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Prakash S, Steers NJ, Li Y, Sanchez-Rodriguez E, Verbitsky M, Robbins I, Simpson J, Pathak S, Raska M, Reily C, Ng A, Liang J, DeMaria N, Katiraei A, Stevens KO, Fischman C, Shapiro S, Kodali S, McCutchan J, Park H, Eliby D, Delsante M, Allegri L, Fiaccadori E, Bodria M, Marasa M, Raveche E, Julian BA, Uhlemann AC, Kiryluk K, Zhang H, D’Agati VD, Sanna-Cherchi S, Novak J, Gharavi AG. Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy. J Clin Invest 2025; 135:e181164. [PMID: 40153534 PMCID: PMC12077892 DOI: 10.1172/jci181164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 03/12/2025] [Indexed: 03/30/2025] Open
Abstract
Aberrant O-glycosylation of the IgA1 hinge region is a characteristic finding in patients with IgA nephropathy (IgAN) and is thought to contribute to immune-complex formation and kidney injury. Other studies have suggested that abnormalities in mucosal immunity and lymphocyte homing are major contributors to disease. We identified a family with IgAN segregating a heterozygous predicted loss-of-function (LOF) variant in GALNT14, the gene encoding N-acetylgalactosaminyltransferase 14, one of the enzymes involved in mucin-type protein O-glycosylation. While GALNT14 is expressed in IgA1-producing cells, carriers of the LOF variant did not have altered levels of poorly glycosylated IgA1, suggesting other disease mechanisms. Investigation of Galnt14-null mice revealed elevated serum IgA levels and ex vivo IgA production by B cells. These mice developed glomerular IgA deposition with aging and after induction of sterile colitis. Galnt14-null mice also displayed an attenuated mucin layer in the colon and redistribution of IgA-producing cells from mucosal to systemic sites. Adoptive-transfer experiments indicated impaired homing of spleen-derived Galnt14-deficient B lymphocytes, resulting in increased retention in peripheral blood. These findings suggest that abnormalities in O-glycosylation alter mucosal immunity and B lymphocyte homing, pointing to an expanded role of aberrant O-glycosylation in the pathogenesis of IgAN.
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Affiliation(s)
- Sindhuri Prakash
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Nicholas J. Steers
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Yifu Li
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Elena Sanchez-Rodriguez
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Miguel Verbitsky
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Isabel Robbins
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Jenna Simpson
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Sharvari Pathak
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | | | - Colin Reily
- Department of Microbiology, and
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Anna Ng
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Judy Liang
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Natalia DeMaria
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Amanda Katiraei
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Kelsey O. Stevens
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Clara Fischman
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Samantha Shapiro
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Swetha Kodali
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Jason McCutchan
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Heekuk Park
- Department of Medicine, Division of Infectious Diseases, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Djamila Eliby
- Department of Medicine, Division of Infectious Diseases, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Marco Delsante
- Departments of Medicine and Surgery, University of Parma, Parma, Italy
| | - Landino Allegri
- Departments of Medicine and Surgery, University of Parma, Parma, Italy
| | - Enrico Fiaccadori
- Departments of Medicine and Surgery, University of Parma, Parma, Italy
| | - Monica Bodria
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Maddalena Marasa
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Elizabeth Raveche
- Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA
| | - Bruce A. Julian
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Anne-Catrin Uhlemann
- Department of Medicine, Division of Infectious Diseases, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Krzysztof Kiryluk
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | - Hong Zhang
- The Renal Division, Peking University First Hospital, Beijing, China
| | - Vivette D. D’Agati
- Department of Pathology and Cell Biology, Division of Renal Pathology, Columbia University Irving Medical Center, New York, New York, USA
| | - Simone Sanna-Cherchi
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
| | | | - Ali G. Gharavi
- Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York, USA
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Wang C, Zhu H, Li Y, Zhang Y, Ye Y, Zhong Y, Qiu S, Xiong X, Jian Z. Bibliometric analysis of the gut microbiota and stroke from 2002 to 2022. Heliyon 2024; 10:e30424. [PMID: 38765104 PMCID: PMC11101820 DOI: 10.1016/j.heliyon.2024.e30424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 04/18/2024] [Accepted: 04/25/2024] [Indexed: 05/21/2024] Open
