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Zhang Y, Wang M, Xu W, Zang H, Yan T, Wu T, Huang K, Chen D, Luo Q, Guo R, Qiu J. Analysis of the Expression Patterns of piRNAs in Response to Microsporidian Invasion in Midgut of Workers ( Apis cerana cerana). Int J Mol Sci 2025; 26:2402. [PMID: 40141043 PMCID: PMC11942432 DOI: 10.3390/ijms26062402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/01/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025] Open
Abstract
Piwi-interacting RNAs (piRNAs) play an essential part in transposon suppression, DNA methylation, and antiviral responses. The current understanding of the roles of piRNAs in honeybees is very limited. This study aims to analyze the expression pattern and regulatory role of piRNAs in the Asian honeybee (Apis cerana) responding to infection by Nosema ceranae, based on previously gained small RNA-seq data. Here, 450 and 422 piRNAs were respectively identified in the midgut tissues of Apis cerana cerana workers at 7 and 10 days post-inoculation (dpi) with N. ceranae, including 539 non-redundant ones. Additionally, one up-regulated (piR-ace-1216942) and one down-regulated (piR-ace-776728) piRNA were detected in the workers' midgut at 7 dpi, targeting 381 mRNAs involved in 31 GO terms, such as metabolic processes, catalytic activity, and organelles, as well as 178 KEGG pathways, including lysosome, MAPK signaling pathway, and purine metabolism. A total of 35 up-regulated and 11 down-regulated piRNAs were screened from the workers' midgut at 10 dpi, targeting 13,511 mRNAs engaged in 50 GO terms, such as biological regulation, transporter activity, and membrane, as well as 389 KEGG pathways, including the JAK-STAT signaling pathway, Hippo signaling pathway, and nitrogen metabolism. Further analysis indicated that 28 differentially expressed piRNAs (DEpiRNAs) in the midgut at 10 dpi could target 299 mRNAs annotated to three cellular immune pathways (lysosome, endocytosis, and phagosome), while 24 DEpiRNAs could target 205 mRNAs relevant to four humoral immune pathways (FoxO, JAK-STAT, NF-κB, and MAPK signaling pathway). Through Sanger sequencing and RT-qPCR, the expression of six randomly selected DEpiRNAs was verified. Moreover, the dual-luciferase reporter gene assay confirmed the binding relationships between piR-ace-446232 and CRT as well as between piR-ace-1008436 and EGFR. Our findings not only contribute to enrich our understanding of the role of piRNAs in honeybees but also provide a basis for exploring the host response to N. ceranae infection mediated by piRNAs.
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Affiliation(s)
- Yiqiong Zhang
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.Z.); (M.W.); (W.X.); (H.Z.); (T.W.); (K.H.); (D.C.)
| | - Mengyi Wang
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.Z.); (M.W.); (W.X.); (H.Z.); (T.W.); (K.H.); (D.C.)
| | - Wenhua Xu
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.Z.); (M.W.); (W.X.); (H.Z.); (T.W.); (K.H.); (D.C.)
| | - He Zang
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.Z.); (M.W.); (W.X.); (H.Z.); (T.W.); (K.H.); (D.C.)
- National & Local United Engineering Laboratory of Natural Biotoxin, Fuzhou 350002, China; (T.Y.); (Q.L.)
- Apitherapy Research Institute of Fujian Province, Fuzhou 350002, China
| | - Tizhen Yan
- National & Local United Engineering Laboratory of Natural Biotoxin, Fuzhou 350002, China; (T.Y.); (Q.L.)
| | - Tao Wu
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.Z.); (M.W.); (W.X.); (H.Z.); (T.W.); (K.H.); (D.C.)
| | - Kaifei Huang
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.Z.); (M.W.); (W.X.); (H.Z.); (T.W.); (K.H.); (D.C.)
| | - Dafu Chen
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.Z.); (M.W.); (W.X.); (H.Z.); (T.W.); (K.H.); (D.C.)
- National & Local United Engineering Laboratory of Natural Biotoxin, Fuzhou 350002, China; (T.Y.); (Q.L.)
- Apitherapy Research Institute of Fujian Province, Fuzhou 350002, China
| | - Qingming Luo
- National & Local United Engineering Laboratory of Natural Biotoxin, Fuzhou 350002, China; (T.Y.); (Q.L.)
| | - Rui Guo
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.Z.); (M.W.); (W.X.); (H.Z.); (T.W.); (K.H.); (D.C.)
- National & Local United Engineering Laboratory of Natural Biotoxin, Fuzhou 350002, China; (T.Y.); (Q.L.)
- Apitherapy Research Institute of Fujian Province, Fuzhou 350002, China
| | - Jianfeng Qiu
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou 350002, China; (Y.Z.); (M.W.); (W.X.); (H.Z.); (T.W.); (K.H.); (D.C.)
- National & Local United Engineering Laboratory of Natural Biotoxin, Fuzhou 350002, China; (T.Y.); (Q.L.)
- Apitherapy Research Institute of Fujian Province, Fuzhou 350002, China
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Wang Z, Gu Y, Qu Y, Huang X, Sun T, Wu W, Hu Q, Chen X, Li Y, Zhao H, Hu Y, Wu B, Xu J. Prevention of Intrauterine Adhesion with Platelet-Rich Plasma Double-Network Hydrogel. Adv Biol (Weinh) 2025; 9:e2400336. [PMID: 39673358 DOI: 10.1002/adbi.202400336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 10/30/2024] [Indexed: 12/16/2024]
Abstract
Intrauterine adhesion (IUA) can negatively impact on pregnancy outcomes, leading to reduced pregnancy rates, secondary infertility, and an increased risk of pregnancy complications. Studies have shown that the application of platelet-rich plasma (PRP) in IUA patients is effective. However, the clinical readhesive rate of IUA after treatment is still high, especially in severe cases. Platelet-rich plasma double-network hydrogel (DN gel) is an engineered PRP double network hydrogel, which is a sodium alginate (SA) based PRP hydrogel with egg carton ion cross-linking and fibrin double network. The results of this study show that intrauterine injection of DN gel has a better effect on promoting endometrial regeneration and enhancing endometrial receptivity than PRP gel. The mechanism is analyzed through single-cell sequencing, which may be achieved by increasing the expression of neutrophils (Neut), natural killer cells (NK), and type I classical dendritic cells (cDC1) in the endometrium and inhibiting the infiltration of M2 macrophages. Overall, based on the good healing efficiency and good biocompatibility of DN gel, it is expected to become a method of treating IUA with better efficacy and faster clinical translation.
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Affiliation(s)
- Zhuomin Wang
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Ying Gu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Yiyuan Qu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Xujia Huang
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Tao Sun
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Wei Wu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
- Department of Assisted Reproduction, Women's Hospital School of Medicine Zhejiang University, Hangzhou, Zhejiang, 310006, China
| | - Qianyu Hu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Xiao Chen
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Yu Li
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Huafei Zhao
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Yingying Hu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Bingbing Wu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Jian Xu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
- Department of Assisted Reproduction, Women's Hospital School of Medicine Zhejiang University, Hangzhou, Zhejiang, 310006, China
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Liu Q, Ou Y, Liu T, He Y, Quan X, Ouyang R, Shi Z. Preliminary evidence of immune infiltration and neutrophil degranulation in peripheral blood of non-obese OSA patients related to cognitive decline. Sci Rep 2025; 15:3481. [PMID: 39875482 PMCID: PMC11775174 DOI: 10.1038/s41598-025-88034-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 01/23/2025] [Indexed: 01/30/2025] Open
Abstract
Obstructive sleep apnea (OSA) patients have varying degrees of cognitive impairment, but the specific pathogenic mechanism is still unclear. Meanwhile, poor compliance with continuous positive airway pressure (CPAP) in OSA prompts better solutions. This study aimed to identify differentially expressed genes between the non-obese OSA patients and healthy controls, and to explore potential biomarkers associated with cognitive impairment. Cohorts of healthy control (n = 20) and non-obese, treatment-naïve OSA patients (n = 20) were recruited. We collected their peripheral blood mononuclear cells and neutrophils, and their cognitive performances were evaluated by the Montreal Cognitive Assessment (MoCA). The differentially expressed genes were identified by bioinformatic analysis and confirmed by PCR. Imbalanced immune cell proportions were assessed by Cibersort. Biomarkers related to enriched cellular pathways were measured by ELISA. OSA patients showed a significant decline in overall cognitive function and were associated with higher daytime sleepiness scores. Multiple signaling pathways were enriched in the non-obese OSA cohort, including upregulation of neutrophil-degranulation. Increased monocyte proportion and decreased NK cell proportion were figured out. The relevant genes, including upregulated defensin alpha 4 (DEFA4), haptoglobin (HP), survivin (BIRC5), and suppressed interferon gamma (IFNG) expression were detected. The relative expression of DEFA4 was significantly correlated with the MoCA score and sleep parameters. Biomarkers such as myeloperoxidase (MPO), H2O2, and lipocalin-2, as representatives of neutrophils' activation, elevated significantly in the OSA group. The data demonstrated a positive correlation between MPO and oxygen desaturation index (ODI) and a negative correlation between MPO and lowest oxygen saturation (LSaO2). The level of Lipocalin-2 was positively correlated with apnea-hypopnea index (AHI) and ODI and negatively correlated with LSaO2 and MoCA score. We also observed a negative correlation between H2O2 and mean oxygen saturation (MSaO2). Degranulation of neutrophils was activated in non-obese OSA patients without other complications. The process is related to OSA severity and cognitive impairment, implying its role in pathogenesis.
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Affiliation(s)
- Qingqing Liu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan, 410011, China
- Diagnosis and Treatment Center of Respiratory Disease in Hunan Province, Changsha, Hunan, 410011, China
| | - Yanru Ou
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan, 410011, China
- Diagnosis and Treatment Center of Respiratory Disease in Hunan Province, Changsha, Hunan, 410011, China
| | - Ting Liu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan, 410011, China
- Diagnosis and Treatment Center of Respiratory Disease in Hunan Province, Changsha, Hunan, 410011, China
| | - Yuming He
- Geneplus-Shenzhen, Shenzhen, 518118, China
| | | | - Ruoyun Ouyang
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, China.
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan, 410011, China.
- Diagnosis and Treatment Center of Respiratory Disease in Hunan Province, Changsha, Hunan, 410011, China.
| | - Zhihui Shi
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, China.
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan, 410011, China.
- Diagnosis and Treatment Center of Respiratory Disease in Hunan Province, Changsha, Hunan, 410011, China.
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Jurjus A, El Masri J, Ghazi M, El Ayoubi LM, Soueid L, Gerges Geagea A, Jurjus R. Mechanism of Action of Melatonin as a Potential Adjuvant Therapy in Inflammatory Bowel Disease and Colorectal Cancer. Nutrients 2024; 16:1236. [PMID: 38674926 PMCID: PMC11054672 DOI: 10.3390/nu16081236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/18/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
Inflammatory bowel disease (IBD), a continuum of chronic inflammatory diseases, is tightly associated with immune system dysregulation and dysbiosis, leading to inflammation in the gastrointestinal tract (GIT) and multiple extraintestinal manifestations. The pathogenesis of IBD is not completely elucidated. However, it is associated with an increased risk of colorectal cancer (CRC), which is one of the most common gastrointestinal malignancies. In both IBD and CRC, a complex interplay occurs between the immune system and gut microbiota (GM), leading to the alteration in GM composition. Melatonin, a neuroendocrine hormone, was found to be involved with this interplay, especially since it is present in high amounts in the gut, leading to some protective effects. Actually, melatonin enhances the integrity of the intestinal mucosal barrier, regulates the immune response, alleviates inflammation, and attenuates oxidative stress. Thereby, the authors summarize the multifactorial interaction of melatonin with IBD and with CRC, focusing on new findings related to the mechanisms of action of this hormone, in addition to its documented positive outcomes on the treatment of these two pathologies and possible future perspectives to use melatonin as an adjuvant therapy.
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Affiliation(s)
- Abdo Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
| | - Jad El Masri
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
- Faculty of Medical Sciences, Lebanese University, Beirut 6573, Lebanon;
| | - Maya Ghazi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
- Faculty of Medical Sciences, Lebanese University, Beirut 6573, Lebanon;
| | | | - Lara Soueid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
| | - Alice Gerges Geagea
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
| | - Rosalyn Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
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Ding S, Zhang T, Lei Y, Liu C, Liu Z, Fu R. The role of TIM3 + NK and TIM3 - NK cells in the immune pathogenesis of severe aplastic anemia. J Transl Int Med 2024; 12:96-105. [PMID: 38525441 PMCID: PMC10956726 DOI: 10.2478/jtim-2023-0104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2024] Open
Abstract
Background Natural killer (NK) cells play important immunoregulatory roles in the immune pathogenesis of severe aplastic anemia (SAA). Our previous research showed that SAA caused a decrease in T cell immunoglobulin mucin-3 (TIM3) expression on NK cells. Here we investigated the expression of surface receptors, and the cytotoxicity of peripheral TIM3+ NK and TIM3- NK cells in patients with SAA. Methods The expressions of surface receptors and cytoplasmic protein of TIM3+ NK and TIM3- NK cells from peripheral blood were detected by FCM. The functions of mDCs, and apoptosis rate of K562 cells after co-culture with TIM3+ NK and TIM3- NK cells were maesured by FCM. Westren-blot was used to detect the changes of TIM3+ NK and TIM3- NK signaling pathway proteins (AKT, P-AKT) and compare the functional activity of the two groups. Results Activating receptors NKG2D and Granzyme B were higher, while inhibiting receptors NKG2A, CD158a and CD158b were lower on TIM3- NK cells compared with TIM3+ NK cells in patients with SAA. In SAA, the expression of CD80 and CD86 on mDCs (Myeloid dendritic cells) was significantly decreased after incubation with TIM3- NK cells. The apoptosis rate (AR) of K562 cells was significantly increased after being incubated with TIM3- NK cells in SAA. The level of signal pathway protein AKT of TIM3- NK cells in SAA was similar to that of TIM3+ NK cells, and the levels of P-AKT and P-AKT/AKT ratio of TIM3- NK cells were significantly higher than those of TIM3+ NK cells. Conclusions Therefore, TIM3 exerts its inhibitory effect on NK cells and participates in the immune pathogenesis of SAA. Low expression of TIM3 contributes to the enhancement of NK cell activity which in turn inhibits the immune activation state of SAA and improves the disease state. Our research may aid the development of new therapeutic strategies based on TIM3-NK cells infusion for the treatment of SAA.
