, receptor-binding domain ,Middle Aged ,Acquired immune system ,ICU, intensive care unit ,MASP-2, MBL-associated serine protease-2 ,VEGF, vascular endothelial growth factor ,NF-kB, nuclear factor kB ,Disease Progression ,Immunotherapy ,Antibody ,Adult ,ACE-2, angiotensin-converting enzyme 2 ,Pulmonary and Respiratory Medicine ,ILCs, innate lymphocytes or innate lymphoid cells ,Antiviral Agents ,Virus ,Diseases of the respiratory system ,03 medical and health sciences ,Immune system ,Humans ,IFN, interferon ,SARS, severe acute respiratory syndrome ,ARDS, acute respiratory distress syndrome ,Aged ,Inflammation ,Innate immune system ,RC705-779 ,SARS-CoV-2 ,business.industry ,COVID-19 ,biochemical phenomena, metabolism, and nutrition ,Respiration, Artificial ,Immunity, Innate ,IL, interleukin ,MAS, macrophage activation syndrome ,SARS-CoV-1, coronavirus-related first severe acute respiratory syndrome ,IVIG, intravenous immunoglobulin ,MERS-CoV, coronavirus-related Middle Eastern Respiratory syndrome ,030228 respiratory system ,DAMPs, damage-associated molecular patterns ,Immunology ,MBL, mannose binding lectin ,biology.protein ,MoAb, monoclonal antibody ,Lung Diseases, Interstitial ,C, complement factor (e.g. C3a, C3b, C4, C5, C5a) ,business ,CoV, coronaviruses - Abstract
SARS-CoV-2 is a new beta coronavirus, similar to SARS-CoV-1, that emerged at the end of 2019 in the Hubei province of China. It is responsible for coronavirus disease 2019 (COVID-19), which was declared a pandemic by the World Health Organization on March 11, 2020. The ability to gain quick control of the pandemic has been hampered by a lack of detailed knowledge about SARS-CoV-2-host interactions, mainly in relation to viral biology and host immune response. The rapid clinical course seen in COVID-19 indicates that infection control in asymptomatic patients or patients with mild disease is probably due to the innate immune response, as, considering that SARS-CoV-2 is new to humans, an effective adaptive response would not be expected to occur until approximately 2–3 weeks after contact with the virus. Antiviral innate immunity has humoral components (complement and coagulation-fibrinolysis systems, soluble proteins that recognize glycans on cell surface, interferons, chemokines, and naturally occurring antibodies) and cellular components (natural killer cells and other innate lymphocytes). Failure of this system would pave the way for uncontrolled viral replication in the airways and the mounting of an adaptive immune response, potentially amplified by an inflammatory cascade. Severe COVID-19 appears to be due not only to viral infection but also to a dysregulated immune and inflammatory response. In this paper, the authors review the most recent publications on the immunobiology of SARS-CoV-2, virus interactions with target cells, and host immune responses, and highlight possible associations between deficient innate and acquired immune responses and disease progression and mortality. Immunotherapeutic strategies targeting both the virus and dysfunctional immune responses are also addressed.
- Published
- 2021
47. Prospects of animal models and their application in studies on adaptive immunity to SARS-CoV-2
- Author
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Xiaohui, Wei, Na, Rong, and Jiangning, Liu
- Subjects
SARS-CoV-2 ,Models, Animal ,Immunology ,Animals ,COVID-19 ,Humans ,Immunology and Allergy ,Adaptive Immunity ,Antiviral Agents - Abstract
The adaptive immune response induced by SARS-CoV-2 plays a key role in the antiviral process and can protect the body from the threat of infection for a certain period of time. However, owing to the limitations of clinical studies, the antiviral mechanisms, protective thresholds, and persistence of the immune memory of adaptive immune responses remain unclear. This review summarizes existing research models for SARS-CoV-2 and elaborates on the advantages of animal models in simulating the clinical symptoms of COVID-19 in humans. In addition, we systematically summarize the research progress on the SARS-CoV-2 adaptive immune response and the remaining key issues, as well as the application and prospects of animal models in this field. This paper provides direction for in-depth analysis of the anti-SARS-CoV-2 mechanism of the adaptive immune response and lays the foundation for the development and application of vaccines and drugs.
