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Sugiyama Y, Konishi H, Dokoshi T, Tanaka H, Kobayashi Y, Sasaki T, Yamamoto K, Sakatani A, Takahashi K, Ando K, Ueno N, Kashima S, Moriichi K, Tanabe H, Okumura T, Fujiya M. hsa_circ_0015388 Reduces Macrophage Derived Reactive Oxygen Species in Crohn's Disease. Inflamm Bowel Dis 2025; 31:1355-1365. [PMID: 39807080 DOI: 10.1093/ibd/izae317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Indexed: 01/16/2025]
Abstract
BACKGROUND Crohn's disease (CD) is a refractory inflammatory bowel disease with an unclear etiology. CircularRNA (circRNA) has been highlighted as a novel class of functional noncoding RNAs associated with the pathogenesis of various diseases. However, the functions of circRNA in CD remain unclear. METHODS Biopsies were obtained from noninflammatory sites in the terminal ileum of the CD group (n = 4) and non-CD group (n = 4) and analyzed for circRNA expression using RNA sequencing. The significantly altered circRNAs were validated in the CD group (n = 45) and non-CD group (n = 15) using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Transcriptome analysis was conducted using circRNA-downregulated macrophage-like THP-1 cells. Reactive oxygen species (ROS) levels, cytokine mRNA expression, phagocytosis, and migration were evaluated in circRNA-downregulated THP-1 cells. RESULTS CircularRNA sequencing analysis revealed significant differences in 31 circRNAs between the CD group and non-CD group. Quantitative reverse transcriptase-polymerase chain reaction analysis for each circRNA demonstrated significant upregulation of hsa_circ_0015388 in the CD group. Hsa_circ_0015388 was expressed in THP-1 cells, but not in HCEC-1CT and Caco-2/bbe. Transcriptome analysis in THP-1 cells transfected with scramble or hsa_circ_0015388 siRNA (small interfering RNA) showed a significant alteration in innate immune response related pathway. Reactive oxygen species production was significantly increased in the hsa_circ_0015388 downregulated THP-1 cells. Reactive oxygen species induction in the hsa_circ_0015388 knocked down THP-1 was diminished by the inhibition of TNFSF10. CONCLUSION A comprehensive analysis of circRNA expression revealed that 31 circRNAs were dysregulated in the CD group. Hsa_circ_0015388 is expressed in macrophages and negatively regulates ROS function inhibiting the TNFSF10 pathway. This study first revealed that hsa_circ_0015388 plays a role in the pathogenesis of CD by suppressing ROS production in macrophages.
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Affiliation(s)
- Yuya Sugiyama
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Hiroaki Konishi
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Tatsuya Dokoshi
- Department of Dermatology, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
| | - Hiroki Tanaka
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Yu Kobayashi
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Takahiro Sasaki
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Koji Yamamoto
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Aki Sakatani
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Keitaro Takahashi
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Katsuyoshi Ando
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Nobuhiro Ueno
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Shin Kashima
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Kentaro Moriichi
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Hiroki Tanabe
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Toshikatsu Okumura
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
| | - Mikihiro Fujiya
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa Hokkaido, 078-8510, Japan
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Saurabh R, Cani A, Möller M, Busch H. Large-scale global retrospective study on the interaction between ancestry and risk of comorbid autoimmune diseases in patients with pemphigus. Sci Rep 2024; 14:30151. [PMID: 39627354 PMCID: PMC11614865 DOI: 10.1038/s41598-024-78031-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: 05/07/2024] [Accepted: 10/28/2024] [Indexed: 12/06/2024] Open
Abstract
The pemphigus family of skin blistering diseases represents a rare yet potentially life-threatening condition characterized by multiple known genetic loci associated with other autoimmune disorders. While several studies have empirically indicated an increased risk of developing additional autoimmune diseases in individuals with pemphigus, the scarcity of data and the rarity of pemphigus have hindered efforts to establish and generalize these associations across diverse populations. In this study, we analyzed a dataset comprising 126 million patients, including 18,000 with pemphigus, to assess the likelihood of developing any of 74 autoimmune diseases following a diagnosis of pemphigus. For a subset of 26 diseases from this list with adequate patient numbers, we conducted further case-control retrospective analyses to quantify the odds and hazard ratios of developing comorbid conditions across various ethnicities. Our findings reveal highly significant and generalizable associations between pemphigus and pemphigoid diseases, discoid lupus erythematosus, lichen planus, and undifferentiated connective tissue disease, among others.
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Affiliation(s)
- Rochi Saurabh
- Lübecker Institute for Experimental Dermatology (LIED), Lübeck, Germany
| | - Anikamila Cani
- Lübecker Institute for Experimental Dermatology (LIED), Lübeck, Germany
| | - Marius Möller
- Lübecker Institute for Experimental Dermatology (LIED), Lübeck, Germany.
| | - Hauke Busch
- Lübecker Institute for Experimental Dermatology (LIED), Lübeck, Germany
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3
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Mu J, Maeda K, Ohashi A, Urano T, Nariai Y, Kamino H, Nakamura M, Yamamura T, Sawada T, Ishikawa E, Murate K, Yamamoto K, Hirose T, Furukawa K, Fujishiro M, Kawashima H. Monoclonal Antibodies Against Mature Interleukin-18 Ameliorate Colitis and Repair Goblet Cell Function. Dig Dis Sci 2024; 69:2573-2585. [PMID: 38713271 PMCID: PMC11258180 DOI: 10.1007/s10620-024-08453-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 04/16/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Numerous biological interventions and small molecules are used to treat Crohn's disease; however, the effectiveness of these treatments varies largely. Non-responsiveness to biological therapies is associated with interleukin (IL)-18 gene polymorphisms and high IL-18 expression has been implicated in the pathogenesis of Crohn's disease. AIMS The aim of this study was to elucidate the expression of precursor and mature IL-18 in patients with Crohn's disease who exhibited varied responses to cytokine-targeted treatments and determine whether selective inhibition of mature IL-18 offers a novel therapeutic avenue. METHODS We generated a monoclonal antibody that specifically recognizes the neoepitope of caspase-cleaved mature IL-18. Expression of precursor and mature IL-18 was analyzed in patients with Crohn's disease. Anti-mature IL-18 monoclonal antibodies were intraperitoneally administered in an acute colitis mouse model, and the disease activity index, body weight loss, tissue pathology, proinflammatory cytokine expression, goblet cell function, and microbiota composition were assessed. RESULTS Precursor and mature IL-18 expression was upregulated and goblet cell function was impaired in patients with Crohn's disease who were unresponsive to biological therapies. Administration of anti-mature IL-18 antibodies ameliorated induced colitis by repairing goblet cell function and restoring the mucus layer. CONCLUSIONS The newly developed monoclonal antibody holds promise as a therapeutic alternative for Crohn's disease.
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Affiliation(s)
- Jingxi Mu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Keiko Maeda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan.
| | - Ayako Ohashi
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Takeshi Urano
- Department of Biochemistry, Shimane University School of Medicine, Izumo, 693-8501, Japan
- mAbProtein Co. Ltd, Izumo, 693-8501, Japan
- Center for Vaccines and Therapeutic Antibodies for Emerging Infectious Diseases, Shimane University, Izumo, 693-8501, Japan
| | - Yuko Nariai
- Center for Vaccines and Therapeutic Antibodies for Emerging Infectious Diseases, Shimane University, Izumo, 693-8501, Japan
| | - Hiroki Kamino
- Center for Vaccines and Therapeutic Antibodies for Emerging Infectious Diseases, Shimane University, Izumo, 693-8501, Japan
| | - Masanao Nakamura
- Department of Endoscopy, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Takeshi Yamamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Tsunaki Sawada
- Department of Endoscopy, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Eri Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Kentaro Murate
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Kenta Yamamoto
- Department of Endoscopy, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Takashi Hirose
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Kazuhiro Furukawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
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Zhou YW, Ren Y, Lu MM, Xu LL, Cheng WX, Zhang MM, Ding LP, Chen D, Gao JG, Du J, Jin CL, Chen CX, Li YF, Cheng T, Jiang PL, Yang YD, Qian PX, Xu PF, Jin X. Crohn's disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data. World J Gastroenterol 2024; 30:34-49. [PMID: 38293325 PMCID: PMC10823898 DOI: 10.3748/wjg.v30.i1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/08/2023] [Accepted: 12/27/2023] [Indexed: 01/06/2024] Open
Abstract
Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.
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Affiliation(s)
- Yu-Wei Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yue Ren
- Department of Gastroenterology, The Second Hospital of Jiaxing, Jiaxing 314000, Zhejiang Province, China
| | - Miao-Miao Lu
- Endoscopy Center, Children’s Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Ling-Ling Xu
- Department of Gastroenterology, The Second People’s Hospital of Yuhang District, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Xin Cheng
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Meng-Meng Zhang
- Department of Gastroenterology, Hangzhou Shangcheng District People’s Hospital, Hangzhou 310003, Zhejiang Province, China
| | - Lin-Ping Ding
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Dong Chen
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Guo Gao
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Juan Du
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Ci-Liang Jin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Chun-Xiao Chen
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yun-Fei Li
- Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Tao Cheng
- Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Peng-Lei Jiang
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Yi-Da Yang
- Department of Infectious Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Peng-Xu Qian
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Peng-Fei Xu
- Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xi Jin
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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Jerkic M, Szaszi K, Laffey JG, Rotstein O, Zhang H. Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury. Int J Mol Sci 2023; 24:ijms24043376. [PMID: 36834784 PMCID: PMC9965074 DOI: 10.3390/ijms24043376] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 01/30/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023] Open
Abstract
Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases.
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Affiliation(s)
- Mirjana Jerkic
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Correspondence:
| | - Katalin Szaszi
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - John G. Laffey
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Anaesthesia and Intensive Care Medicine, School of Medicine, University of Galway, H91 TK33 Galway, Ireland
| | - Ori Rotstein
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - Haibo Zhang
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Department of Anesthesiology and Pain Medicine, Interdepartmental Division of Critical Care Medicine and Department of Physiology, University of Toronto, Toronto, ON M5G 1E2, Canada
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D'Haens G, Danese S, Davies M, Watanabe M, Hibi T. A phase II, Multicentre, Randomised, Double-Blind, Placebo-controlled Study to Evaluate Safety, Tolerability, and Efficacy of Amiselimod in Patients with Moderate to Severe Active Crohn's Disease. J Crohns Colitis 2022; 16:746-756. [PMID: 34758080 DOI: 10.1093/ecco-jcc/jjab201] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Amiselimod is an oral selective S1P1 receptor modulator with potentially fewer adverse effects than fingolimod. We evaluated the safety, tolerability, and clinical efficacy of amiselimod in participants with moderate to severe active Crohn's disease. METHODS This was a phase IIa, multicentre, randomised, double-blind, parallel group, placebo-controlled study comparing amiselimod 0.4 mg with placebo over a 14-Week treatment period. The primary endpoint of the study was the proportion of participants with clinical response (Crohn's Disease activity Index [CDAI] 100) from baseline at Week 12. RESULTS A total of 180 patients were screened and 78 were randomised [40 to amiselimod 0.4 mg and 38 to placebo]. There was no significant difference in the proportion of patients achieving CDAI 100 at Week 12 on amiselimod 0.4 mg and on placebo [48.7% vs. 54.1%, respectively] (odds ratio [OR] [95% confidence interval]: 0.79 [0.31, 1.98]). The results from the secondary endpoint analyses supported the results of the primary endpoint analysis. Treatment with amiselimod 0.4 mg was generally well tolerated, with 71.8% of participants completing the 14-week treatment period. Seven participants had serious adverse events and four discontinued treatment in the amiselimod group. CONCLUSIONS Amiselimod 0.4 mg for 12 weeks was not superior to placebo for the induction of clinical response [CDAI 100] in Crohn's disease. Treatment with amiselimod 0.4 mg was generally well tolerated and no new safety concerns related to amiselimod were reported in this study.