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Affiliation(s)
- Shaoxue Ding
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin300052, China
| | - Tian Zhang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin300052, China
| | - Yingying Lei
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin300052, China
| | - Chunyan Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin300052, China
| | - Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin300052, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin300052, China
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Wang R, Ma X, Zhang X, Jiang D, Mao H, Li Z, Tian Y, Cheng B. Autophagy-mediated NKG2D internalization impairs NK cell function and exacerbates radiation pneumonitis. Front Immunol 2023; 14:1250920. [PMID: 38077388 PMCID: PMC10704197 DOI: 10.3389/fimmu.2023.1250920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 10/24/2023] [Indexed: 12/18/2023] Open
Abstract
Introduction Radiation pneumonitis is a critical complication that constrains the use of radiation therapy for thoracic malignancies, leading to substantial morbidity via respiratory distress and lung function impairment. The role of Natural killer (NK) cells in inflammatory diseases is well-documented; however, their involvement in radiation pneumonitis is not fully understood. Methods To explore the involvement of NK cells in radiation pneumonitis, we analyzed tissue samples for NK cell presence and function. The study utilized immunofluorescence staining, western blotting, and immunoprecipitation to investigate CXCL10 and ROS levels, autophagy activity, and NKG2D receptor dynamics in NK cells derived from patients and animal models subjected to radiation. Result In this study, we observed an augmented infiltration of NK cells in tissues affected by radiation pneumonitis, although their function was markedly diminished. In animal models, enhancing NK cell activity appeared to decelerate the disease progression. Concomitant with the disease course, there was a notable upsurge in CXCL10 and ROS levels. CXCL10 was found to facilitate NK cell migration through CXCR3 receptor activation. Furthermore, evidence of excessive autophagy in patient NK cells was linked to ROS accumulation, as indicated by immunofluorescence and Western blot analyses. The association between the NKG2D receptor and its adaptor proteins (AP2 subunits AP2A1 and AP2M1), LC3, and lysosomes was intensified after radiation exposure, as demonstrated by immunoprecipitation. This interaction led to NKG2D receptor endocytosis and subsequent lysosomal degradation. Conclusion Our findings delineate a mechanism by which radiation-induced lung injury may suppress NK cell function through an autophagy-dependent pathway. The dysregulation observed suggests potential therapeutic targets; hence, modulating autophagy and enhancing NK cell activity could represent novel strategies for mitigating radiation pneumonitis.
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Affiliation(s)
| | | | | | | | | | | | - Yu Tian
- Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bo Cheng
- Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China
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Yu Y, Niu R, Zhao F, Zhao Y, Wang J, Wang J, Cao Q, Fu R, Nateghahmadi MH, Sun Z. Moderate exercise relieves fluoride-induced liver and kidney inflammatory responses through the IKKβ/NFκB pathway. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:78429-78443. [PMID: 35688983 DOI: 10.1007/s11356-022-21360-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/05/2022] [Indexed: 06/15/2023]
Abstract
With the intensification of environmental pollution, the content of fluoride is increasing in human and animal living environments. Long-term fluoride exposure can cause damage to the liver and kidney, which are the main sites for fluoride metabolism, storage and removal. Moreover, exercise often accompanies the entire process of fluoride exposure in humans and animals. However, the mechanism of exercise on fluoride-induced liver and kidney injury remains unclear. Hence, we established a fluoride exposure and/or exercise mouse model to explore the influence of exercise on fluoride-induced liver and kidney inflammation and the potential mechanism. The results showed that fluoride caused obvious structural and functional damage and the notable recruitment of immunocytes in the liver and kidney. In addition, fluoride increased the levels of IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-21, TNF-α, and TGF-β but decreased the ratio of IFN-γ/IL-4 and IL-2/IL-10, which indicated that fluoride disturbed the inflammatory balance and caused hepatonephritis. In addition, the expression levels of IKKβ and NFκB were increased, and the expression of IκBα was decreased after fluoride exposure, indicating that fluoride activated the IKKβ/NFκB pathway. In summary, long-term moderate treadmill exercise relieved fluoride-induced liver and kidney inflammatory responses through the IKKβ/NFκB pathway, and exercise can be used to prevent fluoride-induced liver and kidney damage.
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Affiliation(s)
- Yanghuan Yu
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicne, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China
| | - Ruiyan Niu
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicne, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China
| | - Fangye Zhao
- Department of Sport, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China
| | - Yangfei Zhao
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicne, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China
| | - Jinglu Wang
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicne, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China
| | - Jixiang Wang
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicne, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China
| | - Qiqi Cao
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicne, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China
| | - Rong Fu
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicne, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China
| | - Mohammad Hassan Nateghahmadi
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicne, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China
| | - Zilong Sun
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Veterinary Medicne, Shanxi Agricultural University, Jinzhong, 030801, Shanxi, China.
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Sadeghi Hassanabadi N, Broux B, Marinović S, Gotthardt D. Innate Lymphoid Cells - Neglected Players in Multiple Sclerosis. Front Immunol 2022; 13:909275. [PMID: 35784374 PMCID: PMC9247827 DOI: 10.3389/fimmu.2022.909275] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/20/2022] [Indexed: 12/29/2022] Open
Abstract
Multiple sclerosis (MS) is a highly debilitating autoimmune disease affecting millions of individuals worldwide. Although classically viewed as T-cell mediated disease, the role of innate lymphoid cells (ILC) such as natural killer (NK) cells and ILC 1-3s has become a focal point as several findings implicate them in the disease pathology. The role of ILCs in MS is still not completely understood as controversial findings have been reported assigning them either a protective or disease-accelerating role. Recent findings in experimental autoimmune encephalomyelitis (EAE) suggest that ILCs infiltrate the central nervous system (CNS), mediate inflammation, and have a disease exacerbating role by influencing the recruitment of autoreactive T-cells. Elucidating the detailed role of ILCs and altered signaling pathways in MS is essential for a more complete picture of the disease pathology and novel therapeutic targets. We here review the current knowledge about ILCs in the development and progression of MS and preclinical models of MS and discuss their potential for therapeutic applications.
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Affiliation(s)
| | - Bieke Broux
- University MSCenter; Campus Diepenbeek, Diepenbeek, Belgium
- Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, UHasselt, Diepenbeek, Belgium
| | - Sonja Marinović
- Division of Molecular Medicine, Laboratory of Personalized Medicine, Ruder Boskovic Institute, Zagreb, Croatia
| | - Dagmar Gotthardt
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
- *Correspondence: Dagmar Gotthardt,
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9
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Salminen A. Clinical perspectives on the age-related increase of immunosuppressive activity. J Mol Med (Berl) 2022; 100:697-712. [PMID: 35384505 PMCID: PMC8985067 DOI: 10.1007/s00109-022-02193-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/10/2022] [Accepted: 03/28/2022] [Indexed: 11/10/2022]
Abstract
The aging process is associated with a remodeling of the immune system involving chronic low-grade inflammation and a gradual decline in the function of the immune system. These processes are also called inflammaging and immunosenescence. The age-related immune remodeling is associated with many clinical changes, e.g., risk for cancers and chronic infections increases, whereas the efficiency of vaccination and immunotherapy declines with aging. On the other hand, there is convincing evidence that chronic inflammatory states promote the premature aging process. The inflammation associated with aging or chronic inflammatory conditions stimulates a counteracting immunosuppression which protects tissues from excessive inflammatory injuries but promotes immunosenescence. Immunosuppression is a driving force in tumors and chronic infections and it also induces the tolerance to vaccination and immunotherapies. Immunosuppressive cells, e.g., myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and type M2 macrophages, have a crucial role in tumorigenesis and chronic infections as well as in the tolerance to vaccination and immunotherapies. Interestingly, there is substantial evidence that inflammaging is also associated with an increased immunosuppressive activity, e.g., upregulation of immunosuppressive cells and anti-inflammatory cytokines. Given that both the aging and chronic inflammatory states involve the activation of immunosuppression and immunosenescence, this might explain why aging is a risk factor for tumorigenesis and chronic inflammatory states and conversely, chronic inflammatory insults promote the premature aging process in humans.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
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10
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Stephen B, Hajjar J. Immune System in Action. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1342:1-43. [PMID: 34972961 DOI: 10.1007/978-3-030-79308-1_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells is found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the crosstalk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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Affiliation(s)
- Bettzy Stephen
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Joud Hajjar
- Assistant Professor, Service Chief of Adult Allergy & Immunology, Division of Immunology, Allergy & Retrovirology, Baylor College of Medicine and Texas Children' Hospital, Houston, TX, USA
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11
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Chavez-Dominguez R, Perez-Medina M, Aguilar-Cazares D, Galicia-Velasco M, Meneses-Flores M, Islas-Vazquez L, Camarena A, Lopez-Gonzalez JS. Old and New Players of Inflammation and Their Relationship With Cancer Development. Front Oncol 2021; 11:722999. [PMID: 34881173 PMCID: PMC8645998 DOI: 10.3389/fonc.2021.722999] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 11/04/2021] [Indexed: 12/18/2022] Open
Abstract
Pathogens or genotoxic agents continuously affect the human body. Acute inflammatory reaction induced by a non-sterile or sterile environment is triggered for the efficient elimination of insults that caused the damage. According to the insult, pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostasis-altering molecular processes are released to facilitate the arrival of tissue resident and circulating cells to the injured zone to promote harmful agent elimination and tissue regeneration. However, when inflammation is maintained, a chronic phenomenon is induced, in which phagocytic cells release toxic molecules damaging the harmful agent and the surrounding healthy tissues, thereby inducing DNA lesions. In this regard, chronic inflammation has been recognized as a risk factor of cancer development by increasing the genomic instability of transformed cells and by creating an environment containing proliferation signals. Based on the cancer immunoediting concept, a rigorous and regulated inflammation process triggers participation of innate and adaptive immune responses for efficient elimination of transformed cells. When immune response does not eliminate all transformed cells, an equilibrium phase is induced. Therefore, excessive inflammation amplifies local damage caused by the continuous arrival of inflammatory/immune cells. To regulate the overstimulation of inflammatory/immune cells, a network of mechanisms that inhibit or block the cell overactivity must be activated. Transformed cells may take advantage of this process to proliferate and gradually grow until they become preponderant over the immune cells, preserving, increasing, or creating a microenvironment to evade the host immune response. In this microenvironment, tumor cells resist the attack of the effector immune cells or instruct them to sustain tumor growth and development until its clinical consequences. With tumor development, evolving, complex, and overlapping microenvironments are arising. Therefore, a deeper knowledge of cytokine, immune, and tumor cell interactions and their role in the intricated process will impact the combination of current or forthcoming therapies.
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Affiliation(s)
- Rodolfo Chavez-Dominguez
- Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico.,Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
| | - Mario Perez-Medina
- Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico.,Laboratorio de Quimioterapia Experimental, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Dolores Aguilar-Cazares
- Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico
| | - Miriam Galicia-Velasco
- Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico
| | - Manuel Meneses-Flores
- Departamento de Patología, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico
| | - Lorenzo Islas-Vazquez
- Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico
| | - Angel Camarena
- Laboratorio de Human Leukocyte Antigen (HLA), Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico
| | - Jose S Lopez-Gonzalez
- Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico
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12
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Elemam NM, Ramakrishnan RK, Hundt JE, Halwani R, Maghazachi AA, Hamid Q. Innate Lymphoid Cells and Natural Killer Cells in Bacterial Infections: Function, Dysregulation, and Therapeutic Targets. Front Cell Infect Microbiol 2021; 11:733564. [PMID: 34804991 PMCID: PMC8602108 DOI: 10.3389/fcimb.2021.733564] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Infectious diseases represent one of the largest medical challenges worldwide. Bacterial infections, in particular, remain a pertinent health challenge and burden. Moreover, such infections increase over time due to the continuous use of various antibiotics without medical need, thus leading to several side effects and bacterial resistance. Our innate immune system represents our first line of defense against any foreign pathogens. This system comprises the innate lymphoid cells (ILCs), including natural killer (NK) cells that are critical players in establishing homeostasis and immunity against infections. ILCs are a group of functionally heterogenous but potent innate immune effector cells that constitute tissue-resident sentinels against intracellular and extracellular bacterial infections. Being a nascent subset of innate lymphocytes, their role in bacterial infections is not clearly understood. Furthermore, these pathogens have developed methods to evade the host immune system, and hence permit infection spread and tissue damage. In this review, we highlight the role of the different ILC populations in various bacterial infections and the possible ways of immune evasion. Additionally, potential immunotherapies to manipulate ILC responses will be briefly discussed.