Abstract
Stroke is the fifth leading cause of death worldwide, and the functional status of the gut plays a key role in patients' prognosis. Recent publications have explored the gut association with stroke, but few articles have been published that specifically address a comprehensive bibliometric analysis of the gut microbiota and its association with stroke. To address this gap, we used bibliometric methods to examine the landscape of research concerning the gut and stroke over approximately two decades, utilizing the Web of Science Core Collection (WoSCC). On November 1, 2022, a search was conducted for English-language articles published between 2002 and 2022, with only including original articles. Visual and statistical analyses were performed using CiteSpace, VOSviewer, and Bibliometrix 4.1.0 Package. After screening relevant articles, the results revealed that the number of articles published in this field has progressively increased during the last two decades. In particular, the total number of publications rapidly increased year by year from 2014. Among them, China ranked first in the world with a total of 227 publications. Authorship analysis highlighted Wang Z as the most prolific author, with 18 publications and an H-index of 14, highlighting significant contributions to this field. Meanwhile, the Southern Medical University of China was identified as the most productive institution. Moreover, analysis of keywords revealed that 'cerebral ischemia', 'intestinal microbiota', 'gut microbiota', and 'trimethylamine N-oxide' were popular topics searched, and research on the relationship between stroke and the gut continues to be a research hotspot. In summary, this study presents an overview of the progress and emerging trends in research on the relationship between stroke and gut health over the past two decades, providing a valuable resource for researchers aiming to understand the current state of the field and identify potential directions for future studies.
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Affiliation(s)
- Chaoqun Wang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430000, China
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, 313000, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430000, China
| | - Yuntao Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430000, China
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, 313000, China
| | - Yonggang Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430000, China
| | - Yingze Ye
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430000, China
| | - Yi Zhong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430000, China
| | - Sheng Qiu
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, 313000, China
- Huzhou Key Laboratory of Basic Research and Clinical Translation for Neuromodulation, Huzhou, 313000, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430000, China
- Department of Neurosurgery, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, 313000, China
| | - Zhihong Jian
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430000, China
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Ni J, Zheng J, Mo G, Chen G, Li J, Cao L, Hu B, Liu H. Structural characterization and immunomodulatory effect of a starch-like Grifola frondosa polysaccharides on cyclophosphamide-induced immunosuppression in mice. Carbohydr Res 2024; 535:109011. [PMID: 38150753 DOI: 10.1016/j.carres.2023.109011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 12/29/2023]
Abstract
In this study, a pure Grifola frondosa polysaccharide (GFP-1) was extracted and purified from Grifola frondosa. By HPLC, GC-MS, FT-IR, and NMR analysis, GFP-1 was determined to be a starch-like polysaccharide with an average molecular weight of 3370 kDa. It included three monosaccharides, i.e., glucose, galactose, and mannose. The backbone of GFP-1 consisted of →4)-α-Glcp-(1→ and →4,6)-α-Glcp-(1 → . The side branches were composed of →6)-α-Galp-(1→, α-Glcp-(1→, and a small amount of α-Manp-(1 → . By using a cyclophosphamide (CTX)-induced immunosuppressed mice model, we evaluated the immunomodulatory activity of GFP-1. The results showed that GFP-1 increased the thymic and spleen indices, promoted the level of IgG and IgA in serum, and activated the mitogen-activated protein kinase (MAPK) pathway in CTX-induced mice. Also, GFP-1 significantly promoted the mRNA expression of intestinal barrier factors and protected intestinal structural integrity in immunosuppressed mice. In conclusion, the data presented here suggested that GFP-1 might be a potential immune-enhancing supplement.
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Affiliation(s)
- Jimin Ni
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Junping Zheng
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Guoyan Mo
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Guangming Chen
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Jingjing Li
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Lu Cao
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China
| | - Baifei Hu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China.
| | - Hongtao Liu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan, 430065, PR China.