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Affiliation(s)
- Geert D'Haens
- Inflammatory Bowel Disease Centre, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Silvio Danese
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy
| | - Martin Davies
- Clinical Operations, Mitsubishi Tanabe Pharma Europe, London, UK
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
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Ma S, Zhang J, Liu H, Li S, Wang Q. The Role of Tissue-Resident Macrophages in the Development and Treatment of Inflammatory Bowel Disease. Front Cell Dev Biol 2022; 10:896591. [PMID: 35721513 PMCID: PMC9199005 DOI: 10.3389/fcell.2022.896591] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/09/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a refractory disease with many immune abnormalities and pathologies in the gastrointestinal tract. Because macrophages can distinguish innocuous antigens from potential pathogens to maintain mucosa barrier functions, they are essential cells in the intestinal immune system. With numerous numbers in the intestinal tract, tissue-resident macrophages have a significant effect on the constant regeneration of intestinal epithelial cells and maintaining the immune homeostasis of the intestinal mucosa. They also have a significant influence on IBD through regulating pro-(M1) or anti-inflammatory (M2) phenotype polarization according to different environmental cues. The disequilibrium of the phenotypes and functions of macrophages, disturbed by intracellular or extracellular stimuli, influences the progression of disease. Further investigation of macrophages’ role in the progression of IBD will facilitate deciphering the pathogenesis of disease and exploring novel targets to develop novel medications. In this review, we shed light on the origin and maintenance of intestinal macrophages, as well as the role of macrophages in the occurrence and development of IBD. In addition, we summarize the interaction between gut microbiota and intestinal macrophages, and the role of the macrophage-derived exosome. Furthermore, we discuss the molecular and cellular mechanisms participating in the polarization and functions of gut macrophages, the potential targeted strategies, and current clinical trials for IBD.
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Affiliation(s)
- Shengjie Ma
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
| | - Jiaxin Zhang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
| | - Heshi Liu
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
| | - Shuang Li
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
| | - Quan Wang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
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Tai SL, Mortha A. Macrophage control of Crohn's disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 367:29-64. [PMID: 35461659 DOI: 10.1016/bs.ircmb.2022.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The intestinal tract is the body's largest mucosal surface and permanently exposed to microbial and environmental signals. Maintaining a healthy intestine requires the presence of sentinel grounds keeper cells, capable of controlling immunity and tissue homeostasis through specialized functions. Intestinal macrophages are such cells and important players in steady-state functions and during acute and chronic inflammation. Crohn's disease, a chronic inflammatory condition of the intestinal tract is proposed to be the consequence of an altered immune system through microbial and environmental stimulation. This hypothesis suggests an involvement of macrophages in the regulation of this pathology. Within this chapter, we will discuss intestinal macrophage development and highlight data suggesting their implication in chronic intestinal pathologies like Crohn's disease.
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Affiliation(s)
- Siu Ling Tai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Arthur Mortha
- Department of Immunology, University of Toronto, Toronto, ON, Canada.
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Harnessing murine models of Crohn's disease ileitis to advance concepts of pathophysiology and treatment. Mucosal Immunol 2022; 15:10-26. [PMID: 34316007 DOI: 10.1038/s41385-021-00433-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 02/04/2023]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are both characterized by chronic inflammation and severe dysfunction of the gastrointestinal tract. These two forms of inflammatory bowel disease (IBD) represent distinct clinical disorders with diverse driving mechanisms; however, this divergence is not reflected in currently approved therapeutics that commonly target general proinflammatory pathways. A compelling need therefore remains to understand factors that differentiate the topology and the distinct clinical manifestations of CD versus UC, in order to develop more effective and specialized therapies. Animal models provide valuable platforms for studying IBD heterogeneity and deciphering disease-specific mechanisms. Both the established and the newly developed ileitis mouse models are characterized by various disease initiating mechanisms and diverse phenotypic outcomes that reflect the complexity of human CD-ileitis. Microbial dysbiosis, destruction of epithelial barrier integrity, immune cell deregulation, as well as the recently described genome instability and stromal cell activation have all been proposed as the triggering factors for the development of ileitis-associated pathology. In this review, we aim to critically evaluate the mechanistic underpinnings of murine models of CD-ileitis, discuss their phenotypic similarities to human disease, and envisage their further exploitation for the development of novel targeted and personalized therapeutics.
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10
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Chiaranunt P, Tai SL, Ngai L, Mortha A. Beyond Immunity: Underappreciated Functions of Intestinal Macrophages. Front Immunol 2021; 12:749708. [PMID: 34650568 PMCID: PMC8506163 DOI: 10.3389/fimmu.2021.749708] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract hosts the largest compartment of macrophages in the body, where they serve as mediators of host defense and immunity. Seeded in the complex tissue-environment of the gut, an array of both hematopoietic and non-hematopoietic cells forms their immediate neighborhood. Emerging data demonstrate that the functional diversity of intestinal macrophages reaches beyond classical immunity and includes underappreciated non-immune functions. In this review, we discuss recent advances in research on intestinal macrophage heterogeneity, with a particular focus on how non-immune functions of macrophages impact tissue homeostasis and function. We delve into the strategic localization of distinct gut macrophage populations, describe the potential factors that regulate their identity and functional heterogeneity within these locations, and provide open questions that we hope will inspire research dedicated to elucidating a holistic view on macrophage-tissue cell interactions in the body's largest mucosal organ.
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Affiliation(s)
- Pailin Chiaranunt
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Siu Ling Tai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Louis Ngai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Arthur Mortha
- Department of Immunology, University of Toronto, Toronto, ON, Canada
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11
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Koutroumpakis F, Phillips AE, Yadav D, Machicado JD, Ahsan M, Ramos Rivers C, Tan X, Schwartz M, Proksell S, Johnston E, Dueker J, Hashash JG, Barrie A, Harrison J, Dunn MA, Konnikova L, Hartman DJ, Din H, Babichenko D, Tang G, Binion DG. Serum IgG4 Subclass Deficiency Defines a Distinct, Commonly Encountered, Severe Inflammatory Bowel Disease Subtype. Inflamm Bowel Dis 2021; 27:855-863. [PMID: 32879976 DOI: 10.1093/ibd/izaa230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Immunoglobulin G subclass 4 (IgG4) is hypothesized to play an immunomodulatory role, downregulating humoral immune responses. The role of this anti-inflammatory molecule in inflammatory bowel disease (IBD) has not been fully characterized. We sought to define alterations in serum IgG4 in patients with IBD and their association with multiyear disease severity. METHODS We analyzed metadata derived from curated electronic health records from consented patients with IBD prospectively followed at a tertiary center over a 10-year time period. Patients with IBD with IgG4 serum levels available formed the study population. Demographics and multiyear clinical data were collected and analyzed. We stratified patients with IBD with low, normal, or high serum IgG4 levels. RESULTS We found IgG4 characterized in 1193 patients with IBD and low IgG4 levels in 233 patients (20%) and elevated IgG4 levels in 61 patients (5%). An IgG4 deficiency did not significantly correlate with other antibody deficiencies. In a multiple Poisson regression analysis, low IgG4 was associated with more years on biologic agents (P = 0.002) and steroids (P = 0.049) and more hospital admissions (P < 0.001), clinic visits (P = 0.010), outpatient antibiotic prescriptions (P < 0.001), and CD-related surgeries (P = 0.011) during the study period after controlling for certain confounders. Elevated IgG4 was only associated with primary sclerosing cholangitis (P = 0.011). A cohort of patients with IgG4-deficient severe IBD received intravenous Ig replacement therapy, which benefited and was continued in 10 out of 11 individuals. CONCLUSIONS An IgG4 subclass deficiency, distinct from other antibody deficiencies, occurred commonly in a referral IBD population and was associated with multiple markers of disease severity. This is the first association of IgG4 subclass deficiency with an inflammatory disease process. Further work is needed to define the mechanistic role of IgG4 deficiency in this severe IBD subgroup.
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Affiliation(s)
- Filippos Koutroumpakis
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Anna Evans Phillips
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Dhiraj Yadav
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Jorge D Machicado
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Eau Claire, Wisconsin, United States
| | - Maaz Ahsan
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Claudia Ramos Rivers
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Xiaoqing Tan
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - Marc Schwartz
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Siobhan Proksell
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Elyse Johnston
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Jeffrey Dueker
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Jana G Hashash
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Arthur Barrie
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Janet Harrison
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Michael A Dunn
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Liza Konnikova
- Department of Pediatrics, Division of Newborn Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Douglas J Hartman
- Department of Pathology, Division of Anatomic Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Hasieb Din
- Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Dmitriy Babichenko
- School of Information Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - Gong Tang
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - David G Binion
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
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12
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Mudde ACA, Booth C, Marsh RA. Evolution of Our Understanding of XIAP Deficiency. Front Pediatr 2021; 9:660520. [PMID: 34222142 PMCID: PMC8247594 DOI: 10.3389/fped.2021.660520] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/17/2021] [Indexed: 12/17/2022] Open
Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity first described in 2006. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, susceptibility to infections, splenomegaly, cytopaenias, and other less common autoinflammatory phenomena. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Recently, following the introduction of reduced intensity conditioning (RIC), outcomes of allogeneic haematopoietic stem cell transplantation (HSCT), the only curative treatment option for XIAP deficiency, have improved. The pathophysiology of XIAP deficiency is not fully understood, however it is known that XIAP plays a role in both the innate and adaptive immune response and in immune regulation, most notably through modulation of tumour necrosis factor (TNF)-receptor signalling and regulation of NLRP3 inflammasome activity. In this review we will provide an up to date overview of both the clinical aspects and pathophysiology of XIAP deficiency.
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Affiliation(s)
- Anne C A Mudde
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Claire Booth
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.,Department of Immunology and Gene Therapy, Great Ormond Street Hospital, London, United Kingdom
| | - Rebecca A Marsh
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States
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13
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Abstract
COVID-19 has a benign outcome in most cases, yet it can also be fatal and no specific treatment is available as of yet. Older age and several medical comorbidities are risk factors for COVID-19 complications. We report on an elderly man with a longstanding history of bipolar affective disorder associated with heavy smoking, alcohol abuse and multiple comorbidities, including severe chronic obstructive pulmonary disease and recurrent pulmonary sepsis, who contracted COVID-19 during his inpatient treatment of a manic episode, and who fully recovered from COVID-19 without any need for respiratory support. We discuss how his excessive use of nicotine replacement therapy may have contributed to his emerging unscathed from COVID-19. Nicotine, an α7-nACh receptor agonist, may boost the cholinergic anti-inflammatory pathway and hinder the uncontrolled overproduction of pro-inflammatory cytokines triggered by the SARS-CoV-2 virus, which is understood to be the main pathway to poor outcomes and death in severe COVID-19.