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Affiliation(s)
- Noha Mousaad Elemam
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Rakhee K Ramakrishnan
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jennifer E Hundt
- Lübeck Institute for Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Rabih Halwani
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Prince Abdullah Ben Khaled Celiac Disease Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Azzam A Maghazachi
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada
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13
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Zhang P, Yang CL, Du T, Liu YD, Ge MR, Li H, Liu RT, Wang CC, Dou YC, Duan RS. Diabetes mellitus exacerbates experimental autoimmune myasthenia gravis via modulating both adaptive and innate immunity. J Neuroinflammation 2021; 18:244. [PMID: 34702288 PMCID: PMC8549151 DOI: 10.1186/s12974-021-02298-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/17/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a common concomitant disease of late-onset myasthenia gravis (MG). However, the impacts of DM on the progression of late-onset MG were unclear. METHODS In this study, we examined the immune response in experimental autoimmune myasthenia gravis (EAMG) rats with DM or not. The phenotype and function of the spleen and lymph nodes were determined by flow cytometry. The serum antibodies, Tfh cells, and germinal center B cells were determined by ELISA and flow cytometry. The roles of advanced glycation end products (AGEs) in regulating Tfh cells were further explored in vitro by co-culture assays. RESULTS Our results indicated clinical scores of EAMG rats were worse in diabetes rats compared to control, which was due to the increased production of anti-R97-116 antibody and antibody-secreting cells. Furthermore, diabetes induced a significant upregulation of Tfh cells and the subtypes of Tfh1 and Tfh17 cells to provide assistance for antibody production. The total percentages of B cells were increased with an activated statue of improved expression of costimulatory molecules CD80 and CD86. We found CD4+ T-cell differentiation was shifted from Treg cells towards Th1/Th17 in the DM+EAMG group compared to the EAMG group. In addition, in innate immunity, diabetic EAMG rats displayed more CXCR5 expression on NK cells. However, the expression of CXCR5 on NKT cells was down-regulated with the increased percentages of NKT cells in the DM+EAMG group. Ex vivo studies further indicated that Tfh cells were upregulated by AGEs instead of hyperglycemia. The upregulation was mediated by the existence of B cells, the mechanism of which might be attributed the elevated molecule CD40 on B cells. CONCLUSIONS Diabetes promoted both adaptive and innate immunity and exacerbated clinical symptoms in EAMG rats. Considering the effect of diabetes, therapy in reducing blood glucose levels in MG patients might improve clinical efficacy through suppressing the both innate and adaptive immune responses. Additional studies are needed to confirm the effect of glucose or AGEs reduction to seek treatment for MG.
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Affiliation(s)
- Peng Zhang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China.,Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China.,Shandong Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, 250014, People's Republic of China
| | - Chun-Lin Yang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China.,Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China.,Shandong Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, 250014, People's Republic of China
| | - Tong Du
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China.,Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China.,Shandong Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, 250014, People's Republic of China
| | - Yu-Dong Liu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China.,Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China.,Shandong Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, 250014, People's Republic of China
| | - Meng-Ru Ge
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China.,School of Medicine, Tongji University, Shanghai, 200092, People's Republic of China
| | - Heng Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China.,Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China.,Shandong Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, 250014, People's Republic of China
| | - Ru-Tao Liu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China.,Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China.,Shandong Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, 250014, People's Republic of China
| | - Cong-Cong Wang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China.,Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China.,Shandong Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, 250014, People's Republic of China
| | - Ying-Chun Dou
- College of Basic Medical Sciences, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China
| | - Rui-Sheng Duan
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China. .,Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China. .,Shandong Key Laboratory for Rheumatic Disease and Translational Medicine, Jinan, 250014, People's Republic of China.
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14
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Chen CC, Hung YM, Chiu LT, Chou MC, Chang R, Wei JCC. Association Between Severity of Leptospirosis and Subsequent Major Autoimmune Diseases: A Nationwide Observational Cohort Study. Front Immunol 2021; 12:721752. [PMID: 34566978 PMCID: PMC8461302 DOI: 10.3389/fimmu.2021.721752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/04/2021] [Indexed: 11/17/2022] Open
Abstract
Introduction Infections play a role in autoimmune diseases (AD). Leptospirosis has been linked to the trigger of systemic lupus erythematosus. Objective To investigate subsequent risk of major AD in hospitalized Taiwanese for Leptospirosis. Methods Retrospective observational cohort study was employed. The enrolled period was from 2000 to 2012. In the main model, we extracted 4026 inpatients with leptospirosis from the Taiwan National Health Insurance Research Database (NHIRD) and 16,104 participants without leptospirosis at a 1:4 ratio propensity-score matched (PSM) by age, gender, index year, and comorbidities. The follow-up period was defined as the time from the initial diagnosis of leptospirosis to major AD occurrence or 2013. This study was re-analyzed by frequency-matching as a sensitivity analysis for cross-validation. Univariable and multivariable Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results The adjusted HR (95% CI) of major ADs for the leptospirosis group was 4.45 (3.25–6.79) (p < 0.001) compared to the controls after full adjustment. The risk of major ADs was 5.52-fold (95% CI, 3.82–7.99) higher in leptospirosis patients hospitalized for seven days and above than the controls, while 2.80-fold (95% CI, 1.68–5.61) in those hospitalized less than seven days. The sensitivity analysis yields consistent findings. Stratified analysis revealed that the association between leptospirosis and major ADs was generalized in both genders, and all age groups. Conclusions Symptomatic leptospirosis is associated with increased rate of subsequent major ADs, and the risk seems to be higher in severe cases.
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Affiliation(s)
- Chih-Chung Chen
- Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Yao-Min Hung
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,College of Health and Nursing, Meiho University, Pingtung, Taiwan.,Department of Internal Medicine, Kaohsiung Municipal United Hospital, Kaohsiung, Taiwan.,School of Medicine, National Yang Ming University, Taipei, Taiwan
| | - Lu-Ting Chiu
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Mei-Chia Chou
- Department of Physical Therapy, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan.,Department of Recreation and Sports Management, Tajen University, Pingtung County, Taiwan.,Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Pingtung Branch, Pingtung County, Taiwan
| | - Renin Chang
- Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Recreation and Sports Management, Tajen University, Pingtung County, Taiwan
| | - James Cheng-Chung Wei
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Division of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
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15
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NK Cell Patterns in Idiopathic Inflammatory Myopathies with Pulmonary Affection. Cells 2021; 10:cells10102551. [PMID: 34685530 PMCID: PMC8534165 DOI: 10.3390/cells10102551] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/14/2021] [Accepted: 09/20/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Pulmonary affection (PA) is associated with a substantial increase in morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). However, the underlying immune mechanisms of PA remain enigmatic and prompt deeper immunological analyses. Importantly, the Janus-faced role of natural killer (NK) cells, capable of pro-inflammatory as well as regulatory effects, might be of interest for the pathophysiologic understanding of PA in IIM. METHODS To extend our understanding of immunological alterations in IIM patients with PA, we compared the signatures of NK cells in peripheral blood using multi-color flow cytometry in IIM patients with (n = 12, of which anti-synthetase syndrome = 8 and dermatomyositis = 4) or without PA (n = 12). RESULTS We did not observe any significant differences for B cells, CD4, and CD8 T cells, while total NK cell numbers in IIM patients with PA were reduced compared to non-PA patients. NK cell alterations were driven by a particular decrease of CD56dim NK cells, while CD56bright NK cells remained unchanged. Comparisons of the cell surface expression of a large panel of NK receptors revealed an increased mean fluorescence intensity of NKG2D+ on NK cells from patients with PA compared with non-PA patients, especially on the CD56dim subset. NKG2D+ and NKp46+ cell surface levels were associated with reduced vital capacity, serving as a surrogate marker for clinical severity of PA. CONCLUSION Our data illustrate that PA in IIM is associated with alterations of the NK cell repertoire, suggesting a relevant contribution of NK cells in certain IIMs, which might pave the way for NK cell-targeted therapeutic approaches.
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16
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Rolfes L, Schulte-Mecklenbeck A, Schreiber S, Vielhaber S, Herty M, Marten A, Pfeuffer S, Ruck T, Wiendl H, Gross CC, Meuth SG, Boentert M, Pawlitzki M. Amyotrophic lateral sclerosis patients show increased peripheral and intrathecal T-cell activation. Brain Commun 2021; 3:fcab157. [PMID: 34405141 PMCID: PMC8363480 DOI: 10.1093/braincomms/fcab157] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2021] [Indexed: 11/30/2022] Open
Abstract
Several studies suggest a role for the peripheral immune system in the pathophysiology of amyotrophic lateral sclerosis. However, comprehensive studies investigating the intrathecal immune system in amyotrophic lateral sclerosis are rare. To elucidate whether compartment-specific inflammation contributes to amyotrophic lateral sclerosis pathophysiology, we here investigated intrathecal and peripheral immune profiles in amyotrophic lateral sclerosis patients and compared them with controls free of neurological disorders (controls) and patients with dementia or primary progressive multiple sclerosis. Routine CSF parameters were examined in 308 patients, including 132 amyotrophic lateral sclerosis patients. In a subgroup of 41 amyotrophic lateral sclerosis patients, extensive flow-cytometric immune cell profiling in peripheral blood and CSF was performed and compared with data from 26 controls, 25 dementia and 21 multiple sclerosis patients. Amyotrophic lateral sclerosis patients presented with significantly altered proportions of monocyte subsets in peripheral blood and increased frequencies of CD4+ and CD8+ T cells expressing the activation marker HLA-DR in peripheral blood (CD8+) and CSF (CD4+ and CD8+) compared with controls. While dementia and multiple sclerosis patients exhibited a comparable increase in intrathecal CD8+ T-cell activation, CD8+ T-cell activation in the peripheral blood in amyotrophic lateral sclerosis was higher than in multiple sclerosis patients. Furthermore, intrathecal CD4+ T-cell activation in amyotrophic lateral sclerosis surpassed levels in dementia patients. Intrathecal T-cell activation resulted from in situ activation rather than transmigration of activated T cells from the blood. While T-cell activation did not correlate with amyotrophic lateral sclerosis progression, patients with rapid disease progression showed reduced intrathecal levels of immune-regulatory CD56bright natural killer cells. The integration of these parameters into a composite score facilitated the differentiation of amyotrophic lateral sclerosis patients from patients of all other cohorts. To conclude, alterations in peripheral monocyte subsets, as well as increased peripheral and intrathecal activation of CD4+ and CD8+ T cells concomitant with diminished immune regulation by CD56bright natural killer cells, suggest an involvement of these immune cells in amyotrophic lateral sclerosis pathophysiology.
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Affiliation(s)
- Leoni Rolfes
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany.,Department of Neurology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf 40225, Germany
| | - Andreas Schulte-Mecklenbeck
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany
| | - Stefanie Schreiber
- Department of Neurology, Otto-von-Guericke University, Magdeburg 39120, Germany.,German Center for Neurodegenerative Diseases, Magdeburg 39120, Germany.,Center for Behavioral Brain Sciences (CBBS), Magdeburg 39106, Germany
| | - Stefan Vielhaber
- Department of Neurology, Otto-von-Guericke University, Magdeburg 39120, Germany.,German Center for Neurodegenerative Diseases, Magdeburg 39120, Germany.,Center for Behavioral Brain Sciences (CBBS), Magdeburg 39106, Germany
| | - Michael Herty
- Institute of Geometry and Applied Mathematics, RWTH Aachen University, Aachen 52062, Germany
| | - Anika Marten
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany
| | - Steffen Pfeuffer
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany
| | - Tobias Ruck
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany.,Department of Neurology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf 40225, Germany
| | - Heinz Wiendl
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany
| | - Catharina C Gross
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany
| | - Sven G Meuth
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany.,Department of Neurology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf 40225, Germany
| | - Matthias Boentert
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany
| | - Marc Pawlitzki
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany
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Han S, Jung M, Kim AS, Lee DY, Cha BH, Putnam CW, Lim KS, Bull DA, Won YW. Peptide Adjuvant to Invigorate Cytolytic Activity of NK Cells in an Obese Mouse Cancer Model. Pharmaceutics 2021; 13:pharmaceutics13081279. [PMID: 34452238 PMCID: PMC8401452 DOI: 10.3390/pharmaceutics13081279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 11/24/2022] Open
Abstract
Cancer patients who are overweight compared to those with normal body weight have obesity-associated alterations of natural killer (NK) cells, characterized by poor cytotoxicity, slow proliferation, and inadequate anti-cancer activity. Concomitantly, prohibitin overexpressed by cancer cells elevates glucose metabolism, rendering the tumor microenvironment (TME) more tumor-favorable, and leading to malfunction of immune cells present in the TME. These changes cause vicious cycles of tumor growth. Adoptive immunotherapy has emerged as a promising option for cancer patients; however, obesity-related alterations in the TME allow the tumor to bypass immune surveillance and to down-regulate the activity of adoptively transferred NK cells. We hypothesized that inhibiting the prohibitin signaling pathway in an obese model would reduce glucose metabolism of cancer cells, thereby changing the TME to a pro-immune microenvironment and restoring the cytolytic activity of NK cells. Priming tumor cells with an inhibitory the prohibitin-binding peptide (PBP) enhances cytokine secretion and augments the cytolytic activity of adoptively transferred NK cells. NK cells harvested from the PBP-primed tumors exhibit multiple markers associated with the effector function of active NK cells. Our findings suggest that PBP has the potential as an adjuvant to enhance the cytolytic activity of adoptively transferred NK cells in cancer patients with obesity.
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Affiliation(s)
- Seungmin Han
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Minjin Jung
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Angela S. Kim
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Daniel Y. Lee
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Byung-Hyun Cha
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Charles W. Putnam
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Kwang Suk Lim
- Interdisciplinary Program in Biohealth-Machinery Convergence Engineering, Department of Biotechnology and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon 24341, Korea;
| | - David A. Bull
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
| | - Young-Wook Won
- Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, AZ 85724, USA; (S.H.); (M.J.); (A.S.K.); (D.Y.L.); (B.-H.C.); (C.W.P.); (D.A.B.)