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Lu Y, Wu Y, Huang M, Chen J, Zhang Z, Li J, Yang R, Liu Y, Cai S. Fuzhengjiedu formula exerts protective effect against LPS-induced acute lung injury via gut-lung axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 123:155190. [PMID: 37972468 DOI: 10.1016/j.phymed.2023.155190] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 11/01/2023] [Accepted: 11/04/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Acute lung injury (ALI) is distinguished by rapid and severe respiratory distress and prolonged hypoxemia. A traditional Chinese medicine (TCM), known as the Fuzhengjiedu formula (FZJDF), has been shown to have anti-inflammatory benefits in both clinical and experimental studies. The precise underlying processes, nevertheless, are yet unclear. PURPOSE This study sought to enlighten the protective mechanism of FZJDF in ALI through the standpoint of the gut-lung crosstalk. METHODS The impact of FZJDF on lipopolysaccharide (LPS)-induced ALI murine model were investigated, and the lung injury score, serum interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) expression were measured to confirm its anti-inflammatory effects. Additionally, gut microbiota analysis and serum and fecal samples metabolomics were performed using metagenomic sequencing and high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry, respectively. RESULTS FZJDF significantly induced histopathological changes caused by LPS-induced ALI as well as downregulated the serum concentration of IL-1β and TNF-α. Furthermore, FZJDF had an effect in gut microbiota disturbances, and linear discriminant effect size analysis identified signal transduction, cell motility, and amino acid metabolism as the potential mechanisms of action in the FZJDF-treated group. Several metabolites in the LPS and FZJDF groups were distinguished by untargeted metabolomic analysis. Correlations were observed between the relative abundance of microbiota and metabolic products. Comprehensive network analysis revealed connections among lung damage, gut microbes, and metabolites. The expression of glycine, serine, glutamate, cysteine, and methionine in the lung and colon tissues was dysregulated in LPS-induced ALI, and FZJDF reversed these trends. CONCLUSION This study revealed that FZJDF considerably protected against LPS-induced ALI in mice by regulating amino acid metabolism via the gut-microbiota-lung axis and offered thorough and in-depth knowledge of the multi-system linkages of systemic illnesses.
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Affiliation(s)
- Yue Lu
- The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yuan Wu
- The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Mengfen Huang
- The Ninth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jiankun Chen
- The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Emerging Infectious Diseases, Guangzhou, Guangdong, China
| | - Zhongde Zhang
- The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jiqiang Li
- The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Emerging Infectious Diseases, Guangzhou, Guangdong, China.
| | - Rongyuan Yang
- The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Emerging Infectious Diseases, Guangzhou, Guangdong, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Yuntao Liu
- The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangzhou Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Emerging Infectious Diseases, Guangzhou, Guangdong, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Shubin Cai
- The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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Friedrich V, Forné I, Matzek D, Ring D, Popper B, Jochum L, Spriewald S, Straub T, Imhof A, Krug A, Stecher B, Brocker T. Helicobacter hepaticus is required for immune targeting of bacterial heat shock protein 60 and fatal colitis in mice. Gut Microbes 2022; 13:1-20. [PMID: 33550886 PMCID: PMC7889221 DOI: 10.1080/19490976.2021.1882928] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Gut microbiota and the immune system are in constant exchange shaping both host immunity and microbial communities. Here, improper immune regulation can cause inflammatory bowel disease (IBD) and colitis. Antibody therapies blocking signaling through the CD40-CD40L axis showed promising results as these molecules are deregulated in certain IBD patients. To better understand the mechanism, we used transgenic DC-LMP1/CD40 animals with a constitutive CD40-signal in CD11c+ cells, causing a lack of intestinal CD103+ dendritic cells (DCs) and failure to induce regulatory T (iTreg) cells. These mice rapidly develop spontaneous fatal colitis, accompanied by dysbiosis and increased inflammatory IL-17+IFN-γ+ Th17/Th1 and IFN-γ + Th1 cells. In the present study, we analyzed the impact of the microbiota on disease development and detected elevated IgA- and IgG-levels in sera from DC-LMP1/CD40 animals. Their serum antibodies specifically bound intestinal bacteria, and by proteome analysis, we identified a 60 kDa chaperonin GroEL (Hsp60) from Helicobacter hepaticus (Hh) as the main specific antigen targeted in the absence of iTregs. When re-derived to a different Hh-free specific-pathogen-free (SPF) microbiota, mice showed few signs of disease, normal microbiota, and no fatality. Upon recolonization of mice with Hh, the disease developed rapidly. Thus, the present work identifies GroEL/Hsp60 as a major Hh-antigen and its role in disease onset, progression, and outcome in this colitis model. Our results highlight the importance of CD103+ DC- and iTreg-mediated immune tolerance to specific pathobionts to maintain healthy intestinal balance.