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Affiliation(s)
- Luiz Dratcu
- Psychiatry, South London and Maudsley NHS Foundation Trust, London, GBR
| | - Xavier Boland
- Psychiatry, South London and Maudsley NHS Foundation Trust, London, GBR
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14
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Kim SJ, Howe C, Mitchell J, Choo J, Powers A, Oikonomopoulos A, Pothoulakis C, Hommes DW, Im E, Rhee SH. Autotaxin loss accelerates intestinal inflammation by suppressing TLR4-mediated immune responses. EMBO Rep 2020; 21:e49332. [PMID: 32875703 DOI: 10.15252/embr.201949332] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 07/20/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022] Open
Abstract
Autotaxin (ATX) converts lysophosphatidylcholine and sphingosyl-phosphorylcholine into lysophosphatidic acid and sphingosine 1-phosphate, respectively. Despite the pivotal function of ATX in lipid metabolism, mechanisms by which ATX regulates immune and inflammatory disorders remain elusive. Here, using myeloid cell lineage-restricted Atx knockout mice, we show that Atx deficiency disrupts membrane microdomains and lipid rafts, resulting in the inhibition of Toll-like receptor 4 (TLR4) complex formation and the suppression of adaptor recruitment, thereby inhibiting TLR4-mediated responses in macrophages. Accordingly, TLR4-induced innate immune functions, including phagocytosis and iNOS expression, are attenuated in Atx-deficient macrophages. Consequently, Atx-/- mice exhibit a higher bacterial prevalence in the intestinal mucosa compared to controls. When combined with global Il10-/- mice, which show spontaneous colitis due to the translocation of luminal commensal microbes into the mucosa, myeloid cell lineage-restricted Atx knockout accelerates colitis development compared to control littermates. Collectively, our data reveal that Atx deficiency compromises innate immune responses, thereby promoting microbe-associated gut inflammation.
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Affiliation(s)
- Su Jin Kim
- Department of Biological Sciences, Oakland University, Rochester, MI, USA.,College of Pharmacy, Pusan National University, Busan, Korea
| | - Cody Howe
- Department of Biological Sciences, Oakland University, Rochester, MI, USA
| | - Jonathon Mitchell
- Department of Biological Sciences, Oakland University, Rochester, MI, USA
| | - Jieun Choo
- College of Pharmacy, Pusan National University, Busan, Korea
| | - Alexandra Powers
- Department of Biological Sciences, Oakland University, Rochester, MI, USA
| | - Angelos Oikonomopoulos
- Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Charalabos Pothoulakis
- Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Daniel W Hommes
- Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Eunok Im
- College of Pharmacy, Pusan National University, Busan, Korea
| | - Sang Hoon Rhee
- Department of Biological Sciences, Oakland University, Rochester, MI, USA
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15
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Unexpected mechanism of colitis amelioration by artesunate, a natural product from Artemisia annua L. Inflammopharmacology 2019; 28:851-868. [PMID: 31865495 DOI: 10.1007/s10787-019-00678-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/28/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Artemisinin and its derivatives are known to exert immunosuppressive effects through modulating adaptive immunity. We investigated a novel role of artesunate in regulating innate immunity, including both macrophages (MΦ) and dendritic cells (DCs), which are known to involve in DSS-induced colitis. METHODS Effects of artesunate on innate immunity were extensively evaluated, both in vivo using DSS-colitis model with WT and T cell-deficient RAG mice (RAG-/-) and in vitro using cell culture models, including in-depth analyses of MΦ/DC apoptosis and cytokine expression by flow cytometry, Western blot, or immunohistology. RESULTS Unexpectedly, artesunate significantly ameliorated the DSS colitis of both WT and RAG1-/- mice with similar potency, suggesting a mechanism that involves primarily innate rather than adaptive immunity. In vivo mechanistic studies revealed that artesunate markedly induced apoptosis of lamina propria MΦs and DCs and suppressed mucosal TNF-α and IL-12p70 in DSS-colitis. In vitro, artesunate potently induced a dose- and time-dependent apoptosis of murine bone marrow-derived DCs and human THP-1 MΦs, through the caspases-9-mediated intrinsic pathway. Artesunate significantly decreased the secretion of IL-12p40/70 by DCs and TNF-α by MΦs. Furthermore, a combination of artesunate with an immunomodulator (methotrexate/triptolide/azathioprine) exhibited superior potency in promoting apoptosis of MΦs than any individual drug alone. CONCLUSIONS The immunomodulatory mechanism of artesunate in colitis involves a novel and potent induction of the intrinsic apoptosis pathway of proliferating MΦs and DCs and suppression of IL-12 and TNF-α. Artemisinin and its derivatives are promising new therapeutic alternatives for IBD, either alone or in combination with other immunomodulators.
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16
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Gutiérrez-González M, Farías C, Tello S, Pérez-Etcheverry D, Romero A, Zúñiga R, Ribeiro CH, Lorenzo-Ferreiro C, Molina MC. Optimization of culture conditions for the expression of three different insoluble proteins in Escherichia coli. Sci Rep 2019; 9:16850. [PMID: 31727948 PMCID: PMC6856375 DOI: 10.1038/s41598-019-53200-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 10/12/2019] [Indexed: 02/06/2023] Open
Abstract
Recombinant protein expression for structural and therapeutic applications requires the use of systems with high expression yields. Escherichia coli is considered the workhorse for this purpose, given its fast growth rate and feasible manipulation. However, bacterial inclusion body formation remains a challenge for further protein purification. We analyzed and optimized the expression conditions for three different proteins: an anti-MICA scFv, MICA, and p19 subunit of IL-23. We used a response surface methodology based on a three-level Box-Behnken design, which included three factors: post-induction temperature, post-induction time and IPTG concentration. Comparing this information with soluble protein data in a principal component analysis revealed that insoluble and soluble proteins have different optimal conditions for post-induction temperature, post-induction time, IPTG concentration and in amino acid sequence features. Finally, we optimized the refolding conditions of the least expressed protein, anti-MICA scFv, using a fast dilution protocol with different additives, obtaining soluble and active scFv for binding assays. These results allowed us to obtain higher yields of proteins expressed in inclusion bodies. Further studies using the system proposed in this study may lead to the identification of optimal environmental factors for a given protein sequence, favoring the acceleration of bioprocess development and structural studies.
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Affiliation(s)
- Matías Gutiérrez-González
- Centro de Inmunobiotecnología, Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Programa de Doctorado en Farmacología, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Camila Farías
- Centro de Inmunobiotecnología, Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Samantha Tello
- Centro de Inmunobiotecnología, Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Diana Pérez-Etcheverry
- Área de Biotecnología, Instituto Polo Tecnológico de Pando, Facultad de Química, Universidad de la República Oriental del Uruguay, Montevideo, Uruguay
| | - Alfonso Romero
- Centro de Inmunobiotecnología, Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Roberto Zúñiga
- Centro de Inmunobiotecnología, Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Carolina H Ribeiro
- Centro de Inmunobiotecnología, Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Carmen Lorenzo-Ferreiro
- Área de Biotecnología, Instituto Polo Tecnológico de Pando, Facultad de Química, Universidad de la República Oriental del Uruguay, Montevideo, Uruguay
| | - María Carmen Molina
- Centro de Inmunobiotecnología, Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
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17
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Sutcliffe S, Kalyan S, Pankovich J, Chen JMH, Gluck R, Thompson D, Bosiljcic M, Bazett M, Fedorak RN, Panaccione R, Axler J, Marshall JK, Mullins DW, Kabakchiev B, McGovern DPB, Jang J, Coldman A, Vandermeirsch G, Bressler B, Gunn H. Novel Microbial-Based Immunotherapy Approach for Crohn's Disease. Front Med (Lausanne) 2019; 6:170. [PMID: 31380382 PMCID: PMC6659126 DOI: 10.3389/fmed.2019.00170] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 07/08/2019] [Indexed: 12/21/2022] Open
Abstract
Background: Current Crohn's disease (CD) therapies focus on suppressing immune function and come with consequent risk, such as infection and cancer. Notwithstanding, most CD patients still experience disease progression. There is a need for new CD treatment strategies that offer better health outcomes for patients. Aims: To assess safety, efficacy, and tolerability of a novel microbial-derived immunotherapy, QBECO, that aims to restore rather than suppress immune function in CD. Methods: A randomized, double-blind, placebo-controlled trial was conducted in 68 patients with moderate-to-severe CD. Primary endpoints: safety and Week 8 clinical improvement. Secondary endpoints: Week 8 clinical response and remission. Week 8 responders continued blinded treatment through Week 16; non-responders received open-label QBECO from Weeks 9–16. Exploratory analyses included immune biomarker and genotype assessments. Results: QBECO was well-tolerated. Mean reduction in Crohn's Disease Activity Index (CDAI) score was −68 for QBECO vs. −31 for placebo at Week 8. Improvement with QBECO continued through Week 16 (-130 CDAI reduction). Week 8 QBECO clinical response, improvement and remission rates were 41.2%, 32.4%, 29.4% vs. 26.5%, 23.5%, 23.5% for placebo. TNFα inhibitor-naïve subjects achieved higher response rates at Week 8 with QBECO (64%) vs. placebo (26%). Specific immune biomarkers were identified that linked to QBECO response. Conclusion: This proof-of-concept study supports further investigation for the use of QBECO as a novel immunotherapy approach for CD. Biomarker analyses suggests it may be feasible to personalize CD treatment with QBECO. Larger trials are now needed to confirm clinical improvement and the unique biological findings. Clinical Trial Number: NCT01809275 (https://clinicaltrials.gov/ct2/show/NCT01809275)
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Affiliation(s)
| | - Shirin Kalyan
- Qu Biologics Inc., Vancouver, BC, Canada.,Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | | | | | | | - Darby Thompson
- Emmes Canada, Burnaby, BC, Canada.,Department of Statistics and Actuarial Sciences, Simon Fraser University, Burnaby, BC, Canada
| | | | | | - Richard N Fedorak
- Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | - Remo Panaccione
- Inflammatory Bowel Disease Unit, University of Calgary, Calgary, AB, Canada
| | - Jeffrey Axler
- Toronto Digestive Disease Associates Inc., Vaughan, ON, Canada
| | - John K Marshall
- Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - David W Mullins
- Department of Microbiology, Immunology and Medical Education, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
| | - Boyko Kabakchiev
- Zane Cohen Centre for Digestive Diseases, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | | | - Julie Jang
- Qu Biologics Inc., Vancouver, BC, Canada
| | - Andrew Coldman
- Cancer Control Research, British Columbia Cancer Agency, Vancouver, BC, Canada
| | | | - Brian Bressler
- Gastrointestinal Research Institute, Vancouver, BC, Canada
| | - Hal Gunn
- Qu Biologics Inc., Vancouver, BC, Canada
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18
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Farjadian F, Ghasemi A, Gohari O, Roointan A, Karimi M, Hamblin MR. Nanopharmaceuticals and nanomedicines currently on the market: challenges and opportunities. Nanomedicine (Lond) 2019; 14:93-126. [PMID: 30451076 PMCID: PMC6391637 DOI: 10.2217/nnm-2018-0120] [Citation(s) in RCA: 333] [Impact Index Per Article: 55.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 10/15/2018] [Indexed: 12/23/2022] Open
Abstract
There has been a revolution in nanotechnology and nanomedicine. Since 1980, there has been a remarkable increase in approved nano-based pharmaceutical products. These novel nano-based systems can either be therapeutic agents themselves, or else act as vehicles to carry different active pharmaceutical agents into specific parts of the body. Currently marketed nanostructures include nanocrystals, liposomes and lipid nanoparticles, PEGylated polymeric nanodrugs, other polymers, protein-based nanoparticles and metal-based nanoparticles. A range of issues must be addressed in the development of these nanostructures. Ethics, market size, possibility of market failure, costs and commercial development, are some topics which are on the table to be discussed. After passing all the ethical and biological assessments, and satisfying the investors as to future profitability, only a handful of these nanoformulations, successfully obtained marketing approval. We survey the range of nanomedicines that have received regulatory approval and are marketed. We discuss ethics, costs, commercial development and possible market failure. We estimate the global nanomedicine market size and future growth. Our goal is to summarize the different approved nanoformulations on the market, and briefly cover the challenges and future outlook.