- Correspondence:
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Schwichtenberg SC, Wisgalla A, Schroeder-Castagno M, Alvarez-González C, Schlickeiser S, Siebert N, Bellmann-Strobl J, Wernecke KD, Paul F, Dörr J, Infante-Duarte C. Fingolimod Therapy in Multiple Sclerosis Leads to the Enrichment of a Subpopulation of Aged NK Cells. Neurotherapeutics 2021; 18:1783-1797. [PMID: 34244929 PMCID: PMC8608997 DOI: 10.1007/s13311-021-01078-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 02/04/2023] Open
Abstract
Fingolimod is an approved oral treatment for relapsing-remitting multiple sclerosis (RRMS) that modulates agonistically the sphingosin-1-phosphate receptor (S1PR), inhibiting thereby the egress of lymphocytes from the lymph nodes. In this interventional prospective clinical phase IV trial, we longitudinally investigated the impact of fingolimod on frequencies of NK cell subpopulations by flow cytometry in 17 RRMS patients at baseline and 1, 3, 6, and 12 months after treatment initiation. Clinical outcome was assessed by the Expanded Disability Status Scale (EDSS) and annualized relapse rates (ARR). Over the study period, median EDSS remained stable from month 3 to month 12, and ARR decreased compared to ARR in the 24 months prior treatment. Treatment was paralleled by an increased frequency of circulating NK cells, due primarily to an increase in CD56dimCD94low mature NK cells, while the CD56bright fraction and CD127+ innate lymphoid cells (ILCs) decreased over time. An unsupervised clustering algorithm further revealed that a particular fraction of NK cells defined by the expression of CD56dimCD16++KIR+/-NKG2A-CD94-CCR7+/-CX3CR1+/-NKG2C-NKG2D+NKp46-DNAM1++CD127+ increased during treatment. This specific phenotype might reflect a status of aged, fully differentiated, and less functional NK cells. Our study confirms that fingolimod treatment affects both NK cells and ILC. In addition, our study suggests that treatment leads to the enrichment of a specific NK cell subset characterized by an aged phenotype. This might limit the anti-microbial and anti-tumour NK cell activity in fingolimod-treated patients.
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Affiliation(s)
- Svenja C Schwichtenberg
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Institute for Medical Immunology, Campus Virchow Klinikum, Augustenburger Platz 1 (Südstr. 2/Föhrer Str. 15), 13353, Berlin, Germany
| | - Anne Wisgalla
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Institute for Medical Immunology, Campus Virchow Klinikum, Augustenburger Platz 1 (Südstr. 2/Föhrer Str. 15), 13353, Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Institute for "Psychiatrie Und Medizinische Klinik M.S. Psychosomatik,", Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany
| | - Maria Schroeder-Castagno
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Institute for Medical Immunology, Campus Virchow Klinikum, Augustenburger Platz 1 (Südstr. 2/Föhrer Str. 15), 13353, Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Neurocure Cluster of Excellence, Campus Mitte, Sauerbruchweg 5, 10117, Berlin, Germany
| | - Cesar Alvarez-González
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Institute for Medical Immunology, Campus Virchow Klinikum, Augustenburger Platz 1 (Südstr. 2/Föhrer Str. 15), 13353, Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Neurocure Cluster of Excellence, Campus Mitte, Sauerbruchweg 5, 10117, Berlin, Germany
| | - Stephan Schlickeiser
- BIH Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Föhrer Str. 15, 13353, Berlin, Germany
| | - Nadja Siebert
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Neurocure Cluster of Excellence, Campus Mitte, Sauerbruchweg 5, 10117, Berlin, Germany
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine & Charité - Universitätsmedizin Berlin, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Judith Bellmann-Strobl
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Neurocure Cluster of Excellence, Campus Mitte, Sauerbruchweg 5, 10117, Berlin, Germany
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine & Charité - Universitätsmedizin Berlin, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Klaus-Dieter Wernecke
- Charité - Universitätsmedizin Berlin and CRO SOSTANA GmbH, Wildensteiner Straße 27, 10318, Berlin, Germany
| | - Friedemann Paul
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Neurocure Cluster of Excellence, Campus Mitte, Sauerbruchweg 5, 10117, Berlin, Germany
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine & Charité - Universitätsmedizin Berlin, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Jan Dörr
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Neurocure Cluster of Excellence, Campus Mitte, Sauerbruchweg 5, 10117, Berlin, Germany
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine & Charité - Universitätsmedizin Berlin, Robert-Rössle-Straße 10, 13125, Berlin, Germany
- Current Affiliation: Multiple Sclerosis Center, Oberhavel Kliniken, Marwitzer Straße 91, 16761, Hennigsdorf, Germany
| | - Carmen Infante-Duarte
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Institute for Medical Immunology, Campus Virchow Klinikum, Augustenburger Platz 1 (Südstr. 2/Föhrer Str. 15), 13353, Berlin, Germany.
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine & Charité - Universitätsmedizin Berlin, Robert-Rössle-Straße 10, 13125, Berlin, Germany.
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Wang CM, Tan KP, Jan Wu YJ, Lin JC, Zheng JW, Yu AL, Wu JM, Chen JY. MICA*019 Allele and Soluble MICA as Biomarkers for Ankylosing Spondylitis in Taiwanese. J Pers Med 2021; 11:jpm11060564. [PMID: 34208618 PMCID: PMC8235541 DOI: 10.3390/jpm11060564] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/23/2022] Open
Abstract
MICA (major histocompatibility complex class I chain-related gene A) interacts with NKG2D on immune cells to regulate host immune responses. We aimed to determine whether MICA alleles are associated with AS susceptibility in Taiwanese. MICA alleles were determined through haplotype analyses of major MICA coding SNP (cSNP) data from 895 AS patients and 896 normal healthy controls in Taiwan. The distributions of MICA alleles were compared between AS patients and normal healthy controls and among AS patients, stratified by clinical characteristics. ELISA was used to determine soluble MICA (sMICA) levels in serum of AS patients and healthy controls. Stable cell lines expressing four major MICA alleles (MICA*002, MICA*008, MICA*010 and MICA*019) in Taiwanese were used for biological analyses. We found that MICA*019 is the only major MICA allele significantly associated with AS susceptibility (PFDR = 2.25 × 10−115; OR, 14.90; 95% CI, 11.83–18.77) in Taiwanese. In addition, the MICA*019 allele is associated with syndesmophyte formation (PFDR = 0.0017; OR, 1.69; 95% CI, 1.29–2.22) and HLA-B27 positivity (PFDR = 1.45 × 10−33; OR, 28.79; 95% CI, 16.83–49.26) in AS patients. Serum sMICA levels were significantly increased in AS patients as compared to healthy controls. Additionally, MICA*019 homozygous subjects produced the highest levels of sMICA, compared to donors with other genotypes. Furthermore, in vitro experiments revealed that cells expressing MICA*019 produced the highest level of sMICA, as compared to other major MICA alleles. In summary, the MICA*019 allele, producing the highest levels of sMICA, is a significant risk factor for AS and syndesmophyte formation in Taiwanese. Our data indicate that a high level of sMICA is a biomarker for AS.
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Affiliation(s)
- Chin-Man Wang
- Department of Rehabilitation, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan;
| | - Keng-Poo Tan
- Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan; (K.-P.T.); (Y-.J.J.W.); (J.-C.L.); (J.-W.Z.)
| | - Yeong-Jian Jan Wu
- Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan; (K.-P.T.); (Y-.J.J.W.); (J.-C.L.); (J.-W.Z.)
| | - Jing-Chi Lin
- Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan; (K.-P.T.); (Y-.J.J.W.); (J.-C.L.); (J.-W.Z.)
| | - Jian-Wen Zheng
- Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan; (K.-P.T.); (Y-.J.J.W.); (J.-C.L.); (J.-W.Z.)
| | - Alice L. Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan 33375, Taiwan;
- Department of Pediatrics, University of California, San Diego, CA 92103, USA
| | - Jian-Ming Wu
- Department of Veterinary and Biomedical Sciences, Department of Medicine, University of Minnesota, Minneapolis, MN 55108, USA;
| | - Ji-Yih Chen
- Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan; (K.-P.T.); (Y-.J.J.W.); (J.-C.L.); (J.-W.Z.)
- Correspondence: ; Tel.: +886-3-328-1200 (ext. 2410); Fax: 886-3-3288-287
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20
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Manolakou T, Verginis P, Boumpas DT. DNA Damage Response in the Adaptive Arm of the Immune System: Implications for Autoimmunity. Int J Mol Sci 2021; 22:5842. [PMID: 34072535 PMCID: PMC8198144 DOI: 10.3390/ijms22115842] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 12/25/2022] Open
Abstract
In complex environments, cells have developed molecular responses to confront threats against the genome and achieve the maintenance of genomic stability assuring the transfer of undamaged DNA to their progeny. DNA damage response (DDR) mechanisms may be activated upon genotoxic or environmental agents, such as cytotoxic drugs or ultraviolet (UV) light, and during physiological processes requiring DNA transactions, to restore DNA alterations that may cause cellular malfunction and affect viability. In addition to the DDR, multicellular organisms have evolved specialized immune cells to respond and defend against infections. Both adaptive and innate immune cells are subjected to DDR processes, either as a prerequisite to the immune response, or as a result of random endogenous and exogenous insults. Aberrant DDR activities have been extensively studied in the immune cells of the innate arm, but not in adaptive immune cells. Here, we discuss how the aberrant DDR may lead to autoimmunity, with emphasis on the adaptive immune cells and the potential of therapeutic targeting.
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Affiliation(s)
- Theodora Manolakou
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;
- School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Panayotis Verginis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 700 13 Heraklion, Greece;
- Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, University of Crete Medical School, 700 13 Heraklion, Greece
| | - Dimitrios T. Boumpas
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;
- Joint Rheumatology Program, 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, 124 62 Athens, Greece
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21
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Müller I, Janson L, Sauter M, Pappritz K, Linthout SV, Tschöpe C, Klingel K. Myeloid-Derived Suppressor Cells Restrain Natural Killer Cell Activity in Acute Coxsackievirus B3-Induced Myocarditis. Viruses 2021; 13:v13050889. [PMID: 34065891 PMCID: PMC8151145 DOI: 10.3390/v13050889] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/03/2021] [Accepted: 05/10/2021] [Indexed: 12/13/2022] Open
Abstract
Murine models of coxsackievirus B3 (CVB3)-induced myocarditis well represent the different outcomes of this inflammatory heart disease. Previously, we found that CVB3-infected A.BY/SnJ mice, susceptible for severe acute and chronic myocarditis, have lower natural killer (NK) cell levels than C57BL/6 mice, with mild acute myocarditis. There is evidence that myeloid-derived suppressor cells (MDSC) may inhibit NK cells, influencing the course of myocarditis. To investigate the MDSC/NK interrelationship in acute myocarditis, we used CVB3-infected A.BY/SnJ mice. Compared to non-infected mice, we found increased cell numbers of MDSC in the spleen and heart of CVB3-infected A.BY/SnJ mice. In parallel, S100A8 and S100A9 were increased in the heart, spleen, and especially in splenic MDSC cells compared to non-infected mice. In vitro experiments provided evidence that MDSC disrupt cytotoxic NK cell function upon co-culturing with MDSC. MDSC-specific depletion by an anti-Ly6G antibody led to a significant reduction in the virus load and injury in hearts of infected animals. The decreased cardiac damage in MDSC-depleted mice was associated with fewer Mac3+ macrophages and CD3+ T lymphocytes and a reduced cardiac expression of S100A8, S100A9, IL-1β, IL-6, and TNF-α. In conclusion, impairment of functional NK cells by MDSC promotes the development of chronic CVB3 myocarditis in A.BY/SnJ mice.
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Affiliation(s)
- Irene Müller
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 10017 Berlin, Germany; (I.M.); (K.P.); (S.V.L.); (C.T.)
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10017 Berlin, Germany
| | - Lisa Janson
- Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, 72076 Tübingen, Germany; (L.J.); (M.S.)
| | - Martina Sauter
- Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, 72076 Tübingen, Germany; (L.J.); (M.S.)
| | - Kathleen Pappritz
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 10017 Berlin, Germany; (I.M.); (K.P.); (S.V.L.); (C.T.)
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10017 Berlin, Germany
| | - Sophie Van Linthout
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 10017 Berlin, Germany; (I.M.); (K.P.); (S.V.L.); (C.T.)
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10017 Berlin, Germany
| | - Carsten Tschöpe
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 10017 Berlin, Germany; (I.M.); (K.P.); (S.V.L.); (C.T.)
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10017 Berlin, Germany
- Department of Cardiology, Campus Virchow Clinic, Charité-Universitätsmedizin Berlin, 10017 Berlin, Germany
| | - Karin Klingel
- Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, 72076 Tübingen, Germany; (L.J.); (M.S.)
- Correspondence: ; Tel.: +49-7071-2980205
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Jiang H, Li Z, Yu L, Zhang Y, Zhou L, Wu J, Yuan J, Han M, Xu T, He J, Wang S, Yu C, Pan S, Wu M, Liu H, Zeng H, Song Z, Wang Q, Qu S, Zhang J, Huang Y, Han J. Immune Phenotyping of Patients With Acute Vogt-Koyanagi-Harada Syndrome Before and After Glucocorticoids Therapy. Front Immunol 2021; 12:659150. [PMID: 33995378 PMCID: PMC8113950 DOI: 10.3389/fimmu.2021.659150] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/12/2021] [Indexed: 11/13/2022] Open
Abstract
Previous studies have established that disturbed lymphocytes are involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) syndrome. Accordingly, glucocorticoids (GCs), with their well-recognized immune-suppressive function, have been widely used for treatment of VKH patients with acute relapses. However, the systemic response of diverse immune cells to GC therapy in VKH is poorly characterized. To address this issue, we analyzed immune cell subpopulations and their phenotype, as well as cytokine profiles in peripheral blood from VKH patients (n=25) and health controls (HCs, n=21) by flow cytometry and luminex technique, respectively. For 16 patients underwent GC therapy (methylprednisolone, MP), the aforementioned measurements as well as the transcriptome data from patients before and after one-week’s GC therapy were also compared to interrogate the systemic immune response to GC therapy. Lymphocyte composition in the blood was different in VKH patients and HCs. VKH patients had significantly higher numbers of T cells with more activated, polarized and differentiated phenotype, more unswitched memory B cells and monocytes, as compared to HCs. MP treatment resulted in decreased frequencies of T cells and NK cells, inhibited NK cell activation and T cell differentiation, and more profoundly, a marked shift in the distribution of monocyte subsets. Collectively, our findings suggest that advanced activation and differentiation, as well as dysregulated numbers of peripheral lymphocytes are the major immunological features of VKH, and GC therapy with MP not only inhibits T cell activation directly, but also affects monocyte subsets, which might combinatorically result in the inhibition of the pathogenic immune response.