- Published
- 2022
48. Research progress on Toll-like receptor signal transduction and its roles in antimicrobial immune responses
- Author
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Guoqiang Zhu, Li Yan, Siqi Lian, Pengpeng Xia, Qiangde Duan, Xia Meng, and Yunping Wu
- Subjects
Microorganism ,Chemokine ,Signal transduction ,Adaptive Immunity ,Applied Microbiology and Biotechnology ,03 medical and health sciences ,Immune system ,Anti-Infective Agents ,Animals ,Receptor ,030304 developmental biology ,0303 health sciences ,Toll-like receptor ,Innate immune system ,biology ,030306 microbiology ,Toll-Like Receptors ,Pattern recognition receptor ,General Medicine ,Mini-Review ,Acquired immune system ,Immunity, Innate ,Cell biology ,biology.protein ,Anti-infective immunity ,Biotechnology - Abstract
When microorganisms invade a host, the innate immune system first recognizes the pathogen-associated molecular patterns of these microorganisms through pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are known transmembrane PRRs existing in both invertebrates and vertebrates. Upon ligand recognition, TLRs initiate a cascade of signaling events; promote the pro-inflammatory cytokine, type I interferon, and chemokine expression; and play an essential role in the modulation of the host's innate and adaptive immunity. Therefore, it is of great significance to improve our understanding of antimicrobial immune responses by studying the role of TLRs and their signal molecules in the host's defense against invading microbes. This paper aims to summarize the specificity of TLRs in recognition of conserved microbial components, such as lipoprotein, lipopolysaccharide, flagella, endosomal nucleic acids, and other bioactive metabolites derived from microbes. This set of interactions helps to elucidate the immunomodulatory effect of TLRs and the signal transduction changes involved in the infectious process and provide a novel therapeutic strategy to combat microbial infections.
- Published
- 2021
49. Interlocked feedback loops balance the adaptive immune response
- Author
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Lingli, Zhou, Fengqing, Fu, Yao, Wang, and Ling, Yang
- Subjects
Feedback, Physiological ,Computer Simulation ,Adaptive Immunity ,Models, Biological ,Feedback - Abstract
Adaptive immune responses can be activated by harmful stimuli. Upon activation, a cascade of biochemical events ensues the proliferation and the differentiation of T cells, which can remove the stimuli and undergo cell death to maintain immune cell homeostasis. However, normal immune processes can be disrupted by certain dysregulations, leading to pathological responses, such as cytokine storms and immune escape. In this paper, a qualitative mathematical model, composed of key feedback loops within the immune system, was developed to study the dynamics of various response behaviors. First, simulation results of the model well reproduce the results of several immune response processes, particularly pathological immune responses. Next, we demonstrated how the interaction of positive and negative feedback loops leads to irreversible bistable, reversible bistable and monostable, which characterize different immune response processes: cytokine storm, normal immune response, immune escape. The stability analyses suggest that the switch-like behavior is the basis of rapid activation of the immune system, and a balance between positive and negative regulation loops is necessary to prevent pathological responses. Furthermore, we have shown how the treatment moves the system back to a healthy state from the pathological immune response. The bistable mechanism that revealed in this work is helpful to understand the dynamics of different immune response processes.
- Published
- 2022
50. Changing the paradigm of IFN-γ at the interface between innate and adaptive immunity: Macrophage-derived IFN-γ
- Author
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Soraya Mezouar, Jean-Louis Mege, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille)
- Subjects
0301 basic medicine ,Immunology ,Adaptive Immunity ,Biology ,Models, Biological ,Interferon-gamma ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Placenta ,medicine ,Animals ,Humans ,Immunology and Allergy ,[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology ,ComputingMilieux_MISCELLANEOUS ,[SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases ,Fetus ,Innate immune system ,Macrophages ,Cell Biology ,Acquired immune system ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Immunity, Innate ,3. Good health ,Crosstalk (biology) ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Ifn gamma ,Signal Transduction - Abstract
IFN-γ plays a critical role in the immune response to bacterial infections. It is established that IFN-γ is mainly produced by NK/ILC1 cells and T cells, and most of papers have rejected the biologic reality of alternative sources for more than 20 years. Here, we are proposing to revisit this dogma and discuss the role of macrophage-derived IFN-γ in bacterial infections. Our hypothesis is based on a panel of publications and is recently revived by our results on placenta, a chimeric organ in which the immune response is tailored to protect the fetus from mother’s immune response. The culture of purified placental macrophages is associated with a production of IFN-γ that may contribute to fetal protection from bacterial infections before eliciting a Th1-like immune response potentially pathogenic for pregnancy. Hence, macrophage IFN-γ may be a novel actor of early crosstalk between innate and adaptive immunity in the context of host defense against bacterial infections.
- Published
- 2020
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