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Affiliation(s)
- Fatemeh Farjadian
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz 71468-64685, Iran
| | - Amir Ghasemi
- Department of Materials Science & Engineering, Sharif University of Technology, Tehran 11365-9466, Iran
- Advances Nanobiotechnology & Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14496-4535, Iran
| | - Omid Gohari
- Department of Materials Science & Engineering, Sharif University of Technology, Tehran 11365-9466, Iran
| | - Amir Roointan
- Department of Medical Biotechnology, School of Advanced Medical Sciences & Technologies, Shiraz University of Medical Science, Shiraz 71348-14336, Iran
| | - Mahdi Karimi
- Cellular & Molecular Research Center, Iran University of Medical Sciences, Tehran 14496-14535, Iran
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14496-14535, Iran
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA
- Harvard – MIT Division of Health Sciences & Technology, Cambridge, MA 02139, USA
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19
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Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 2017; 17:78. [PMID: 29282366 PMCID: PMC6168198 DOI: 10.1038/nrd.2017.267] [Citation(s) in RCA: 269] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This corrects the article DOI: 10.1038/nrd.2017.201.
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20
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Rubio CA, Langner C, Schmidt PT. Partial to complete abrogation of the subepithelial macrophage barrier against the gut microbiota in patients with ulcerative colitis and Crohn's colitis. Histopathology 2017; 72:580-587. [PMID: 29023984 DOI: 10.1111/his.13417] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 10/08/2017] [Indexed: 02/06/2023]
Abstract
AIMS The integrity of the band of indigenous macrophages in the subepithelial layer of the lamina propria (SLP) is crucial in preventing the commensal gut microbiota from attacking the host. The breakdown of the SLP macrophage barrier results in microbiota inflow and improper immune responses; this might lead to inflammatory bowel disease (IBD). During inflammation, the SLP macrophage barrier is reinforced by inflammation-elicited macrophages (IEMs), which are derived from blood-circulating monocytes. The aim was to explore the characteristics of the SLP macrophage band in a cohort of biopsies without inflammation, in patients with ulcerative colitis in remission (UCre), and in patients with right-sided Crohn's colitis (RCC). METHODS AND RESULTS Endoscopic biopsies were taken from endoscopically normal descending colon in 247 patients; 80 with IBD (27 UCre and 53 RCC), and 167 without IBD [90 had colonic diarrhoea, 63 were enrolled in a colorectal cancer (CRC) surveillance programme, seven had microscopic colitis in remission, and seven had miscellaneous colonic ailments]. Sections showed no inflammatory changes; they were immunostained with CD68. Among patients with UCre and RCC, the SLP band of CD68+ macrophages was fragmented or minute in 59% (47/80) and negative in 9% (7/80). In contrast, only 31% (51/167) of the biopsies from control patients had a fragmented/minute SLP band of CD68+ macrophages, and none had a negative SLP band of CD68+ macrophages (IBD versus controls, P < 0.05). CONCLUSIONS The finding that the SLP macrophage barrier was fragmented to totally abrogated in UCre and RCC patients suggests a longlasting defect in the SLP CD68+ macrophage barrier in these patients. The lack of ongoing inflammation in colonic biopsies should rule out the participation of bone marrow-derived IEMs in the abrogation of the SLP macrophage barrier reported here.
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Affiliation(s)
- Carlos A Rubio
- Department of Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden
| | - Cord Langner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Peter T Schmidt
- Department of Medicine, Karolinska Institute, Centre for Digestive Diseases, University Hospital, Stockholm, Sweden
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21
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JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 2017; 16:843-862. [PMID: 29104284 DOI: 10.1038/nrd.2017.201] [Citation(s) in RCA: 698] [Impact Index Per Article: 87.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The discovery of cytokines as key drivers of immune-mediated diseases has spurred efforts to target their associated signalling pathways. Janus kinases (JAKs) are essential signalling mediators downstream of many pro-inflammatory cytokines, and small-molecule inhibitors of JAKs (jakinibs) have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Building on the clinical success of first-generation jakinibs, second-generation compounds that claim to be more selective are currently undergoing development and proceeding to clinical trials. However, important questions remain about the advantages and limitations of improved JAK selectivity, optimal routes and dosing regimens and how best to identify patients who will benefit from jakinibs. This Review discusses the biology of jakinibs from a translational perspective, focusing on recent insights from clinical trials, the development of novel agents and the use of jakinibs in a spectrum of immune and inflammatory diseases.
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22
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Ahmed SS, Dey N, Ashour AS, Sifaki-Pistolla D, Bălas-Timar D, Balas VE, Tavares JMRS. Effect of fuzzy partitioning in Crohn's disease classification: a neuro-fuzzy-based approach. Med Biol Eng Comput 2017; 55:101-115. [PMID: 27106754 DOI: 10.1007/s11517-016-1508-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 03/31/2016] [Indexed: 02/08/2023]
Abstract
Crohn's disease (CD) diagnosis is a tremendously serious health problem due to its ultimately effect on the gastrointestinal tract that leads to the need of complex medical assistance. In this study, the backpropagation neural network fuzzy classifier and a neuro-fuzzy model are combined for diagnosing the CD. Factor analysis is used for data dimension reduction. The effect on the system performance has been investigated when using fuzzy partitioning and dimension reduction. Additionally, further comparison is done between the different levels of the fuzzy partition to reach the optimal performance accuracy level. The performance evaluation of the proposed system is estimated using the classification accuracy and other metrics. The experimental results revealed that the classification with level-8 partitioning provides a classification accuracy of 97.67 %, with a sensitivity and specificity of 96.07 and 100 %, respectively.
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Affiliation(s)
- Sk Saddam Ahmed
- Department of CSE, JIS College of Engineering, Kalyani, West Bengal, India
| | - Nilanjan Dey
- Department of Information Technology, Techno India College of Technology, Kolkata, India
| | - Amira S Ashour
- Department of Electronics and Electrical Communications Engineering, Faculty of Engineering, Tanta University, Tanta, Egypt.
- College of Computers and IT, Taif University, Ta'if, Saudi Arabia.
| | - Dimitra Sifaki-Pistolla
- Clinic of Social and Family Medicine, Faculty of Medicine, University of Crete, Crete, Greece
| | - Dana Bălas-Timar
- Faculty of Educational Sciences, Psychology and Social Sciences, Aurel Vlaicu University of Arad, Arad, Romania
| | - Valentina E Balas
- Faculty of Engineering, Aurel Vlaicu University of Arad, Arad, Romania
| | - João Manuel R S Tavares
- Instituto de Ciência e Inovação em Engenharia Mecânica e Engenharia Industrial, Departamento de Engenharia Mecânica, Faculdade de Engenharia, Universidade do Porto, Rua Dr. Roberto Frias, s/n, 4200-465, Porto, Portugal
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Timmermans WMC, van Laar JAM, van Hagen PM, van Zelm MC. Immunopathogenesis of granulomas in chronic autoinflammatory diseases. Clin Transl Immunology 2016; 5:e118. [PMID: 28090320 PMCID: PMC5192066 DOI: 10.1038/cti.2016.75] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Revised: 11/11/2016] [Accepted: 11/12/2016] [Indexed: 12/23/2022] Open
Abstract
Granulomas are clusters of immune cells. These structures can be formed in reaction to infection and display signs of necrosis, such as in tuberculosis. Alternatively, in several immune disorders, such as sarcoidosis, Crohn's disease and common variable immunodeficiency, non-caseating granulomas are formed without an obvious infectious trigger. Despite advances in our understanding of the human immune system, the pathogenesis underlying these non-caseating granulomas in chronic inflammatory diseases is still poorly understood. Here, we review the current knowledge about the immunopathogenesis of granulomas, and we discuss how the involved immune cells can be targeted with novel therapeutics.
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Affiliation(s)
- Wilhelmina Maria Cornelia Timmermans
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Jan Alexander Michael van Laar
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Petrus Martinus van Hagen
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Menno Cornelis van Zelm
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
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Loganes C, Pin A, Naviglio S, Girardelli M, Bianco AM, Martelossi S, Tommasini A, Piscianz E. Altered pattern of tumor necrosis factor-alpha production in peripheral blood monocytes from Crohn's disease. World J Gastroenterol 2016; 22:9117-9126. [PMID: 27895399 PMCID: PMC5107593 DOI: 10.3748/wjg.v22.i41.9117] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 08/25/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the inflammatory state in Crohn's disease (CD) patients and correlate it with genetic background and microbial spreading. METHODS By means of flow cytometry, production of tumor necrosis factor-alpha (TNF-α) was measured in peripheral blood monocytes from patients suffering from CD, ulcerative colitis (UC) and in healthy subjects after stimulation of the NOD2 and TLR pathways. CD patients were genotyped for the three most common NOD2 variants (R702W, G908R and L1007Pfs*2) and basal production of TNF-α was correlated to NOD2 genotype. Also, production of TNF-α was correlated to plasmatic levels of LPS Binding Protein (LBP), soluble (s) CD14 and to the activity state of the disease. RESULTS The patients with CD were characterized by a significantly higher monocyte basal expression of TNF-α compared with healthy subjects and UC patients, and after stimulation with Pam3CSK4 (ligand of TLR2/1) and MDP-L18 (ligand of NOD2) this difference was maintained, while other microbial stimuli (LPS, ligand of TLR4 and PolyI:C, ligand of TLR3) induced massive activation in CD monocytes as well as in UC and in healthy control cells. There was no significant difference in the production of TNF-α between patients who carried CD-associated heterozygous or homozygous variants in NOD2 and patients with wild type NOD2 genotype. Although serum LBP levels have been shown to correlate positively with the state of activity of the disease, TNF-α production did not show a clear correlation with either LBP or sCD14 levels in plasma. Moreover, no clear correlation was seen between TNF-α production and activity indices in either CD or UC. CONCLUSION Peripheral monocytes from CD express higher basal and stimulated TNF-α than controls, regardless of NOD2 genotype and without a clear correlation with disease activity.
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Balakrishnan A, Schnare M, Chakravortty D. Of Men Not Mice: Bactericidal/Permeability-Increasing Protein Expressed in Human Macrophages Acts as a Phagocytic Receptor and Modulates Entry and Replication of Gram-Negative Bacteria. Front Immunol 2016; 7:455. [PMID: 27822215 PMCID: PMC5075746 DOI: 10.3389/fimmu.2016.00455] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 10/11/2016] [Indexed: 12/31/2022] Open
Abstract
Macrophages as immune cells prevent the spreading of pathogens by means of active phagocytosis and killing. We report here the presence of an antimicrobial protein, bactericidal/permeability-increasing protein (BPI) in human macrophages, which actively participates in engulfment and killing of Gram-negative pathogens. Our studies revealed increased expression of BPI in human macrophages during bacterial infection and upon stimulation with various pathogen-associated molecular patterns, viz., LPS and flagellin. Furthermore, during the course of an infection, BPI interacted with Gram-negative bacteria, resulting in enhanced phagocytosis and subsequent control of the bacterial replication. However, it was observed that bacteria which can maintain an active replicating niche (Salmonella Typhimurium) avoid the interaction with BPI during later stages of infection. On the other hand, Salmonella mutants, which cannot maintain a replicating niche, as well as Shigella flexneri, which quit the endosomal vesicle, showed interaction with BPI. These results propose an active role of BPI in Gram-negative bacterial clearance by human macrophages.