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Affiliation(s)
- Verena Friedrich
- Institute for Immunology, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Ignasi Forné
- Protein Analysis Unit, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Dana Matzek
- Core Facility Animal Models, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Diana Ring
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany
| | - Bastian Popper
- Core Facility Animal Models, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Lara Jochum
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany
| | - Stefanie Spriewald
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany
| | - Tobias Straub
- Core Facility Bioinformatics, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Axel Imhof
- Protein Analysis Unit, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Anne Krug
- Institute for Immunology, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Bärbel Stecher
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, Munich, Germany,German Center for Infection Research (DZIF), Partner Site, Munich, Germany
| | - Thomas Brocker
- Institute for Immunology, BioMedical Center, Faculty of Medicine, LMU Munich, Munich, Germany,CONTACT Thomas Brocker Institute for Immunology, BioMedical Center, Faculty of Medicine, LMU Munich, Munich82152, Germany
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Oh JH, Rehermann B. Natural versus Laboratory World: Incorporating Wild-Derived Microbiota into Preclinical Rodent Models. THE JOURNAL OF IMMUNOLOGY 2021; 207:1703-1709. [PMID: 34544812 DOI: 10.4049/jimmunol.2100426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/28/2021] [Indexed: 01/12/2023]
Abstract
Advances in data collection (high-throughput shotgun metagenomics, transcriptomics, and metabolomics) and analysis (bioinformatics and multiomics) led to the realization that all mammals are metaorganisms, shaped not only by their own genome but also by the genomes of the microbes that colonize them. To date, most studies have focused on the bacterial microbiome, whereas curated databases for viruses, fungi, and protozoa are still evolving. Studies on the interdependency of microbial kingdoms and their combined effects on host physiology are just starting. Although it is clear that past and present exposure to commensals and pathogens profoundly affect human physiology, such exposure is lacking in standard preclinical models such as laboratory mice. Laboratory mouse colonies are repeatedly rederived in germ-free status and subjected to restrictive, pathogen-free housing conditions. This review summarizes efforts to bring the wild microbiome into the laboratory setting to improve preclinical models and their translational research value.
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Affiliation(s)
- Ji Hoon Oh
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
| | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
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Tolerogenic Immunoregulation towards Salmonella Enteritidis Contributes to Colonization Persistence in Young Chicks. Infect Immun 2021; 89:e0073620. [PMID: 34031125 PMCID: PMC8281283 DOI: 10.1128/iai.00736-20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Long-term survival and the persistence of bacteria in the host suggest either host unresponsiveness or induction of an immunological tolerant response to the pathogen. The role of the host immunological response to persistent colonization of Salmonella Enteritidis (SE) in chickens remains poorly understood. In the current study, we performed a cecal tonsil transcriptome analysis in a model of SE persistent infection in 2-week-old chickens to comprehensively examine the dynamics of host immunological responses in the chicken gastrointestinal tract. Our results revealed overall host tolerogenic adaptive immune regulation in a major gut-associated lymphoid tissue, the cecal tonsil, during SE infection. Specifically, we observed consistent downregulation of the metallothionein 4 gene at all four postinfection time points (3, 7, 14, and 21 days postinfection [dpi]), which suggested potential pathogen-associated manipulation of the host zinc regulation as well as a possible immune modulatory effect. Furthermore, delayed activation in the B cell receptor signaling pathway and failure to sustain its active state during the lag phase of infection were further supported by an insignificant production of both intestinal and circulatory antibodies. Tug-of-war for interleukin 2 (IL-2) regulation between effector T cells and regulatory T cells appears to have consequences for upregulation in the transducer of ERBB2 (TOB) pathway, a negative regulator of T cell proliferation. In conclusion, this work highlights the overall host tolerogenic immune response that promotes persistent colonization by SE in young layer chicks.