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Affiliation(s)
- Han Jiang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaohui Li
- Retinal and Vitreous Diseases Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Long Yu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Zhang
- Ophthalmic Imaging Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Li Zhou
- Cataract Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Jianhua Wu
- Retinal and Vitreous Diseases Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Jing Yuan
- Retinal and Vitreous Diseases Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Mengyao Han
- Retinal and Vitreous Diseases Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Tao Xu
- Retinal and Vitreous Diseases Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Junwen He
- Retinal and Vitreous Diseases Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Shan Wang
- Ophthalmic Imaging Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Chengfeng Yu
- Retinal and Vitreous Diseases Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Sha Pan
- Retinal and Vitreous Diseases Department of Wuhan Aier Eye Hospital, Wuhan University, Wuhan, China
| | - Min Wu
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hangyu Liu
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haihong Zeng
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhu Song
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiangqiang Wang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shen Qu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junwei Zhang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yafei Huang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junyan Han
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Liu M, Liang S, Zhang C. NK Cells in Autoimmune Diseases: Protective or Pathogenic? Front Immunol 2021; 12:624687. [PMID: 33777006 PMCID: PMC7994264 DOI: 10.3389/fimmu.2021.624687] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 02/22/2021] [Indexed: 12/12/2022] Open
Abstract
Autoimmune diseases generally result from the loss of self-tolerance (i.e., failure of the immune system to distinguish self from non-self), and are characterized by autoantibody production and hyperactivation of T cells, which leads to damage of specific or multiple organs. Thus, autoimmune diseases can be classified as organ-specific or systemic. Genetic and environmental factors contribute to the development of autoimmunity. Recent studies have demonstrated the contribution of innate immunity to the onset of autoimmune diseases. Natural killer (NK) cells, which are key components of the innate immune system, have been implicated in the development of multiple autoimmune diseases such as systemic lupus erythematosus, type I diabetes mellitus, and autoimmune liver disease. However, NK cells have both protective and pathogenic roles in autoimmunity depending on the NK cell subset, microenvironment, and disease type or stage. In this work, we review the current knowledge of the varied roles of NK cell subsets in systemic and organic-specific autoimmune diseases and their clinical potential as therapeutic targets.
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Affiliation(s)
- Meifang Liu
- Key Lab for Immunology in Universities of Shandong Province, School of Basic Medical Sciences, Weifang Medical University, Weifang, China
| | - Shujuan Liang
- Key Lab for Immunology in Universities of Shandong Province, School of Basic Medical Sciences, Weifang Medical University, Weifang, China
| | - Cai Zhang
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Institute of Immunopharmaceutical Sciences, Shandong University, Jinan, China
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Wu Y, Luo J, Garden OA. Immunoregulatory Cells in Myasthenia Gravis. Front Neurol 2020; 11:593431. [PMID: 33384654 PMCID: PMC7769807 DOI: 10.3389/fneur.2020.593431] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/23/2020] [Indexed: 12/22/2022] Open
Abstract
Myasthenia gravis (MG) is a T cell-dependent, B-cell mediated autoimmune disease caused by antibodies against the nicotinic acetylcholine receptor or other components of the post-synaptic muscle endplate at the neuromuscular junction. These specific antibodies serve as excellent biomarkers for diagnosis, but do not adequately substitute for clinical evaluations to predict disease severity or treatment response. Several immunoregulatory cell populations are implicated in the pathogenesis of MG. The immunophenotype of these populations has been well-characterized in human peripheral blood. CD4+FoxP3+ regulatory T cells (Tregs) are functionally defective in MG, but there is a lack of consensus on whether they show numerical perturbations. Myeloid-derived suppressor cells (MDSCs) have also been explored in the context of MG. Adoptive transfer of CD4+FoxP3+ Tregs or MDSCs suppresses ongoing experimental autoimmune MG (EAMG), a rodent model of MG, suggesting a protective role of both populations in this disease. An imbalance between follicular Tregs and follicular T helper cells is found in untreated MG patients, correlating with disease manifestations. There is an inverse correlation between the frequency of circulating IL-10–producing B cells and clinical status in MG patients. Taken together, both functional and numerical defects in various populations of immunoregulatory cells in EAMG and human MG have been demonstrated, but how they relate to pathogenesis and whether these cells can serve as biomarkers of disease activity in humans deserve further exploration.
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Affiliation(s)
- Ying Wu
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Jie Luo
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Oliver A Garden
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
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25
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Salminen A. Hypoperfusion is a potential inducer of immunosuppressive network in Alzheimer's disease. Neurochem Int 2020; 142:104919. [PMID: 33242538 DOI: 10.1016/j.neuint.2020.104919] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 10/12/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease which causes a non-reversible cognitive impairment and dementia. The primary cause of late-onset AD remains unknown although its pathology was discovered over a century ago. Recently, the vascular hypothesis of AD has received backing from evidence emerging from neuroimaging studies which have revealed the presence of a significant hypoperfusion in the brain regions vulnerable to AD pathology. In fact, hypoxia can explain many of the pathological changes evident in AD pathology, e.g. the deposition of β-amyloid plaques and chronic low-grade inflammation. Hypoxia-inducible factor-1α (HIF-1α) stimulates inflammatory responses and modulates both innate and adaptive immunity. It is known that hypoxia-induced inflammation evokes compensatory anti-inflammatory response involving tissue-resident microglia/macrophages and infiltrated immune cells. Hypoxia/HIF-1α induce immunosuppression by (i) increasing the expression of immunosuppressive genes, (ii) stimulating adenosinergic signaling, (iii) enhancing aerobic glycolysis, i.e. lactate production, and (iv) augmenting the secretion of immunosuppressive exosomes. Interestingly, it seems that these common mechanisms are also involved in the pathogenesis of AD. In AD pathology, an enhanced immunosuppression appears, e.g. as a shift in microglia/macrophage phenotypes towards the anti-inflammatory M2 phenotype and an increase in the numbers of regulatory T cells (Treg). The augmented anti-inflammatory capacity promotes the resolution of acute inflammation but persistent inflammation has crucial effects not only on immune cells but also harmful responses to the homeostasis of AD brain. I will examine in detail the mechanisms of the hypoperfusion/hypoxia-induced immunosuppressive state in general and especially, in its association with AD pathogenesis. These immunological observations support the vascular hypothesis of AD pathology.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
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26
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Nersesian S, Schwartz SL, Grantham SR, MacLean LK, Lee SN, Pugh-Toole M, Boudreau JE. NK cell infiltration is associated with improved overall survival in solid cancers: A systematic review and meta-analysis. Transl Oncol 2020; 14:100930. [PMID: 33186888 PMCID: PMC7670197 DOI: 10.1016/j.tranon.2020.100930] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/20/2020] [Accepted: 10/23/2020] [Indexed: 01/03/2023] Open
Abstract
The immune landscape of a tumor is highly connected to patient prognosis and response to treatment, but little is known about how natural killer (NK) cells predict overall survival (OS) among patients with solid tumors. We present the first meta-analysis on NK cell infiltration into solid tumors as a prognostic indicator for OS, considering cancer types independently, and together. Samples were collected from 1973 to 2016 with results published between 1989 and 2020. From 53 studies, we found that NK cell infiltration corresponds with decreased risk of death (HR=0.34, 95% CI: 0.26-0.46; p<0.0001). Among studies that investigated the prognostic potential of NK cells in specific regions of the tumor, intraepithelial infiltration was better predictive of OS than NK infiltration in the tumor-adjacent stroma. Generally, NK cell infiltration is lower in advanced-stage and lower-grade tumors; nevertheless, it remains prognostically beneficial. This meta-analysis highlights an important prognostic role of NK cells in solid tumors, but exposes that few studies have considered the contributions of NK cells. Toward NK cell-based immunotherapies, it will be important to understand the conditions under which NK cells can be effective agents of tumor control.
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Affiliation(s)
- Sarah Nersesian
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Sarah L Schwartz
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Stephanie R Grantham
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Leah K MacLean
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - Stacey N Lee
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Morgan Pugh-Toole
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Jeanette E Boudreau
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pathology, Dalhousie University, Halifax, NS, Canada.
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27
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Klöß S, Dehmel S, Braun A, Parnham MJ, Köhl U, Schiffmann S. From Cancer to Immune-Mediated Diseases and Tolerance Induction: Lessons Learned From Immune Oncology and Classical Anti-cancer Treatment. Front Immunol 2020; 11:1423. [PMID: 32733473 PMCID: PMC7360838 DOI: 10.3389/fimmu.2020.01423] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/02/2020] [Indexed: 12/27/2022] Open
Abstract
Success in cancer treatment over the last four decades has ranged from improvements in classical drug therapy to immune oncology. Anti-cancer drugs have also often proven beneficial for the treatment of inflammatory and autoimmune diseases. In this review, we report on challenging examples that bridge between treatment of cancer and immune-mediated diseases, addressing mechanisms and experimental models as well as clinical investigations. Patient-derived tumor xenograft (PDX) (humanized) mouse models represent useful tools for preclinical evaluation of new therapies and biomarker identification. However, new developments using human ex vivo approaches modeling cancer, for example in microfluidic human organs-on-chips, promise to identify key molecular, cellular and immunological features of human cancer progression in a fully human setting. Classical drugs which bridge the gap, for instance, include cytotoxic drugs, proteasome inhibitors, PI3K/mTOR inhibitors and metabolic inhibitors. Biologicals developed for cancer therapy have also shown efficacy in the treatment of autoimmune diseases. In immune oncology, redirected chimeric antigen receptor (CAR) T cells have achieved spectacular remissions in refractory B cell leukemia and lymphoma and are currently under development for tolerance induction using cell-based therapies such as CAR Tregs or NK cells. Finally, a brief outline will be given of the lessons learned from bridging cancer and autoimmune diseases as well as tolerance induction.
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Affiliation(s)
- Stephan Klöß
- Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.,Institute of Cellular Therapeutics, Hannover Medical School (MHH), Hanover, Germany
| | - Susann Dehmel
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
| | - Armin Braun
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
| | - Michael J Parnham
- Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Frankfurt, Germany.,Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Frankfurt, Germany
| | - Ulrike Köhl
- Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.,Institute of Cellular Therapeutics, Hannover Medical School (MHH), Hanover, Germany.,Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Frankfurt, Germany.,Institute of Clinical Immunology, University of Leipzig, Leipzig, Germany
| | - Susanne Schiffmann
- Institute of Clinical Pharmacology, University Hospital Frankfurt, Frankfurt, Germany.,Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Translational Medicine and Pharmacology (TMP), Frankfurt, Germany
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McQuaid SL, Loughran ST, Power PA, Maguire P, Szczygiel A, Johnson PA. Low-dose IL-2 induces CD56 bright NK regulation of T cells via NKp44 and NKp46. Clin Exp Immunol 2020; 200:228-241. [PMID: 31989589 PMCID: PMC7232012 DOI: 10.1111/cei.13422] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2020] [Indexed: 12/16/2022] Open
Abstract
Low-dose interleukin (IL)-2 has shown clinical benefits in patients with autoimmune and inflammatory diseases. Both regulatory T cells (Tregs ) and natural killer (NK) cells are increased in response to low-dose IL-2 immunotherapy. The role of regulatory T cells in autoimmune diseases has been extensively studied; however, NK cells have not been as thoroughly explored. It has not been well reported whether the increase in NK cells is purely an epiphenomenon or carries actual benefits for patients with autoimmune diseases. We demonstrate that low-dose IL-2 expands the primary human CD56bright NK cells resulting in a contact-dependent cell cycle arrest of effector T cells (Teffs ) via retention of the cycle inhibitor p21. We further show that NK cells respond via IL-2R-β, which has been shown to be significant for immunity by regulating T cell expansion. Moreover, we demonstrate that blocking NK receptors NKp44 and NKp46 but not NKp30 could abrogate the regulation of proliferation associated with low-dose IL-2. The increase in NK cells was also accompanied by an increase in Treg cells, which is dependent on the presence of CD56bright NK cells. These results not only heighten the importance of NK cells in low-dose IL-2 therapy but also identify key human NK targets, which may provide further insights into the therapeutic mechanisms of low-dose IL-2 in autoimmunity.