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Affiliation(s)
- Arjun Balakrishnan
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Markus Schnare
- Institute for Immunology, University of Marburg, Marburg, Germany
| | - Dipshikha Chakravortty
- Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, India
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Preservation Analysis of Macrophage Gene Coexpression Between Human and Mouse Identifies PARK2 as a Genetically Controlled Master Regulator of Oxidative Phosphorylation in Humans. G3-GENES GENOMES GENETICS 2016; 6:3361-3371. [PMID: 27558669 PMCID: PMC5068955 DOI: 10.1534/g3.116.033894] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Macrophages are key players involved in numerous pathophysiological pathways and an in-depth characterization of their gene regulatory networks can help in better understanding how their dysfunction may impact on human diseases. We here conducted a cross-species network analysis of macrophage gene expression data between human and mouse to identify conserved networks across both species, and assessed whether such networks could reveal new disease-associated regulatory mechanisms. From a sample of 684 individuals processed for genome-wide macrophage gene expression profiling, we identified 27 groups of coexpressed genes (modules). Six modules were found preserved (P < 10−4) in macrophages from 86 mice of the Hybrid Mouse Diversity Panel. One of these modules was significantly [false discovery rate (FDR) = 8.9 × 10−11] enriched for genes belonging to the oxidative phosphorylation (OXPHOS) pathway. This pathway was also found significantly (FDR < 10−4) enriched in susceptibility genes for Alzheimer, Parkinson, and Huntington diseases. We further conducted an expression quantitative trait loci analysis to identify SNP that could regulate macrophage OXPHOS gene expression in humans. This analysis identified the PARK2 rs192804963 as a trans-acting variant influencing (minimal P-value = 4.3 × 10−8) the expression of most OXPHOS genes in humans. Further experimental work demonstrated that PARK2 knockdown expression was associated with increased OXPHOS gene expression in THP1 human macrophages. This work provided strong new evidence that PARK2 participates to the regulatory networks associated with oxidative phosphorylation and suggested that PARK2 genetic variations could act as a trans regulator of OXPHOS gene macrophage expression in humans.
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27
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Chuang LS, Villaverde N, Hui KY, Mortha A, Rahman A, Levine AP, Haritunians T, Evelyn Ng SM, Zhang W, Hsu NY, Facey JA, Luong T, Fernandez-Hernandez H, Li D, Rivas M, Schiff ER, Gusev A, Schumm LP, Bowen BM, Sharma Y, Ning K, Remark R, Gnjatic S, Legnani P, George J, Sands BE, Stempak JM, Datta LW, Lipka S, Katz S, Cheifetz AS, Barzilai N, Pontikos N, Abraham C, Dubinsky MJ, Targan S, Taylor K, Rotter JI, Scherl EJ, Desnick RJ, Abreu MT, Zhao H, Atzmon G, Pe'er I, Kugathasan S, Hakonarson H, McCauley JL, Lencz T, Darvasi A, Plagnol V, Silverberg MS, Muise AM, Brant SR, Daly MJ, Segal AW, Duerr RH, Merad M, McGovern DPB, Peter I, Cho JH. A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF. Gastroenterology 2016; 151:710-723.e2. [PMID: 27377463 PMCID: PMC5037012 DOI: 10.1053/j.gastro.2016.06.045] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 06/27/2016] [Accepted: 06/28/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. METHODS We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor β common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony-stimulating factor-responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared. RESULTS In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P = 8.52 × 10(-4)); the finding was validated in the replication cohort (combined P = 3.42 × 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal-regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony-stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to granulocyte-macrophage colony-stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance. CONCLUSIONS In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony-stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.
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Affiliation(s)
- Ling-Shiang Chuang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nicole Villaverde
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ken Y Hui
- Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut; Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Arthur Mortha
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Adeeb Rahman
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Adam P Levine
- Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom
| | - Talin Haritunians
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Sok Meng Evelyn Ng
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Wei Zhang
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Nai-Yun Hsu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jody-Ann Facey
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Tramy Luong
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Dalin Li
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Manuel Rivas
- Department of Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts; Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics Research, University of Oxford, Oxford, United Kingdom
| | - Elena R Schiff
- Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom
| | - Alexander Gusev
- Department of Epidemiology, Harvard University, Boston, Massachusetts
| | - L Phillip Schumm
- Department of Health Studies, University of Chicago, Chicago, Illinois
| | - Beatrice M Bowen
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Department of Genetics, Yale University, New Haven, Connecticut
| | - Yashoda Sharma
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Kaida Ning
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Department of Molecular and Computational Biology, University of Southern California, Los Angeles, California
| | - Romain Remark
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sacha Gnjatic
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Peter Legnani
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - James George
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Bruce E Sands
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Joanne M Stempak
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Lisa W Datta
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Seth Lipka
- Department of Internal Medicine, University of South Florida, Tampa, Florida
| | - Seymour Katz
- Department of Medicine, New York University School of Medicine, New York, New York
| | - Adam S Cheifetz
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Nir Barzilai
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
| | - Nikolas Pontikos
- Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom
| | - Clara Abraham
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Marla J Dubinsky
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Stephan Targan
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Kent Taylor
- Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Harbor-University of California Los Angeles Medical Center, Torrance, California
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Harbor-University of California Los Angeles Medical Center, Torrance, California
| | - Ellen J Scherl
- The Division of Gastroenterology and Hepatology, Sanford I. Weill College of Cornell University-New York Presbyterian Hospital, New York, New York
| | - Robert J Desnick
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Maria T Abreu
- Division of Gastroenterology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Hongyu Zhao
- Department of Biostatistics, Yale University, New Haven, Connecticut
| | - Gil Atzmon
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
| | - Itsik Pe'er
- Department of Computer Science, Columbia University, New York, New York
| | | | - Hakon Hakonarson
- Centre for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Human Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jacob L McCauley
- John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida; Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida
| | - Todd Lencz
- Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York
| | - Ariel Darvasi
- Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Vincent Plagnol
- Genetics Institute, Division of Biosciences, University College, London, United Kingdom
| | - Mark S Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Aleixo M Muise
- Inflammatory Bowel Disease Centre and Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Steven R Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Mark J Daly
- Department of Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Genetics, Harvard Medical School, Boston, Massachusetts
| | - Anthony W Segal
- Centre for Molecular Medicine, Division of Medicine, University College, London, United Kingdom
| | - Richard H Duerr
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Miriam Merad
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Judy H Cho
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
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Genua M, Ingangi V, Fonteyne P, Piontini A, Yousif AM, Merlino F, Grieco P, Malesci A, Carriero MV, Danese S. Treatment with a Urokinase Receptor-derived Cyclized Peptide Improves Experimental Colitis by Preventing Monocyte Recruitment and Macrophage Polarization. Inflamm Bowel Dis 2016; 22:2390-401. [PMID: 27537052 DOI: 10.1097/mib.0000000000000896] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Leukocyte migration across the blood barrier and into tissues represents a key process in the pathogenesis of inflammatory bowel diseases. The urokinase receptor (urokinase-type plasminogen activator receptor) is a master regulator of leukocyte recruitment. We recently found that cyclization of the urokinase-type plasminogen activator receptor-derived peptide Ser-Arg-Ser-Arg-Tyr [SRSRY] inhibits transendothelial migration of monocytes. Now, we have explored the effects of [SRSRY] administration during experimental colitis. METHODS The effects of [SRSRY] on cytokine profile, cytoskeletal organization, and cell migration were investigated using phorbol-12-myristate acetate-differentiated THP-1 cells exposed to polarizing stimuli. In vivo, [SRSRY] was intraperitoneally administered during dextran sodium sulfate- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in wild-type or urokinase-type plasminogen activator receptor knockout mice. Levels of pro-inflammatory cytokines and inflammatory monocytes in mucosal infiltrates were assessed by enzyme-linked immunosorbent assay and flow cytometry, respectively. RESULTS [SRSRY] prevents M0 to M1 transition and migration of M1 polarized macrophages. In vivo, [SRSRY] reduces intestinal inflammation diminishing body weight loss and disease activity index. These beneficial effects are accompanied by a reduction of interleukin 1β, interleukin 6, and tumor necrosis factor α, an increase of interleukin 10, and an abridged recruitment of inflammatory monocytes to the inflamed tissue. CONCLUSIONS Altogether, these findings indicate that [SRSRY] may be considered as a new drug useful for the pharmacological treatment of chronic inflammatory diseases, such as inflammatory bowel diseases.
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Affiliation(s)
- Marco Genua
- *IBD Center, Humanitas Research Institute, Rozzano, Italy; †Department of Translational Medicine, Università degli Studi di Milano, Milan, Italy; ‡Neoplastic Progression Unit, Department of Experimental Oncology, IRCCS Istituto Nazionale Tumori "Fondazione G. Pascale," Naples, Italy; §SUN, Second University of Naples, Naples, Italy; ‖Department of Pharmacy, University Federico II, Naples, Italy; and ¶Hunimed-Humanitas University, Milan, Italy
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Parkos CA. Neutrophil-Epithelial Interactions: A Double-Edged Sword. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:1404-16. [PMID: 27083514 DOI: 10.1016/j.ajpath.2016.02.001] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 01/25/2016] [Accepted: 02/01/2016] [Indexed: 02/07/2023]
Abstract
In recent years, it has become clear that innate immune cells termed neutrophils act as double-edged swords by playing essential roles in clearing infection but also causing tissue damage, yet being critical for wound healing. Neutrophil recruitment to sites of injured tissue or infection has been well studied, and many of the molecular events that regulate passage of leukocytes out of the microcirculation are now understood. However, after exiting the circulation, the molecular details that regulate neutrophil passage to end targets, such mucosal surfaces, are just beginning to be appreciated. Given that migration of neutrophils across mucosal epithelia is associated with disease symptoms and disruption of critical barrier function in disorders such as inflammatory bowel disease, there has been long-standing interest in understanding the molecular basis and functional consequences of neutrophil-epithelial interactions. It is a great honor that my work was recognized by the Rous-Whipple Award this past year, giving me the opportunity to summarize what we have learned during the past few decades about leukocyte interactions with epithelial cells.
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Affiliation(s)
- Charles A Parkos
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
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Casanova JL. Severe infectious diseases of childhood as monogenic inborn errors of immunity. Proc Natl Acad Sci U S A 2015; 112:E7128-37. [PMID: 26621750 PMCID: PMC4697435 DOI: 10.1073/pnas.1521651112] [Citation(s) in RCA: 163] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.
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MESH Headings
- Adolescent
- Candidiasis, Chronic Mucocutaneous/genetics
- Candidiasis, Chronic Mucocutaneous/immunology
- Child
- Complement System Proteins/genetics
- Encephalitis, Herpes Simplex/genetics
- Encephalitis, Herpes Simplex/immunology
- Epidermodysplasia Verruciformis/genetics
- Epidermodysplasia Verruciformis/immunology
- Genetic Diseases, Inborn/genetics
- Genetic Diseases, Inborn/immunology
- Genetic Predisposition to Disease
- Humans
- Immunologic Deficiency Syndromes/genetics
- Immunologic Deficiency Syndromes/immunology
- Infections/genetics
- Infections/immunology
- Influenza, Human/genetics
- Influenza, Human/immunology
- Interferon-gamma/genetics
- Interferon-gamma/immunology
- Lymphoproliferative Disorders/genetics
- Lymphoproliferative Disorders/immunology
- Malaria/genetics
- Malaria/immunology
- Models, Genetic
- Models, Immunological
- Mycobacterium Infections/genetics
- Mycobacterium Infections/immunology
- Neisseria/immunology
- Neisseria/pathogenicity
- Pneumococcal Infections/genetics
- Pneumococcal Infections/immunology
- Tinea/genetics
- Tinea/immunology
- Young Adult
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Affiliation(s)
- Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, New York, NY 10065; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, 75015 Paris, France; Imagine Institute, Paris Descartes University, 75015 Paris, France; Pediatric Hematology and Immunology Unit, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, 75015 Paris, France
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Kühl AA, Erben U, Kredel LI, Siegmund B. Diversity of Intestinal Macrophages in Inflammatory Bowel Diseases. Front Immunol 2015; 6:613. [PMID: 26697009 PMCID: PMC4670857 DOI: 10.3389/fimmu.2015.00613] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 11/22/2015] [Indexed: 12/23/2022] Open
Abstract
Macrophages as innate immune cells and fast responders to antigens play a central role in protecting the body from the luminal content at a huge interface. Chronic inflammation in inflammatory bowel diseases massively alters the number and the subset diversity of intestinal macrophages. We here address the diversity within the human intestinal macrophage compartment at the level of similarities and differences between homeostasis and chronic intestinal inflammation as well as between UC and CD, including the potential role of macrophage subsets for intestinal fibrosis. Hallmark of macrophages is their enormous plasticity, i.e., their capacity to integrate signals from their environment thereby changing their phenotype and functions. Tissue-resident macrophages located directly beneath the surface epithelium in gut homeostasis are mostly tolerogenic. The total number of macrophages increases with luminal contents entering the mucosa through a broken intestinal barrier in ulcerative colitis (UC) as well as in Crohn's disease (CD). Although not fully understood, the resulting mixtures of tissue-resident and tissue-infiltrating macrophages in both entities are diverse with respect to their phenotypes and their distribution. Macrophages in UC mainly act within the intestinal mucosa. In CD, macrophages can also be found in the muscularis and the mesenteric fat tissue compartment. Taken together, the present knowledge on human intestinal macrophages so far provides a good starting point to dig deeper into the similarities and differences of functional subsets and to finally use their phenotypical diversity as markers for complex local milieus in health and disease.
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Affiliation(s)
- Anja A Kühl
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin , Berlin , Germany ; Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin , Berlin , Germany
| | - Ulrike Erben
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin , Berlin , Germany ; Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin , Berlin , Germany
| | - Lea I Kredel
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin , Berlin , Germany
| | - Britta Siegmund
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin , Berlin , Germany ; Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin , Berlin , Germany
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Däbritz J. GM-CSF and the role of myeloid regulatory cells in the pathogenesis and treatment of Crohn's disease. Mol Cell Pediatr 2015; 2:12. [PMID: 26626346 PMCID: PMC4666883 DOI: 10.1186/s40348-015-0024-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 11/20/2015] [Indexed: 12/19/2022] Open
Abstract
Background Intestinal monocytes/macrophages sustain the intestinal immune homeostasis and might be an attractive therapeutic target for the management of inflammatory bowel disease (IBD). Granulocyte macrophage colony-stimulating factor (GM-CSF) exerts beneficial effects on intestinal inflammation and promotes signal transducer and activator of transcription 3 (STAT3)-mediated expansion of myeloid-derived suppressor cells (MDSCs). However, the full action mechanism of GM-CSF, and especially whether monocytes mediate its therapeutic effects in vivo, had not been previously elucidated. Conclusions This review article summarizes recent developments in the immunology of mucosal diseases and describes new aspects of the role of myeloid regulatory cells in IBD and the function of GM-CSF in maintaining the intestinal immune homeostasis in Crohn’s disease (CD). This review article highlights the exploration of stimulating in addition to suppressive therapies for patients with IBD and underpins that myeloid regulatory cells might become a promising novel cell-based therapeutic option.
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Affiliation(s)
- Jan Däbritz
- Present address: Department of Pediatrics, University Hospital Rostock, Ernst-Heydemann-Str. 8, 18057, Rostock, Germany. .,Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany. .,Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, 50 Flemington Road, Parkville, VIC, 3052, Australia.
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Leppkes M, Neurath MF, Herrmann M, Becker C. Immune deficiency vs. immune excess in inflammatory bowel diseases-STAT3 as a rheo-STAT of intestinal homeostasis. J Leukoc Biol 2015; 99:57-66. [PMID: 26232455 DOI: 10.1189/jlb.5mr0515-221r] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 07/02/2015] [Indexed: 12/17/2022] Open
Abstract
Genome-wide association studies have provided many genetic alterations, conferring susceptibility to multifactorial polygenic diseases, such as inflammatory bowel diseases. Yet, how specific genetic alterations functionally affect intestinal inflammation often remains elusive. It is noteworthy that a large overlap of genes involved in immune deficiencies with those conferring inflammatory bowel disease risk has been noted. This has provided new arguments for the debate on whether inflammatory bowel disease arises from either an excess or a deficiency in the immune system. In this review, we highlight the functional effect of an inflammatory bowel disease-risk allele, which cannot be deduced from genome-wide association studies data alone. As exemplified by the transcription factor signal transducer and activator of transcription 3 (STAT3), we show that a single gene can have a plethora of effects in various cell types of the gut. These effects may individually contribute to the restoration of intestinal homeostasis on the one hand or pave the way for excessive immunopathology on the other, as an inflammatory "rheo-STAT".
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Affiliation(s)
- Moritz Leppkes
- *Medical Clinic 1 and Medical Clinic 3, University Clinic, Friedrich Alexander University, Erlangen, Germany
| | - Markus F Neurath
- *Medical Clinic 1 and Medical Clinic 3, University Clinic, Friedrich Alexander University, Erlangen, Germany
| | - Martin Herrmann
- *Medical Clinic 1 and Medical Clinic 3, University Clinic, Friedrich Alexander University, Erlangen, Germany
| | - Christoph Becker
- *Medical Clinic 1 and Medical Clinic 3, University Clinic, Friedrich Alexander University, Erlangen, Germany
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Combinatorial Intervention with Mesenchymal Stem Cells and Granulocyte Colony-Stimulating Factor in a Rat Model of Ulcerative Colitis. Dig Dis Sci 2015; 60:1948-57. [PMID: 25894931 DOI: 10.1007/s10620-015-3655-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Accepted: 03/30/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Bone marrow mesenchymal stem cells sometimes improve symptoms of inflammatory bowel disease. AIM To test the effects of combined granulocyte colony-stimulating factor (G-CSF) and MSC therapy in a rat model of ulcerative colitis (UC). METHODS Seventy-two rats with TNBS-induced UC were divided into control or treatment groups: control (no disease and no treatment), no treatment (model), 5-aminosalicylate (5-ASA) enema, or MSCs (labeled with BrdU) with (MSC/GCSF) or without (MSC) G-CSF, and G-CSF alone (GCSF). On days 14 and 28 post-treatment, macroscopic and histological appearances were assessed and the disease activity index (DAI) scored to evaluate the severity of disease. BrdU-labeled MSCs were identified by immunofluorescence to confirm transplantation and their location. The inflammatory profile of each group was evaluated by measuring expression of nuclear NF-κB p65, serum TNF-α, and IL-10 and by activity of mucosal myeloperoxidase (MPO). RESULTS Rats receiving MSC and G-CSF combination therapy had increased recruitment of MSCs to the colonic mucosa compared with rats receiving MSC transplantation alone. On day 28, the DAI, MPO activity, serum TNF-α and IL-10 levels, and NF-κB p65 expression in the combination therapy group were significantly lower compared to animals receiving no treatment, MSCs alone, or G-CSF alone (P < 0.05). CONCLUSION Intravenously transplanted MSCs migrate and distribute to the colon to effectively alleviate the symptoms of UC, while G-CSF enhances this effect via an anti-inflammatory effect and improvement in the pathologic features of UC. G-CSF may be a promising therapeutic regulator of MSCs that can improve therapeutic outcomes in patients with UC.
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Site-Specific Immunomodulator: A Novel Treatment for Crohn's Disease. Gastroenterol Res Pract 2015; 2015:231243. [PMID: 26064087 PMCID: PMC4443884 DOI: 10.1155/2015/231243] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 04/27/2015] [Indexed: 01/13/2023] Open
Abstract
We investigated the mechanism of action, safety, and efficacy of the Site-Specific Immunomodulator (SSI) QBECO, a novel immunotherapy for Crohn's disease (CD). Using human monocytic THP-1 cells, we demonstrate that SSI QBECO (derived from the common colon bacteria E. coli) activates macrophages to an M1 phenotype (associated with enhanced capacity to eliminate bacteria and activate innate immune responses). We assessed SSI QBECO in a compassionate use protocol of ten adult patients with active CD. Patients with moderate to severe clinical symptoms receiving conventional CD treatments and/or complementary therapies were included, except patients receiving anti-TNF medications. SSI QBECO was self-administered subcutaneously every second day, for a minimum of 2.5 months and a maximum of 11 months. All 10 patients reported improvement of symptoms while on the SSI QBECO treatment. Seven patients reported full resolution of clinical symptoms during a course of SSI QBECO of at least three months. Three patients have experienced ongoing sustained clinical remission after discontinuing all medications, including SSI treatment. The longest case of clinical remission is still ongoing (>4 years). No serious severe adverse clinical events were reported. Collectively, we conclude that treatment with the immunoactive SSI QBECO was well tolerated and effective for treatment of Crohn's disease in this case series.
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Kirino Y, Remmers EF. Genetic architectures of seropositive and seronegative rheumatic diseases. Nat Rev Rheumatol 2015; 11:401-14. [PMID: 25907699 DOI: 10.1038/nrrheum.2015.41] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and some other rheumatic diseases are genetically complex, with evidence of familial clustering, but not of Mendelian inheritance. These diseases are thought to result from contributions and interactions of multiple genetic and nongenetic risk factors, which have small effects individually. Genome-wide association studies (GWAS) of large collections of data from cases and controls have revealed many genetic factors that contribute to non-Mendelian rheumatic diseases, thus providing insights into associated molecular mechanisms. This Review summarizes methods for the identification of gene variants that influence genetically complex diseases and focuses on what we have learned about the rheumatic diseases for which GWAS have been reported. Our review of the disease-associated loci identified to date reveals greater sharing of risk loci among the groups of seropositive (diseases in which specific autoantibodies are often present) or seronegative diseases than between these two groups. The nature of the shared and discordant loci suggests important similarities and differences among these diseases.