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Affiliation(s)
- S. L. McQuaid
- Viral Immunology LaboratorySchool of Nursing, Psychotherapy and Community HealthDublin City UniversityDublinIreland
- Mason Technology LtdDublinIreland
| | - S. T. Loughran
- Viral Immunology LaboratorySchool of Nursing, Psychotherapy and Community HealthDublin City UniversityDublinIreland
- Department of Applied ScienceDundalk Institute of TechnologyDundalkIreland
| | - P. A. Power
- Viral Immunology LaboratorySchool of Nursing, Psychotherapy and Community HealthDublin City UniversityDublinIreland
- Technological University DublinDublinIreland
| | - P. Maguire
- Viral Immunology LaboratorySchool of Nursing, Psychotherapy and Community HealthDublin City UniversityDublinIreland
- School of BiotechnologyDublin City UniversityDublinIreland
| | - A. Szczygiel
- Viral Immunology LaboratorySchool of Nursing, Psychotherapy and Community HealthDublin City UniversityDublinIreland
| | - P. A. Johnson
- Viral Immunology LaboratorySchool of Nursing, Psychotherapy and Community HealthDublin City UniversityDublinIreland
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The correlation of thyroid autoimmunity and peripheral and uterine immune status in women with recurrent miscarriage. J Reprod Immunol 2020; 139:103118. [PMID: 32193011 DOI: 10.1016/j.jri.2020.103118] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 02/22/2020] [Accepted: 03/09/2020] [Indexed: 01/23/2023]
Abstract
PROBLEM Thyroid autoimmunity (TAI), which is the most prevalent cause of thyroid dysfunction in women of reproductive age, is associated with increased risk of miscarriages and adverse pregnancy outcomes. However, the exact pathophysiology of TAI is still unknown. We aim at investigating the relationship between TAI and the peripheral and uterine immune markers in women with recurrent miscarriage (RM). METHOD OF STUDY Peripheral blood and endometrial tissue samples were collected during mid-luteal phase of 242 RM women to evaluate the prevalence of TAI, the thyroid function, the percentages of peripheral blood and endometrial lymphocytes, the levels of peripheral blood T helper 1 (Th1) cytokine and natural killer (NK) cell cytotoxicity. RESULTS There was no relationship between TAI and peripheral immune parameters. However, the percentage of endometrial Regulatory T (Treg) cells was significantly higher in RM women who were thyroid antibody positive than in those who were antibody negative (p ＜ 0.05). CONCLUSION Thyroid antibody positivity seems to be part of a more generalized immune dysfunction. The increased endometrial Treg cells in RM patients with TAI may ameliorate coincidental TAI during pregnancy by linked suppression and prevent the over-reactive status of the immune system.
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Salem ML, El-Naggar SA, Mobasher MA, Elgharabawy RM. The Toll-Like Receptor 3 Agonist Polyriboinosinic Polyribocytidylic Acid Increases the Numbers of NK Cells with Distinct Phenotype in the Liver of B6 Mice. J Immunol Res 2020; 2020:2489407. [PMID: 32211442 PMCID: PMC7077049 DOI: 10.1155/2020/2489407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 02/15/2020] [Indexed: 02/07/2023] Open
Abstract
One of the activating factors of the cells of the innate immune system is the agonists of toll-like receptors (TLRs). Our earlier publications detailed how poly(I:C), a TLR3 agonist, elevates the NK cell population and the associated antigen-specific CD8+ T cell responses. This study involved a single treatment of the B6 mice with poly(I:C) intraperitoneally. To perform a detailed phenotypic analysis, mononuclear cells were prepared from each of the liver, peripheral blood, and spleen. These cells were then examined for their NK cell population by flow cytometric analysis following cell staining with indicated antibodies. The findings of the study showed that the NK cell population of the liver with an NK1.1highCD11bhighCD11chigh B220+Ly6G- phenotype was elevated following the treatment with poly(I:C). In the absence of CD11b molecule (CR3-/- mice), poly(I:C) can still increase the remained numbers of NK cells with NK1.1+CD11b- and NK1.1+Ly6G- phenotypes in the liver while their numbers in the blood decrease. After the treatment with anti-AGM1 Ab, which induced depletion of NK1.1+CD11b+ cells and partial depletion of CD3+NK1.1+ and NK1.1+CD11b- cell populations, poly(I:C) normalized the partial decreases in the numbers of NK cells concomitant with increased numbers of NK1.1-CD11b+ cell population in both liver and blood. Regarding mice with a TLR3-/- phenotype, their injection with poly(I:C) resulted in the partial elevation in the NK cell population as compared to wild-type B6 mice. To summarise, the TLR3 agonist poly(I:C) results in the elevation of a subset of liver NK cells expressing the two myeloid markers CD11c and CD11b. The effect of poly(I:C) on NK cells is partially dependent on TLR3 and independent of the presence of CD11b.
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Affiliation(s)
- Mohamed L. Salem
- Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
- Center of Excellence in Cancer Research, New Tanta University Teaching Hospital, Tanta University, Egypt
| | - Sabry A. El-Naggar
- Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
- Center of Excellence in Cancer Research, New Tanta University Teaching Hospital, Tanta University, Egypt
| | - Maysa A. Mobasher
- Biochemistry Division, Department of Pathology, College of Medicine, Jouf University, Sakakah, Saudi Arabia
- Department of Clinical Pathology, El Ahrar Educational Hospital, Ministry of Health, Zagazig, Egypt
| | - Rehab M. Elgharabawy
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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31
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Salminen A. Activation of immunosuppressive network in the aging process. Ageing Res Rev 2020; 57:100998. [PMID: 31838128 DOI: 10.1016/j.arr.2019.100998] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/29/2019] [Accepted: 12/09/2019] [Indexed: 12/19/2022]
Abstract
Chronic low-grade inflammation has a key role in the aging process, a state called inflammaging. It is known that the chronic inflammatory condition generates counteracting immunosuppressive state in many diseases. Inflammaging is also associated with an immune deficiency; generally termed as immunosenescence, although it is not known whether it represents the senescence of immune cells or the active remodeling of immune system. Evidence has accumulated since the 1970's indicating that immunosenescence might be caused by an increased activity of immunosuppressive cells rather than cellular senescence. Immune cells display remarkable plasticity; many of these cells can express both proinflammatory and immunosuppressive phenotypes in a context-dependent manner. The immunosuppressive network involves the regulatory subtypes of T (Treg) and B (Breg) cells as well as regulatory phenotypes of macrophages (Mreg), dendritic (DCreg), natural killer (NKreg), and type II natural killer T (NKT) cells. The immunosuppressive network also includes monocytic (M-MDSC) and polymorphonuclear (PMN-MDSC) myeloid-derived suppressor cells which are immature myeloid cells induced by inflammatory mediators. This co-operative network is stimulated in chronic inflammatory conditions preventing excessive inflammatory responses but at the same time they exert harmful effects on the immune system and tissue homeostasis. Recent studies have revealed that the aging process is associated with the activation of immunosuppressive network, especially the functions of MDSCs, Tregs, and Mregs are increased. I will briefly review the properties of the regulatory phenotypes of immune cells and examine in detail the evidences for an activation of immunosuppressive network with aging.
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Overview of Basic Immunology and Clinical Application. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1244:1-36. [PMID: 32301008 DOI: 10.1007/978-3-030-41008-7_1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and cross-talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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Yang CL, Zhang P, Liu RT, Zhang N, Zhang M, Li H, Du T, Li XL, Dou YC, Duan RS. CXCR5-negative natural killer cells ameliorate experimental autoimmune myasthenia gravis by suppressing follicular helper T cells. J Neuroinflammation 2019; 16:282. [PMID: 31884963 PMCID: PMC6935501 DOI: 10.1186/s12974-019-1687-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 12/20/2019] [Indexed: 02/08/2023] Open
Abstract
Background Recent studies have demonstrated that natural killer (NK) cells can modulate other immune components and are involved in the development or progression of several autoimmune diseases. However, the roles and mechanisms of NK cells in regulating experimental autoimmune myasthenia gravis (EAMG) remained to be illustrated. Methods To address the function of NK cells in experimental autoimmune myasthenia gravis in vivo, EAMG rats were adoptively transferred with splenic NK cells. The serum antibodies, and splenic follicular helper T (Tfh) cells and germinal center B cells were determined by ELISA and flow cytometry. The roles of NK cells in regulating Tfh cells were further verified in vitro by co-culturing splenocytes or isolated T cells with NK cells. Moreover, the phenotype, localization, and function differences between different NK cell subtypes were determined by flow cytometry, immunofluorescence, and ex vivo co-culturation. Results In this study, we found that adoptive transfer of NK cells ameliorated EAMG symptoms by suppressing Tfh cells and germinal center B cells. Ex vivo studies indicated NK cells inhibited CD4+ T cells and Tfh cells by inducing the apoptosis of T cells. More importantly, NK cells could be divided into CXCR5- and CXCR5+ NK subtypes according to the expression of CXCR5 molecular. Compared with CXCR5- NK cells, which were mainly localized outside B cell zone, CXCR5+ NK were concentrated in the B cell zone and exhibited higher expression levels of IL-17 and ICOS, and lower expression level of CD27. Ex vivo studies indicated it was CXCR5- NK cells not CXCR5+ NK cells that suppressed CD4+ T cells and Tfh cells. Further analysis revealed that, compared with CXCR5- NK cells, CXCR5+ NK cells enhanced the ICOS expression of Tfh cells. Conclusions These findings highlight the different roles of CXCR5- NK cells and CXCR5+ NK cells. It was CXCR5- NK cells but not CXCR5+ NK cells that suppressed Tfh cells and inhibited the autoimmune response in EAMG models.
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Affiliation(s)
- Chun-Lin Yang
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China
| | - Peng Zhang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, People's Republic of China
| | - Ru-Tao Liu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, People's Republic of China
| | - Na Zhang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, People's Republic of China
| | - Min Zhang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, People's Republic of China
| | - Heng Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, People's Republic of China
| | - Tong Du
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China
| | - Xiao-Li Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, People's Republic of China
| | - Ying-Chun Dou
- College of Basic Medical Sciences, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China
| | - Rui-Sheng Duan
- Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766, Jingshi Road, Jinan, 250014, People's Republic of China. .,Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, People's Republic of China.
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Furlan R, Melloni E, Finardi A, Vai B, Di Toro S, Aggio V, Battistini L, Borsellino G, Manfredi E, Falini A, Colombo C, Poletti S, Benedetti F. Natural killer cells protect white matter integrity in bipolar disorder. Brain Behav Immun 2019; 81:410-421. [PMID: 31254622 DOI: 10.1016/j.bbi.2019.06.037] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 06/08/2019] [Accepted: 06/25/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Bipolar Disorder (BD) associates with disrupted white matter (WM) microstructure and functional connectivity, and with a perturbation of the immune system. Higher cytokines, and reduced T cells, correlated with WM disruption and fMRI responses. A core component of the innate immune system, natural killer (NK) cells were detected in brain parenchyma, but never studied in BD. METHODS We studied Diffusion Tensor Imaging (DTI) measures of water diffusion, fMRI corticolimbic functional response and connectivity, and multi-parameter cytofluorometry analysis of NK (CD56+) subpopulations, in 30 inpatients with active Bipolar Disorder type I. NK cells were also obtained in 36 healthy controls. RESULTS Patients had significantly higher circulating counts of CD56+GMCSF+, CD56+INFγ+, and CD56+IL17+. NK cell levels positively associated to fractional anisotropy (FA) measures. CD56+TNFα+, CD56+INFγ+, and CD56+GMCSF+ directly correlated with FA, and inversely with radial (RD) and mean (MD) diffusivity. Duration of lithium treatment associated with higher CD56+TNFα+, CD56+IL2+, and CD56+IL4+, and positively associated with FA in tracts were NKs had significant effects. A mediation model suggested a partial mediation of CD56+TNFα+ cells, higher in patients on lithium, on the effects of lithium on FA. Frequencies of the same cytokine-producing NK cells also influenced fMRI cortico-limbic functional connectivity during processing of both, emotional and non-emotional stimuli. DISCUSSION Higher circulating cytokine-producing NK cells associated with lithium treatment, and with DTI measures of WM integrity, partially mediating the effect of lithium on WM. The same cells associated with fMRI responses and connectivity, thus suggesting an effect on structural and functional connectomics in BD.
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Affiliation(s)
- Roberto Furlan
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Elisa Melloni
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Annamaria Finardi
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Benedetta Vai
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Sara Di Toro
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Veronica Aggio
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | | | | | | | - Andrea Falini
- University Vita-Salute San Raffaele, Italy; Department of Neuroradiology, San Raffaele Scientific Institute, Milano, Italy
| | - Cristina Colombo
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Sara Poletti
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Francesco Benedetti
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy.
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Ray AK, Somanchi SS, Dastgheyb N, Aquino-Lopez A, Cobanoglu ZE, Geier B, Lee DA. Expression of carcinoma, apoptosis, and cell-death-related genes are determinants for sensitivity of pediatric cancer cell lines to lysis by natural killer cells. Pediatr Blood Cancer 2019; 66:e27783. [PMID: 31304677 DOI: 10.1002/pbc.27783] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 03/13/2019] [Accepted: 03/23/2019] [Indexed: 11/09/2022]
Abstract
Natural killer (NK) cells have potential utility in pediatric cancer immunotherapy for their ability to lyse diverse tumor targets, lack of dependence on mutation-associated tumor antigens, and for their relative safety demonstrated so far in clinical trials. Here, we evaluate the cytotoxic potential of expanded NK cells against a well-characterized panel of pediatric cancer cell lines representing Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, lymphoma, leukemia, and brain tumors. We correlate their sensitivity NK cell lysis with tumor phenotypic, transcriptomic, and genetic determinants, and correlate known immunogenetic determinants with donor NK cell potency. Although ligand expression on cell lines stratified according to hematologic versus nonhematologic cancer types, the sensitivity to NK cell lysis varied widely and did not correlate with cancer type, expression of individual activating or inhibitory ligands, gene-expression clusters of NK cell ligands, disease status (newly diagnosed or relapsed), or MYCN amplification. Rather, sensitivity to NK cell-mediated lysis was associated with a novel 96-gene cluster of predominantly carcinoma-, apoptosis-, and cell death-related pathways, and with functional p53 status. NK cell potency was strongly associated with activating KIR gene content, but not with KIR/KIR-ligand mismatch. This study suggests that adoptive immunotherapy with expanded NK cells has the potential for a wide range of pediatric cancers, identifies potential biomarkers of efficacy and response, and establishes a foundation for using this cell line panel for the preclinical evaluation of immunotherapies.