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Affiliation(s)
- Yohei Kirino
- Yokohama City University Graduate School of Medicine, Department of Internal Medicine and Clinical Immunology, 3-9 Fukuura, Kanazawa-Ku, Yokohama 236-0004, Japan
| | - Elaine F Remmers
- National Institutes of Health, National Human Genome Research Institute, Inflammatory Disease Section, 10 Center Drive, MSC 1849, Bethesda, MD 20892, USA
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Genua M, D'Alessio S, Cibella J, Gandelli A, Sala E, Correale C, Spinelli A, Arena V, Malesci A, Rutella S, Ploplis VA, Vetrano S, Danese S. The urokinase plasminogen activator receptor (uPAR) controls macrophage phagocytosis in intestinal inflammation. Gut 2015; 64:589-600. [PMID: 24848264 DOI: 10.1136/gutjnl-2013-305933] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Inflammation plays crucial roles in the pathogenesis of several chronic inflammatory disorders, including Crohn's disease (CD) and UC, the two major forms of IBD. The urokinase plasminogen activator receptor (uPAR) exerts pleiotropic functions over the course of both physiological and pathological processes. uPAR not only has a key role in fibrinolysis but also modulates the development of protective immunity. Additionally, uPAR supports extracellular matrix degradation and regulates cell migration, adhesion and proliferation, thus influencing the development of inflammatory and immune responses. This study aimed to evaluate the role of uPAR in the pathogenesis of IBD. DESIGN The functional role of uPAR was assessed in established experimental models of colitis. uPAR deficiency effects on cytokine release, polarisation and bacterial phagocytosis were analysed in colonic macrophages. uPAR expression was analysed in surgical specimens collected from normal subjects and patients with IBD. RESULTS In mice, uPAR expression is positively regulated as colitis progresses. uPAR-KO mice displayed severe inflammation compared with wild-type littermates, as indicated by clinical assessment, endoscopy and colon histology. The absence of uPAR led to an increased production of inflammatory cytokines by macrophages that showed an M1 polarisation and impaired phagocytosis. In human IBD, CD68(+) macrophages derived from the inflamed mucosa expressed low levels of uPAR. CONCLUSIONS These findings point to uPAR as an essential component of intestinal macrophage functions and unravel a new potential target to control mucosal inflammation in IBD.
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Affiliation(s)
- Marco Genua
- IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy Department of Translational Medicine, University of Milan, Milan, Italy
| | - Silvia D'Alessio
- IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Javier Cibella
- IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy
| | | | - Emanuela Sala
- IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Carmen Correale
- IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Antonino Spinelli
- Department of Translational Medicine, University of Milan, Milan, Italy Department of Surgery-IBD Surgery Unit, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Vincenzo Arena
- Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Alberto Malesci
- IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy Department of Translational Medicine, University of Milan, Milan, Italy
| | - Sergio Rutella
- Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Victoria A Ploplis
- W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, USA
| | - Stefania Vetrano
- IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Silvio Danese
- IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy
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Aguilar C, Latour S. X-linked inhibitor of apoptosis protein deficiency: more than an X-linked lymphoproliferative syndrome. J Clin Immunol 2015; 35:331-8. [PMID: 25737324 DOI: 10.1007/s10875-015-0141-9] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 02/09/2015] [Indexed: 01/01/2023]
Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency (also known as X-linked lymphoproliferative syndrome type 2, XLP-2) is a rare primary immunodeficiency. Since the disease was first described in 2006, more than 70 patients suffering from XIAP-deficiency have been reported, thus extending the clinical presentations of the disease. The main clinical features of XLP-2 are (i) elevated susceptibility to hemophagocytic lymphohistiocytosis (HLH, frequently in response to infection with Epstein-Barr virus (EBV)), (ii) recurrent splenomegaly and (iii) inflammatory bowel disease (IBD) with the characteristics of Crohn's disease. XIAP deficiency is now considered to be one of the genetic causes of IBD in infancy. Although XIAP is an anti-apoptotic molecule, it is also involved in many other pathways, including the regulation of innate immunity and inflammation. XIAP is required for signaling through the Nod-like receptors NOD1 and 2, which are intracellular sensors of bacterial infection. XIAP-deficient T cells (including innate natural killer T cells and mucosal-associated invariant T cells) are overly sensitive to apoptosis. NOD2 function is impaired in XIAP-deficient monocytes. However, the physiopathological mechanisms underlying the clinical phenotypes in XIAP deficiency, notably the HLH and the EBV susceptibility, are not well understood. Here, we review the clinical aspects, molecular etiology and physiopathology of XIAP deficiency.
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Affiliation(s)
- Claire Aguilar
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Descartes-Sorbonne Paris Cité University of Paris and Institut Imagine, Paris, France
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XIAP deficiency syndrome in humans. Semin Cell Dev Biol 2015; 39:115-23. [DOI: 10.1016/j.semcdb.2015.01.015] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 01/29/2015] [Accepted: 01/30/2015] [Indexed: 01/15/2023]
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Däbritz J, Weinhage T, Varga G, Wirth T, Walscheid K, Brockhausen A, Schwarzmaier D, Brückner M, Ross M, Bettenworth D, Roth J, Ehrchen JM, Foell D. Reprogramming of monocytes by GM-CSF contributes to regulatory immune functions during intestinal inflammation. THE JOURNAL OF IMMUNOLOGY 2015; 194:2424-38. [PMID: 25653427 DOI: 10.4049/jimmunol.1401482] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF-activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell-induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-γ in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn's disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.
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Affiliation(s)
- Jan Däbritz
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany; Interdisciplinary Center of Clinical Research, University Hospital Münster, Münster 48149, Germany; Gastrointestinal Research in Inflammation & Pathology, Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, Parkville 3052, Victoria, Australia; Department of Pediatrics, University of Melbourne, Melbourne Medical School, Parkville 3052, Victoria, Australia;
| | - Toni Weinhage
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Georg Varga
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Timo Wirth
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Karoline Walscheid
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Anne Brockhausen
- Department of Dermatology, University Hospital Münster, Münster 48149, Germany; Institute of Immunology, University Hospital Münster, Münster 48149, Germany; and
| | - David Schwarzmaier
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany
| | - Markus Brückner
- Department of Medicine B, University Hospital Münster, Münster 48149, Germany
| | - Matthias Ross
- Department of Medicine B, University Hospital Münster, Münster 48149, Germany
| | - Dominik Bettenworth
- Department of Medicine B, University Hospital Münster, Münster 48149, Germany
| | - Johannes Roth
- Interdisciplinary Center of Clinical Research, University Hospital Münster, Münster 48149, Germany; Institute of Immunology, University Hospital Münster, Münster 48149, Germany; and
| | - Jan M Ehrchen
- Interdisciplinary Center of Clinical Research, University Hospital Münster, Münster 48149, Germany; Department of Dermatology, University Hospital Münster, Münster 48149, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster 48149, Germany; Interdisciplinary Center of Clinical Research, University Hospital Münster, Münster 48149, Germany
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Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy. Nat Genet 2015; 47:267-71. [PMID: 25642632 DOI: 10.1038/ng.3212] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 01/09/2015] [Indexed: 12/19/2022]
Abstract
Genome-wide association studies (GWAS) have led to the discovery of several susceptibility loci for leprosy with robust evidence, providing biological insight into the role of host genetic factors in mycobacterial infection. However, the identified loci only partially explain disease heritability, and additional genetic risk factors remain to be discovered. We performed a 3-stage GWAS of leprosy in the Chinese population using 8,313 cases and 16,017 controls. Besides confirming all previously published loci, we discovered six new susceptibility loci, and further gene prioritization analysis of these loci implicated BATF3, CCDC88B and CIITA-SOCS1 as new susceptibility genes for leprosy. A systematic evaluation of pleiotropic effects demonstrated a high tendency for leprosy susceptibility loci to show association with autoimmunity and inflammatory diseases. Further analysis suggests that molecular sensing of infection might have a similar pathogenic role across these diseases, whereas immune responses have discordant roles in infectious and inflammatory diseases.
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Smith AM, Sewell GW, Levine AP, Chew TS, Dunne J, O'Shea NR, Smith PJ, Harrison PJ, Macdonald CM, Bloom SL, Segal AW. Disruption of macrophage pro-inflammatory cytokine release in Crohn's disease is associated with reduced optineurin expression in a subset of patients. Immunology 2015; 144:45-55. [PMID: 24943399 PMCID: PMC4264909 DOI: 10.1111/imm.12338] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 06/09/2014] [Accepted: 06/16/2014] [Indexed: 12/18/2022] Open
Abstract
Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with Escherichia coli were shown to release attenuated levels of tumour necrosis factor and interferon-γ with normal secretion of interleukin-8 (IL-8), IL-10 and IL-6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with small interfering RNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD.
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Affiliation(s)
- Andrew M Smith
- Microbial Diseases, Eastman Dental Institute, University College London, London, UK
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Zeissig Y, Petersen BS, Milutinovic S, Bosse E, Mayr G, Peuker K, Hartwig J, Keller A, Kohl M, Laass MW, Billmann-Born S, Brandau H, Feller AC, Röcken C, Schrappe M, Rosenstiel P, Reed JC, Schreiber S, Franke A, Zeissig S. XIAP variants in male Crohn's disease. Gut 2015; 64:66-76. [PMID: 24572142 DOI: 10.1136/gutjnl-2013-306520] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The genetic basis of inflammatory bowel disease (IBD) is incompletely understood. The aim of this study was to identify rare genetic variants involved in the pathogenesis of IBD. DESIGN Exome sequencing and immunological profiling were performed in a patient with early onset Crohn's disease (CD). The coding region of the gene encoding X-linked inhibitor of apoptosis protein (XIAP) was sequenced in samples of 275 paediatric IBD and 1047 adult-onset CD patients. XIAP genotyping was performed in samples of 2680 IBD patients and 2864 healthy controls. Functional effects of the variants identified were investigated in primary cells and cultured cell lines. RESULTS Our results demonstrate the frequent occurrence of private variants in XIAP in about four percent of male patients with paediatric-onset CD. While XIAP mutations are known to be associated with the primary immunodeficiency (PID) X-linked lymphoproliferative disease type 2 (XLP2), CD patients described here exhibited intestinal inflammation in the absence of XLP2 and harboured a spectrum of mutations partially distinct from that observed in XLP2. The majority of XIAP variants identified was associated with a selective defect in NOD1/2 signalling, impaired NOD1/2-mediated activation of NF-κB, and altered NF-κB-dependent cytokine production. CONCLUSIONS This study reveals the unanticipated, frequent occurrence of XIAP variants in male paediatric-onset CD. The link between XIAP and NOD1/2, and the association of XIAP variants with XLP2, support the concept of PID in a subset of IBD patients. Moreover, these studies provide a rationale for the implementation of XIAP sequencing in clinical diagnostics in male patients with severe CD.
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Affiliation(s)
- Yvonne Zeissig
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Britt-Sabina Petersen
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | | | - Esther Bosse
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Gabriele Mayr
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Kenneth Peuker
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Jelka Hartwig
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Andreas Keller
- Clinical Bioinformatics, Saarland University, Saarbrücken, Germany
| | - Martina Kohl
- Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Martin W Laass
- Children's Hospital, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Germany
| | - Susanne Billmann-Born
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Heide Brandau
- Department of General Pediatrics, University Medical Center Schleswig-Holstein, Lübeck, Germany
| | - Alfred C Feller
- Institute of Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany
| | - Christoph Röcken
- Institute of Pathology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Martin Schrappe
- Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - John C Reed
- Sanford-Burnham Medical Research Institute, La Jolla, California, USA
| | - Stefan Schreiber
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Sebastian Zeissig
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
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Bernasconi E, D'Angelo F, Michetti P, Velin D. Critical role of the GM-CSF signaling pathway in macrophage pro-repair activities. Pathobiology 2014; 81:183-9. [PMID: 25170537 DOI: 10.1159/000365395] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 06/20/2014] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Macrophages play a critical role in intestinal wound repair. However, the molecular pathways that regulate macrophage wound repair activities remain poorly understood. The aim of this study was to evaluate the role of GM-CSF receptor signaling in the wound repair activities of macrophages. METHODS Murine macrophages were differentiated from bone marrow cells and human macrophages from monocytes isolated from peripheral blood mononuclear cells of Crohn's disease (CD) patients. In vitro models were used to study the repair activities of macrophages. RESULTS We provide evidence that GM-CSF receptor signaling is required for murine macrophages to promote epithelial repair. In addition, we demonstrate that the deficient repair properties of macrophages from CD patients with active disease can be recovered via GM-CSF therapy. CONCLUSION Our data support a critical role of the GM-CSF signaling pathway in the pro-repair activities of mouse and human macrophages.