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Affiliation(s)
- Anish K Ray
- Department of Hematology/Oncology, Cook Children's Hospital, Fort Worth, Texas
| | - Srinivas S Somanchi
- Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Neda Dastgheyb
- Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Arianexys Aquino-Lopez
- Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zehra E Cobanoglu
- Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Brian Geier
- Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio
| | - Dean A Lee
- Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio
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Li Y, Liu B, Ding S, Liu C, Chen T, Li L, Shao Z, Fu R. Availability of NK cell expansion agent combined with recombinant IL‑2 and IL‑15 stimulation on the expansion and high‑purity of NK cells in patients with immune‑related pancytopenia in vitro. Mol Med Rep 2019; 20:4358-4366. [PMID: 31545423 DOI: 10.3892/mmr.2019.10654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/06/2019] [Indexed: 11/05/2022] Open
Abstract
Natural killer (NK) cells are a group of large granular lymphocytes that play an important regulatory role in innate immunity and adaptive immunity. Immune‑related pancytopenia (IRP) is a type of pancytopenia resulting from bone marrow hematopoietic cells that were destroyed or suppressed by auto‑antibodies. The specific mechanism of IRP is not clear. In the present study, it was identified that the percentage of NK cells in peripheral blood lymphocytes was decreased in patients with IRP. Subsequently, high purity NK cells were extracted from 6 untreated patients with IRP using the immunomagnetic beads sorting, magnetic‑activated cell‑sorting method, which were then cultured then in RPMI‑1640 medium containing 20% FBS. NK cell expansion agents, with or without recombinant interleukin (IL)‑15, were used to amplify high‑purity NK cells on the basic of recombinant IL‑2. Expression of the activated receptors NKG2‑D type II integral membrane protein (NKG2D) and natural killer cell p46‑related protein (NKp46), and the inhibitory receptors CD158a and NKG2‑A/NKG2‑B type II integral membrane protein (NKG2A), in CD56+ NK cells were detected by flow cytometry before and after cell culture. It was observed that treatment with an NK cell expansion agent combined with the stimulation of recombinant IL‑2 and recombinant IL‑15 could increase the number whilst maintaining the purity of NK cells. There were no significant changes in the expression of NKG2D, NKp46, NKG2A and CD158a in patients with IRP before and after NK cell culture. This new amplification method lays a foundation for clinical NK cell immunotherapy and anti‑tumor applications.
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Affiliation(s)
- Yang Li
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Bingnan Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Shaoxue Ding
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Chunyan Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Tong Chen
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Lijuan Li
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Zonghong Shao
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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Sequential combination therapy with interferon, interleukin-2 and therapeutic vaccine in entecavir-suppressed chronic hepatitis B patients: the Endeavor study. Hepatol Int 2019; 13:573-586. [PMID: 31172415 DOI: 10.1007/s12072-019-09956-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 05/18/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Switching from nucleos(t)ide analogues to interferon (IFN) improves hepatitis B surface antigen (HBsAg) loss. We aimed to evaluate whether combining immunomodulators such as interleukin-2 (IL-2) and therapeutic vaccine with IFN enhances HBsAg loss in entecavir (ETV)-suppressed patients. METHODS Ninety-four patients exhibiting virological suppression and hepatitis B e antigen (HBeAg) loss following ETV treatment were randomized 1:1:1 to receive ETV (group I) or IFN (group II) for 48 weeks, or IFN and vaccine for 48 weeks plus IL-2 for 12 weeks (group III). The primary endpoint was HBsAg loss at week 48. Peripheral natural killer (NK) cells and regulatory T cells (Treg) were measured as immune checkpoint indicators. RESULTS Mean HBsAg decline at week 48 was significantly greater in group III (0.85 log 10 IU/mL) and group II (0.74 log 10 IU/mL), than in group I (0.13 log 10 IU/mL). At week 48, 9.38%, 3.03%, and 3.70% of subjects in group III, II, and I, respectively, achieved HBsAg loss. Among patients with baseline HBsAg titers ranging from 100 to 1500 IU/mL, HBsAg loss rate was 27.3, 7.1, and 0% in group III, II, and I, respectively. Responders in group III showed a significantly higher increase in CD56bright CD16-NK cells from week 24 to 36, and a significant decline in Treg from week 12 to 24 than non-responders. CONCLUSION For ETV-suppressed patients, particularly those with low baseline HBsAg levels, combination therapy with IFN and other immunomodulators may enhance HBsAg loss, while successful response correlates with partial restoration of NK cells and Tregs.
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Li Y, Ding S, Liu C, Chen T, Liu H, Li L, Shao Z, Fu R. Abnormalities of quantities and functions of CD56bright natural killer cells in non-severe aplastic Anemia. ACTA ACUST UNITED AC 2019; 24:405-412. [PMID: 30907293 DOI: 10.1080/16078454.2019.1590963] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVES The mechanism of non-severe aplastic anemia (NSAA) is not clear. It may be different from severe aplastic anemia (SAA). CD56bright NK cells (regulatory NK cells) is a subgroup of NK cells that produce immunoregulatory cytokines and express high-affinity IL-2 receptor. To investigate CD56bright NK cells quantities and function in patients with NSAA and to explore how CD56bright NK cells participate in the progress of this disease. METHODS In this study, we analyzed the quantitative and functional changes of CD56bright NK cells in peripheral blood of patients with NSAA by using Flow Cytometry (FCM) before and after immunosuppressive therapy (IST). The expressions of activating receptor (NKG2D, NKp46, NKp44), inhibitory receptor (NKG2A, CD158a, CD158b) and perforin and granzyme B were detected by FCM. IL-2 and IL-18 levels in serum were detected by ELISA. The correlation between these parameters and clinical indicators of patients were evaluated. RESULTS We found that the percentage of CD56bright NK cells in newly diagnosed NSAA patients was higher than that in normal controls (p = .011, p < .05). The median expression of NKG2D in patients with NSAA was higher compared to that in normal controls (p = .021, p < .05), and the expression of CD158a was lower (p = .047, p < .05). The concentrations of IL-2 and IL-18 in the serum of patients with NSAA were higher than those in normal group. CONCLUSION These findings suggest that increased and activated CD56bright NK cells might play a protective role in the pathogenesis of NSAA.
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Ott M, Avendaño-Guzmán E, Ullrich E, Dreyer C, Strauss J, Harden M, Schön M, Schön MP, Bernhardt G, Stadelmann C, Wegner C, Brück W, Nessler S. Laquinimod, a prototypic quinoline-3-carboxamide and aryl hydrocarbon receptor agonist, utilizes a CD155-mediated natural killer/dendritic cell interaction to suppress CNS autoimmunity. J Neuroinflammation 2019; 16:49. [PMID: 30808363 PMCID: PMC6390632 DOI: 10.1186/s12974-019-1437-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 02/17/2019] [Indexed: 12/18/2022] Open
Abstract
Background Quinoline-3-carboxamides, such as laquinimod, ameliorate CNS autoimmunity in patients and reduce tumor cell metastasis experimentally. Previous studies have focused on the immunomodulatory effect of laquinimod on myeloid cells. The data contained herein suggest that quinoline-3-carboxamides improve the immunomodulatory and anti-tumor effects of NK cells by upregulating the adhesion molecule DNAX accessory molecule-1 (DNAM-1). Methods We explored how NK cell activation by laquinimod inhibits CNS autoimmunity in experimental autoimmune encephalomyelitis (EAE), the most utilized model of MS, and improves immunosurveillance of experimental lung melanoma metastasis. Functional manipulations included in vivo NK and DC depletion experiments and in vitro assays of NK cell function. Clinical, histological, and flow cytometric read-outs were assessed. Results We demonstrate that laquinimod activates natural killer (NK) cells via the aryl hydrocarbon receptor and increases their DNAM-1 cell surface expression. This activation improves the cytotoxicity of NK cells against B16F10 melanoma cells and augments their immunoregulatory functions in EAE by interacting with CD155+ dendritic cells (DC). Noteworthy, the immunosuppressive effect of laquinimod-activated NK cells was due to decreasing MHC class II antigen presentation by DC and not by increasing DC killing. Conclusions This study clarifies how DNAM-1 modifies the bidirectional crosstalk of NK cells with CD155+ DC, which can be exploited to suppress CNS autoimmunity and strengthen tumor surveillance. Electronic supplementary material The online version of this article (10.1186/s12974-019-1437-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Martina Ott
- Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Erika Avendaño-Guzmán
- Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Evelyn Ullrich
- LOEWE Center for Cell and Gene Therapy, Goethe University, Frankfurt am Main, Germany.,Division of Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, Hospital of the Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Carolin Dreyer
- Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Judith Strauss
- Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Center Göttingen, Göttingen, Germany
| | - Markus Harden
- Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany
| | - Margarete Schön
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany
| | - Michael P Schön
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.,Lower Saxony Institute of Occupational Dermatology, University Medical Center Göttingen and University of Osnabrück, Göttingen, Germany
| | - Günter Bernhardt
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Gebäude I11 OE 5240, 30625, Hannover, Germany
| | - Christine Stadelmann
- Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Christiane Wegner
- Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.,Present Address: Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Wolfgang Brück
- Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Stefan Nessler
- Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
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Hui KF, Yiu SPT, Tam KP, Chiang AKS. Viral-Targeted Strategies Against EBV-Associated Lymphoproliferative Diseases. Front Oncol 2019; 9:81. [PMID: 30873380 PMCID: PMC6400835 DOI: 10.3389/fonc.2019.00081] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 01/29/2019] [Indexed: 12/14/2022] Open
Abstract
Epstein-Barr virus (EBV) is strongly associated with a spectrum of EBV-associated lymphoproliferative diseases (EBV-LPDs) ranging from post-transplant lymphoproliferative disorder, B cell lymphomas (e.g., endemic Burkitt lymphoma, Hodgkin lymphoma, and diffuse large B cell lymphoma) to NK or T cell lymphoma (e.g., nasal NK/T-cell lymphoma). The virus expresses a number of latent viral proteins which are able to manipulate cell cycle and cell death processes to promote survival of the tumor cells. Several FDA-approved drugs or novel compounds have been shown to induce killing of some of the EBV-LPDs by inhibiting the function of latent viral proteins or activating the viral lytic cycle from latency. Here, we aim to provide an overview on the mechanisms by which EBV employs to drive the pathogenesis of various EBV-LPDs and to maintain the survival of the tumor cells followed by a discussion on the development of viral-targeted strategies based on the understanding of the patho-mechanisms.
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Affiliation(s)
- Kwai Fung Hui
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong
| | - Stephanie Pei Tung Yiu
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong
| | - Kam Pui Tam
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong
| | - Alan Kwok Shing Chiang
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.,Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, Hong Kong
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Chen T, Liu C, Li L, Liu H, Wang T, Shao Z, Fu R. CD56 bright natural killer cells exhibit abnormal phenotype and function in severe aplastic anemia. Int J Lab Hematol 2019; 41:353-363. [PMID: 30779419 DOI: 10.1111/ijlh.12982] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 01/14/2019] [Accepted: 01/16/2019] [Indexed: 11/28/2022]
Abstract
INTRODUCTION CD56bright NK cells have been highlighted to serve immunoregulatory functions. However, their roles in severe aplastic anemia (SAA) have not been elucidated. METHODS Here, we investigated the quantities, phenotypes, cytokine secretion abilities, and the cytotoxicities of peripheral CD56bright NK cells along with CD56dim NK cells obtained from patients with SAA, SAA in remission (R-SAA), and healthy controls (HC). RESULTS We observed the decreased quantities of CD56bright NK cells in SAA compared with in R-SAA and HC. In SAA, the quantities of CD56bright NK cells correlated with the disease severity. Activating receptors NKp46 and NKp44 on CD56bright NK cells were upregulated while inhibiting receptor NKG2A was downregulated in SAA. CD56bright NK cells obtained from SAA patients produced increased IL-10 and decreased IFN-γ in vitro compared with cells obtained from HC, while TNF-α and IL-13 productions were not different between two groups. Under a 7-day prestimulation with IL-2 and IL-12, the serum concentrations of which were higher in SAA patients, CD56bright NK obtained from HC also produced increased IL-10 mRNAs. There were no differences of cytotoxicites between CD56bright NK cells in SAA and in HC. CONCLUSION We discovered that CD56bright NK cells exhibited abnormal receptor expressions and cytokine production in SAA, and they were related with the severity of illness.
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Affiliation(s)
- Tong Chen
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - ChunYan Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - LiJuan Li
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Ting Wang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - ZongHong Shao
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
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42
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Xiao F, Ai G, Yan W, Wan X, Luo X, Ning Q. Intrahepatic recruitment of cytotoxic NK cells contributes to autoimmune hepatitis progression. Cell Immunol 2018; 327:13-20. [DOI: 10.1016/j.cellimm.2017.12.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 11/21/2017] [Accepted: 12/20/2017] [Indexed: 12/31/2022]
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Sharma R, Kinsey GR. Regulatory T cells in acute and chronic kidney diseases. Am J Physiol Renal Physiol 2018; 314:F679-F698. [PMID: 28877881 PMCID: PMC6031912 DOI: 10.1152/ajprenal.00236.2017] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 08/18/2017] [Accepted: 09/04/2017] [Indexed: 02/07/2023] Open
Abstract
Foxp3-expressing CD4+ regulatory T cells (Tregs) make up one subset of the helper T cells (Th) and are one of the major mechanisms of peripheral tolerance. Tregs prevent abnormal activation of the immune system throughout the lifespan, thus protecting from autoimmune and inflammatory diseases. Recent studies have elucidated the role of Tregs beyond autoimmunity. Tregs play important functions in controlling not only innate and adaptive immune cell activation, but also regulate nonimmune cell function during insults and injury. Inflammation contributes to a multitude of acute and chronic diseases affecting the kidneys. This review examines the role of Tregs in pathogenesis of renal inflammatory diseases and explores the approaches for enhancing Tregs for prevention and therapy of renal inflammation.
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Affiliation(s)
- Rahul Sharma
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia , Charlottesville, Virginia
| | - Gilbert R Kinsey
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia , Charlottesville, Virginia
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Jud A, Kotur M, Berger C, Gysin C, Nadal D, Lünemann A. Tonsillar CD56brightNKG2A+ NK cells restrict primary Epstein-Barr virus infection in B cells via IFN-γ. Oncotarget 2018; 8:6130-6141. [PMID: 28008151 PMCID: PMC5351618 DOI: 10.18632/oncotarget.14045] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 12/13/2016] [Indexed: 01/04/2023] Open
Abstract
Natural killer (NK) cells constitute the first line of defense against viruses and cancers cells. Epstein–Barr virus (EBV) was the first human virus to be directly implicated in carcinogenesis, and EBV infection is associated with a broad spectrum of B cell lymphomas. How NK cells restrict EBV-associated oncogenesis is not understood. Here, we investigated the efficacies and mechanisms of distinct NK cell subsets from tonsils, the portal of entry of EBV, in limiting EBV infection in naïve, germinal center-associated and memory B cells. We found that CD56bright and NKG2A expression sufficiently characterizes the potent anti-EBV capacity of tonsillar NK cells. We observed restriction of EBV infection in B cells as early as 18 hours after infection. The restriction was most efficient in naïve B cells and germinal center-associated B cells, the B cell subsets that exhibited highest susceptibility to EBV infection in vitro. IFN-γ release by and partially NKp44 engagement of CD56bright and NKG2A positive NK cells mediated the restriction that eventually inhibited B-cell transformation. Thus, harnessing CD56brightNKG2A+ NK cell function might be promising to improve treatment strategies that target EBV-associated B cell lymphomas.
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Affiliation(s)
- Aurelia Jud
- Children's Research Center, University Children's Hospital, Experimental Infectious Diseases and Cancer Research, Zurich, Switzerland
| | - Monika Kotur
- Children's Research Center, University Children's Hospital, Experimental Infectious Diseases and Cancer Research, Zurich, Switzerland
| | - Christoph Berger
- Children's Research Center, University Children's Hospital, Experimental Infectious Diseases and Cancer Research, Zurich, Switzerland.,Division of Infectious Diseases, and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Claudine Gysin
- Children's Research Center, University Children's Hospital, ENT Clinic, Zurich, Switzerland
| | - David Nadal
- Children's Research Center, University Children's Hospital, Experimental Infectious Diseases and Cancer Research, Zurich, Switzerland.,Division of Infectious Diseases, and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Anna Lünemann
- Children's Research Center, University Children's Hospital, Experimental Infectious Diseases and Cancer Research, Zurich, Switzerland
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Stephen B, Hajjar J. Overview of Basic Immunology and Translational Relevance for Clinical Investigators. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 995:1-41. [DOI: 10.1007/978-3-030-02505-2_1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Natural killer cells play an essential role in resolution of antigen-induced inflammation in mice. Mol Immunol 2017; 93:1-8. [PMID: 29112834 DOI: 10.1016/j.molimm.2017.10.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 10/19/2017] [Accepted: 10/25/2017] [Indexed: 12/29/2022]
Abstract
This study examined whether NK cells are important for resolution of antigen-induced inflammation. C57BL/6 mice were immunized twice with methylated BSA (mBSA) and inflammation induced by intraperitoneal injection of mBSA. Mice were injected intravenously with anti-asialo GM1 (αASGM1) or a control antibody 24h prior to peritonitis induction and peritoneal exudate collected at different time points. Expression of surface molecules and apoptosis on peritoneal cells was determined by flow cytometry and concentration of chemokines, cytokines, soluble cytokine receptors and lipid mediators by ELISA and LC-MS/MS. Apoptosis in parathymic lymph nodes and spleens was determined by TUNEL staining. Mice administered αASGM1 had lower peritoneal NK cell numbers and a higher number of peritoneal neutrophils 12h after induction of inflammation than control mice. The number of neutrophils was still high in the αASGM1 treated mice when their number had returned to baseline levels in the control mice, 48h after induction of inflammation. Peritoneal concentrations of the neutrophil regulators G-CSF and IL-12p40 were higher at 12h in the αASGM1 treated mice than in the control mice, whereas concentrations of lipid mediators implicated in resolution of inflammation, i.e. LXA4 and PGE2, were lower. Reduced apoptosis was detected in peritoneal neutrophils as well as in draining lymph nodes and spleens from the αASGM1 treated mice compared with that in the control mice. In addition, αASGM1 treated mice had lower number of peritoneal NK cells expressing NKp46 and NKG2D, receptors implicated in NK cell-induced neutrophil apoptosis. Furthermore, αASGM1 treatment completely blocked the increase in CD27+ NK cells that occurred in control mice following induction of inflammation, but CD27+ NK cells have been suggested to have a regulatory role. These results indicate a crucial role for NK cells in resolution of antigen-induced inflammation and suggest their importance in tempering neutrophil recruitment and maintaining neutrophil apoptosis.
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Sake CS, Ngu L, Ambada G, Chedjou JP, Nji N, Tchadji JC, Lissom A, Tchouangueu TF, Djukouo L, Njambe G, Garcia R, Gutierrez A, Bopda Waffo A, Park CG, Mbacham W, Etoa FX, Nchinda GW. The Effect of Antiretroviral Naïve HIV-1 Infection on the Ability of Natural Killer Cells to Produce IFN-γ upon Exposure to Plasmodium falciparum-Infected Erythrocytes. Biomed Hub 2017; 2:1-13. [PMID: 31988903 PMCID: PMC6945957 DOI: 10.1159/000467386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Background In sub-Saharan Africa, intense perennial Plasmodium species transmission coincides with areas of high prevalence of the human immunodeficiency virus type 1 (HIV) infection. This implies that antiretroviral naïve HIV-infected people living within these regions are repeatedly exposed to Plasmodium species infection and consequently malaria. Natural killer (NK) cells are known to contribute to malaria immunity through the production of IFN-γ after exposure to Plasmodium falciparum-infected erythrocytes (infected red blood cells [iRBC]). However, in antiretroviral naïve HIV-1 infection, these functions could be impaired. In this study we assess the ability of NK cells from antiretroviral naïve HIV-1-infected people to respond to iRBC. Method Magnetically sorted NK cells from antiretroviral naïve HIV-1-infected people were tested for their ability to respond to iRBC following in vitro coculture. NK cell IFN-γ production after coculture was measured through multiparametric flow cytometry analysis. Results Our data show a significant reduction (p = 0.03) in IFN-γ production by NK cells from antiretroviral naïve HIV-1-infected people after coculture with iRBCs. This was in contrast to the NK cell response from healthy controls, which demonstrated elevated IFN-γ production. NK cell IFN-γ production from untreated HIV-1-infected participants correlated inversely with the viral load (r = −0.5, p = 0.02) and positively with total helper CD4+ T-cell count (r = 0.4, p = 0.04). Thus, antiretroviral naïve HIV-1 infection can dampen NK cell-mediated immunity to P. falciparum infection in malaria-intense regions. This could in effect escalate morbidity and mortality in people chronically infected with HIV-1.
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Affiliation(s)
- Carole Stéphanie Sake
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon.,Department of Microbiology, University of Yaoundé I, Yaoundé, Cameroon.,Department of Biochemistry, University of Yaoundé I, Yaoundé, Cameroon
| | - Loveline Ngu
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon.,Department of Biochemistry, University of Yaoundé I, Yaoundé, Cameroon
| | - Georgia Ambada
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon.,Department of Animal Biology and Physiology, University of Yaoundé I, Yaoundé, Cameroon
| | - Jean Paul Chedjou
- Department of Animal Biology and Physiology, University of Yaoundé I, Yaoundé, Cameroon.,The Biotechnology Center, University of Yaounde I, Yaoundé, Cameroon
| | - Nadesh Nji
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon
| | - Jules Colince Tchadji
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon.,Department of Animal Biology and Physiology, University of Yaoundé I, Yaoundé, Cameroon
| | - Abel Lissom
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon.,Department of Animal Biology and Physiology, University of Yaoundé I, Yaoundé, Cameroon
| | - Thibau Flaurant Tchouangueu
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon.,Department of Biochemistry, University of Dschang, Dschang, Cameroon
| | - Larissa Djukouo
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon.,Department of Biochemistry, University of Yaoundé I, Yaoundé, Cameroon
| | - Ghislain Njambe
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon.,Department of Animal Biology and Physiology, University of Yaoundé I, Yaoundé, Cameroon
| | - Rosario Garcia
- CSCB (Centre de santé catholique de Bikop), Bikop, Cameroon
| | - Anna Gutierrez
- CSCB (Centre de santé catholique de Bikop), Bikop, Cameroon.,Department of Biological Sciences, Alabama State University, Montgomery, AL, USA
| | - Alain Bopda Waffo
- Department of Biological Sciences, Alabama State University, Montgomery, AL, USA
| | - Chae Gyu Park
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Wilfried Mbacham
- Department of Biochemistry, University of Yaoundé I, Yaoundé, Cameroon.,The Biotechnology Center, University of Yaounde I, Yaoundé, Cameroon.,The Department of Biochemistry and Physiology, Faculty of Medicine, University of Yaounde I, Yaoundé, Cameroon
| | - François-Xavier Etoa
- Department of Microbiology, University of Yaoundé I, Yaoundé, Cameroon.,University of Douala, Douala, Cameroon
| | - Godwin W Nchinda
- Laboratory of Vaccinology/Biobanking, CIRCB, Messa Yaounde, Cameroon
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48
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Erick T, Grigoryan L, Brossay L. Lacrimal Gland NK Cells Are Developmentally and Functionally Similar to Conventional NK Cells. Immunohorizons 2017; 1:2-9. [PMID: 28966997 DOI: 10.4049/immunohorizons.1700008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The murine lacrimal gland (LG), which produces crucial components of the ocular tear film, contains a population of natural killer (NK) cells. LG NK cells appear to belong to the conventional NK cell lineage, based on their cell surface receptor and transcription factor expression, absence in NFIL3-/- mice, and lack of RORγt expression during development. LG NK cells produce IFN-γ during the early stages of systemic murine cytomegalovirus (MCMV) infection. This effector response occurs in the absence of noticeable MCMV replication in the LG, indicating that LG NK cells are being activated by soluble factors. However, the magnitude of LG NK cell IFN-γ production during MCMV infection is significantly lower than spleen and liver NK cells. Adoptive transfer experiments in lymphopenic mice revealed that this hyporesponsive phenotype is tissue-specific, which indicates that that LG NK cells can produce a robust effector response.
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Affiliation(s)
- Timothy Erick
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, 02912, USA
| | - Lilit Grigoryan
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, 02912, USA
| | - Laurent Brossay
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, 02912, USA
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49
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DePaula-Silva AB, Hanak TJ, Libbey JE, Fujinami RS. Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy. J Neuroimmunol 2017; 308:30-42. [PMID: 28237622 DOI: 10.1016/j.jneuroim.2017.02.012] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 02/01/2017] [Accepted: 02/10/2017] [Indexed: 10/20/2022]
Abstract
Mouse models are great tools to study the mechanisms of disease development. Theiler's murine encephalomyelitis virus is used in two distinct viral infection mouse models to study the human diseases multiple sclerosis (MS) and epilepsy. Intracerebral (i.c.) infection of the SJL/J mouse strain results in persistent viral infection of the central nervous system and a MS-like disease, while i.c. infection of the C57BL/6J mouse strain results in acute seizures and epilepsy. Our understanding of how the immune system contributes to the development of two disparate diseases caused by the same virus is presented.
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Affiliation(s)
- Ana Beatriz DePaula-Silva
- Department of Pathology, University of Utah School of Medicine, 15 North Medical Drive East, 2600 EEJMRB, Salt Lake City, UT 84112, USA
| | - Tyler J Hanak
- Department of Pathology, University of Utah School of Medicine, 15 North Medical Drive East, 2600 EEJMRB, Salt Lake City, UT 84112, USA
| | - Jane E Libbey
- Department of Pathology, University of Utah School of Medicine, 15 North Medical Drive East, 2600 EEJMRB, Salt Lake City, UT 84112, USA
| | - Robert S Fujinami
- Department of Pathology, University of Utah School of Medicine, 15 North Medical Drive East, 2600 EEJMRB, Salt Lake City, UT 84112, USA.
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50
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Wałajtys-Rode E, Dzik JM. Monocyte/Macrophage: NK Cell Cooperation-Old Tools for New Functions. Results Probl Cell Differ 2017; 62:73-145. [PMID: 28455707 DOI: 10.1007/978-3-319-54090-0_5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Monocyte/macrophage and natural killer (NK) cells are partners from a phylogenetic standpoint of innate immune system development and its evolutionary progressive interaction with adaptive immunity. The equally conservative ways of development and differentiation of both invertebrate hemocytes and vertebrate macrophages are reviewed. Evolutionary conserved molecules occurring in macrophage receptors and effectors have been inherited by vertebrates after their common ancestor with invertebrates. Cytolytic functions of mammalian NK cells, which are rooted in immune cells of invertebrates, although certain NK cell receptors (NKRs) are mammalian new events, are characterized. Broad heterogeneity of macrophage and NK cell phenotypes that depends on surrounding microenvironment conditions and expression profiles of specific receptors and activation mechanisms of both cell types are discussed. The particular tissue specificity of macrophages and NK cells, as well as their plasticity and mechanisms of their polarization to different functional subtypes have been underlined. The chapter summarized studies revealing the specific molecular mechanisms and regulation of NK cells and macrophages that enable their highly specific cross-cooperation. Attention is given to the evolving role of human monocyte/macrophage and NK cell interaction in pathogenesis of hypersensitivity reaction-based disorders, including autoimmunity, as well as in cancer surveillance and progression.
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Affiliation(s)
- Elżbieta Wałajtys-Rode
- Faculty of Chemistry, Department of Drug Technology and Biotechnology, Warsaw University of Technology, Noakowskiego 3 Str, 00-664, Warsaw, Poland.
| | - Jolanta M Dzik
- Faculty of Agriculture and Biology, Department of Biochemistry, Warsaw University of Life Sciences-SGGW, Warsaw, Poland
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