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Affiliation(s)
- Eric Bernasconi
- Service of Gastroenterology and Hepatology, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
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Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A. A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages. Endocrinology 2014; 155:2725-34. [PMID: 24731098 DOI: 10.1210/en.2013-2066] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Deiodinase type 2 (D2) is a thyroid hormone-activating enzyme converting the prohormone T4 into the active hormone T3. In the present study, we show for the first time that D2 is up-regulated in the mouse liver during acute and chronic inflammation, in close correlation with the proinflammatory cytokine IL-1β and independently of serum T3. Inflammation-induced D2 expression was confirmed in macrophages, in conjunction with selective thyroid hormone transporter (monocarboxylate transporter 10) and thyroid hormone receptor (TR)α1 stimulation, and was absent in hepatocytes. Moreover, D2 knockdown in macrophages resulted in a clear attenuation of the lipopolysaccharide (LPS)-induced IL-1β and GM-CSF expression, in addition to aberrant phagocytosis. Locally produced T3, acting via the TRα, may be instrumental in this novel inflammatory response, because LPS-treated TRα(0/0) mice showed a markedly decreased LPS-induced GM-CSF mRNA expression. We now propose that hepatic D2 favors the innate immune response by specifically regulating cellular thyroid hormone levels in macrophages.
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Affiliation(s)
- J Kwakkel
- Departments of Endocrinology and Metabolism (J.K., O.V.S., E.M.d.V., A.B., E.F.) and Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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Magnusson MK, Wick MJ. Intestinal dendritic cell and macrophage subsets: Tipping the balance to Crohn's disease? Eur J Microbiol Immunol (Bp) 2014; 1:19-24. [PMID: 24466433 DOI: 10.1556/eujmi.1.2011.1.5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Dendritic cells and macrophages play an essential role in immune homeostasis in the intestine. They have the critical task of maintaining the balance between tolerance to the intestinal microflora and potential food antigens while retaining the ability to initiate immunity against pathogens. For patients with Crohn's Disease, the tolerance/immunity balance is disturbed and these individuals suffer from chronic intestinal inflammation driven by aberrant T cell reactivity to intestinal bacteria. As antigen presenting cells are required for T cell activation, intestinal phagocytes with the capacity to present antigens from intestinal bacteria to T cells are likely involved in initiating and propagating Crohn's Disease. Recent data describe unique subsets of human intestinal phagocytes that may be involved in the aberrant reactivity to commensal flora that drives Crohn's Disease pathogenesis. This review summarizes the current knowledge of phagocyte subsets in the intestine and mesenteric lymph nodes in healthy individuals and Crohn's Disease patients. Deciphering the function of intestinal phagocytes in health and disease is crucial to advance our understanding of the cellular mechanisms underlying this debilitating disease, provides a potential way to improve treatment for patients with inflammatory bowel disease.
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Affiliation(s)
- M K Magnusson
- Department of Microbiology and Immunology, University of Gothenburg Gothenburg Sweden
| | - M J Wick
- Department of Microbiology and Immunology, University of Gothenburg Gothenburg Sweden
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Aguilar C, Lenoir C, Lambert N, Bègue B, Brousse N, Canioni D, Berrebi D, Roy M, Gérart S, Chapel H, Schwerd T, Siproudhis L, Schäppi M, Al-Ahmari A, Mori M, Yamaide A, Galicier L, Neven B, Routes J, Uhlig HH, Koletzko S, Patel S, Kanegane H, Picard C, Fischer A, Bensussan NC, Ruemmele F, Hugot JP, Latour S. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J Allergy Clin Immunol 2014; 134:1131-41.e9. [PMID: 24942515 DOI: 10.1016/j.jaci.2014.04.031] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Revised: 04/08/2014] [Accepted: 04/17/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. OBJECTIVE We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. METHODS We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. RESULTS Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. CONCLUSION IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations.
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Affiliation(s)
- Claire Aguilar
- Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Christelle Lenoir
- Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Nathalie Lambert
- Study Center for Primary Immunodeficiencies (CEDI), Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Bernadette Bègue
- University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Interactions of the Intestinal Epithelium and the Immune System, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France
| | - Nicole Brousse
- Pathology Department, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Danielle Canioni
- Pathology Department, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Dominique Berrebi
- Pathology Department, Hospital Robert Debré, APHP, Paris, France; INSERM UMR 843, Hospital Bichat, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France
| | - Maryline Roy
- INSERM UMR 843, Hospital Bichat, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France
| | - Stéphane Gérart
- Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Helen Chapel
- Primary Immunodeficiency Unit, Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Tobias Schwerd
- University of Munich Medical Center, Dr von Hauner Children's Hospital, Munich, Germany
| | - Laurent Siproudhis
- Department of Hepato-Gastroenterology, University Hospital of Rennes, Rennes, France
| | - Michela Schäppi
- Pediatrics Center, Clinique des Grangettes and Medical University Center, Geneva, Switzerland
| | - Ali Al-Ahmari
- Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Alfaisal University, Riyadh, Saudi Arabia
| | - Masaaki Mori
- Department of Pediatrics, City University Medical Center, Yokohama, Japan
| | - Akiko Yamaide
- Division of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan
| | - Lionel Galicier
- Department of Clinical Immunology, Hospital Saint-Louis, APHP, Paris, France
| | - Bénédicte Neven
- Department of Immunology and Haematology, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - John Routes
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wis
| | - Holm H Uhlig
- Translational Gastroenterology Unit and Children's Hospital, University of Oxford, Oxford, United Kingdom
| | - Sibylle Koletzko
- University of Munich Medical Center, Dr von Hauner Children's Hospital, Munich, Germany
| | - Smita Patel
- Primary Immunodeficiency Unit, Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Hirokazu Kanegane
- Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Capucine Picard
- Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Study Center for Primary Immunodeficiencies (CEDI), Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France; Laboratory of Human Genetics of Infectious Diseases, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France
| | - Alain Fischer
- Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Department of Immunology and Haematology, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Nadine Cerf Bensussan
- University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Interactions of the Intestinal Epithelium and the Immune System, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France
| | - Frank Ruemmele
- University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratory of Interactions of the Intestinal Epithelium and the Immune System, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; Pediatric Gastroenterology Unit, Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Jean-Pierre Hugot
- INSERM UMR 843, Hospital Bichat, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France; Pediatric Gastroenterology Unit, Hospital Robert Debré, APHP, Paris, France
| | - Sylvain Latour
- Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Hospital Necker-Enfants Malades, Paris, France; University Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
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Corridoni D, Arseneau KO, Cominelli F. Functional defects in NOD2 signaling in experimental and human Crohn disease. Gut Microbes 2014; 5:340-4. [PMID: 24637801 PMCID: PMC4153771 DOI: 10.4161/gmic.28404] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Increasing evidence suggests that a deficit in innate immunity may play a causative role in the pathogenesis of inflammatory bowel disease. The most compelling support for this hypothesis comes from the genetic association of Crohn disease (CD) with carriage of polymorphisms within the NOD2 gene, which represent the most frequent genetic defect in CD. Our findings suggest that SAMP1/YitFc mice, which develop CD-like ileitis in the absence of NOD2 genetic mutations, fail to respond to MDP administration by displaying decreased innate cytokine production and impaired bacterial clearance before the onset of disease. This provides evidence that dysregulated NOD2 signaling, genetic or functional in nature, predisposes to chronic intestinal inflammation, and supports a new paradigm that CD may occur from a deficit in innate immunity as opposed to an overly aggressive immune response. This new paradigm could lead to potential development of new preventative or therapeutic modalities for patients with CD.
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Affiliation(s)
- Daniele Corridoni
- Department of Medicine; Case Western Reserve University; Cleveland, OH USA,Digestive Health Research Center; Case Western Reserve University; Cleveland, OH USA
| | - Kristen O Arseneau
- Department of Medicine; Case Western Reserve University; Cleveland, OH USA,Digestive Health Research Center; Case Western Reserve University; Cleveland, OH USA
| | - Fabio Cominelli
- Department of Medicine; Case Western Reserve University; Cleveland, OH USA,Digestive Health Research Center; Case Western Reserve University; Cleveland, OH USA,Correspondence to: Fabio Cominelli,
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Salva KA, Stenstrom M, Breadon JY, Odland PB, Bennett D, Longley J, Wood GS. Possible association of cutaneous Rosai-Dorfman disease and chronic Crohn disease: a case series report. JAMA Dermatol 2014; 150:177-81. [PMID: 24305684 DOI: 10.1001/jamadermatol.2013.7609] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
IMPORTANCE Cutaneous Rosai-Dorfman disease (CRDD), a variant of Rosai-Dorfman disease limited to the skin, has a wide range of clinical presentations. Rosai-Dorfman disease is believed to result from an aberrant response to antigens, caused by immunosuppressive macrophages. Macrophage-mediated immunosuppression is also implicated in the pathogenesis of Crohn disease, linking these otherwise unrelated entities. To our knowledge, the coexistence of these disorders has been described in only 2 cases, 1 of them confined to the skin and soft tissue. OBSERVATIONS We present a series of 3 patients who developed purely CRDD in the context of long-standing Crohn disease. Statistical estimates suggested that the association of these 2 disorders is not due to chance (P<.001). CONCLUSIONS AND RELEVANCE Our case series provides the clinical correlate to the pathogenetic parallels between CRDD and Crohn disease. Crohn disease is frequently complicated by various skin manifestations, which may be mimicked by CRDD. Therefore, it may be prudent for clinicians to include CRDD in the list of differential diagnoses when examining skin lesions in patients with Crohn disease.
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Affiliation(s)
- Katrin A Salva
- Department of Dermatology, University of Wisconsin, Madison
| | | | | | | | - Daniel Bennett
- Department of Dermatology, University of Wisconsin, Madison
| | - Jack Longley
- Department of Dermatology, University of Wisconsin, Madison
| | - Gary S Wood
- Department of Dermatology, University of Wisconsin, Madison
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Wolfkamp SCS, Verseyden C, Vogels EWM, Meisner S, Boonstra K, Peters CP, Stokkers PCF, te Velde AA. ATG16L1 and NOD2 polymorphisms enhance phagocytosis in monocytes of Crohn’s disease patients. World J Gastroenterol 2014; 20:2664-2672. [PMID: 24627602 PMCID: PMC3949275 DOI: 10.3748/wjg.v20.i10.2664] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Accepted: 02/07/2013] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn’s disease (CD).
METHODS: In this study, we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls. As both autophagy related like 1 (ATG16L1) and immunity-related guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleotide-binding ligomerization domain-containing protein 2 (NOD2) has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction. The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo™Escherichia coli Bioparticles Phagocytosis kit for flowcytometry.
RESULTS: In this study, we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity (ratio of mean fluorescence intensity) between the patient groups and the healthy controls. CD patients show a significantly higher phagocytic capacity (ratio mean percentage of phagocytic cells) compared to healthy controls (51.91% ± 2.85% vs 37.67% ± 7.06%, P = 0.05). The extend of disease was not of influence. However, variants of ATG16L1 (WT: 2.03 ± 0.19 vs homozygoot variant: 4.38 ± 0.37, P < 0.009) as well as NOD2 (C-ins) (heterozygous variant: 42.08 ± 2.94 vs homozygous variant: 75.58 ± 4.34 (P = 0.05) are associated with the phagocytic activity in patients with CD.
CONCLUSION: Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants. This could be part of the pathophysiological mechanism resulting in the disease.
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