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Chicken Mesenchymal Stem Cells and Their Applications: A Mini Review. Animals (Basel) 2021; 11:ani11071883. [PMID: 34202772 PMCID: PMC8300106 DOI: 10.3390/ani11071883] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/18/2021] [Accepted: 06/19/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Mesenchymal stem cells (MSCs) are multipotent stem cells that are capable of differentiation into bone, muscle, fat, and closely related lineages and express unique and specific cell surface markers. They can be used as an avian culture model to better understand osteogenic, adipogenic, and myogenic pathways. Moreover, MSCs could also be used as a model to study various developmental and physiological processes in avian and other species. To obtain a comprehensive overview of this topic, the keywords “mesenchymal stem cells”, “chicken”, “disease”, “chicken dermatitis”, “viral infections in chicken”, and “antibiotics in chicken” were searched in WOS and PUBMED databases to obtain relevant information. Abstract Mesenchymal stem cells (MSCs) are multipotent progenitor cells that adhere to plastic; express the specific markers CD29, CD44, CD73, CD90, and CD105; and produce cytokines and growth factors supporting and regulating hematopoiesis. MSCs have capacity for differentiating into osteocytes, chondrocytes, adipocytes, and myocytes. They are useful for research toward better understanding the pathogenic potential of the infectious bursal disease virus, mineralization during osteogenesis, and interactions between MSCs as a feeder layer to other cells. MSCs are also important for immunomodulatory cell therapy, can provide a suitable strategy model for coculture with pathogens causing dermatitis disorders in chickens, can be cultured in vitro with probiotics and prebiotics with a view to eliminate the feeding of antibiotic growth promoters, and offer cell-based meat production. Moreover, bone marrow-derived MSCs (BM-MSCs) in coculture with hematopoietic progenitor/stem cells (HPCs/HSCs) can support expansion and regulation of the hematopoiesis process using the 3D-culture system in future research in chickens. MSCs’ several advantages, including ready availability, strong proliferation, and immune modulatory properties make them a suitable model in the field of stem cell research. This review summarizes current knowledge about the general characterization of MSCs and their application in chicken as a model organism.
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Tan J, Cho H, Pholcharee T, Pereira LS, Doumbo S, Doumtabe D, Flynn BJ, Schön A, Kanatani S, Aylor SO, Oyen D, Vistein R, Wang L, Dillon M, Skinner J, Peterson M, Li S, Idris AH, Molina-Cruz A, Zhao M, Olano LR, Lee PJ, Roth A, Sinnis P, Barillas-Mury C, Kayentao K, Ongoiba A, Francica JR, Traore B, Wilson IA, Seder RA, Crompton PD. Functional human IgA targets a conserved site on malaria sporozoites. Sci Transl Med 2021; 13:eabg2344. [PMID: 34162751 PMCID: PMC7611206 DOI: 10.1126/scitranslmed.abg2344] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 04/21/2021] [Indexed: 12/27/2022]
Abstract
Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.
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Affiliation(s)
- Joshua Tan
- Antibody Biology Unit, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD 20852, USA.
| | - Hyeseon Cho
- Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Tossapol Pholcharee
- Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
| | - Lais S Pereira
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Safiatou Doumbo
- Mali International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, BP 1805, Point G, Bamako, Mali
| | - Didier Doumtabe
- Mali International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, BP 1805, Point G, Bamako, Mali
| | - Barbara J Flynn
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Arne Schön
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Sachie Kanatani
- Department of Molecular Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
| | - Samantha O Aylor
- Department of Drug Discovery, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
| | - David Oyen
- Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
| | - Rachel Vistein
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lawrence Wang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Marlon Dillon
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jeff Skinner
- Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Mary Peterson
- Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Shanping Li
- Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Azza H Idris
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Alvaro Molina-Cruz
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Ming Zhao
- Protein Chemistry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Lisa Renee Olano
- Protein Chemistry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Patricia J Lee
- Department of Drug Discovery, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
| | - Alison Roth
- Department of Drug Discovery, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
| | - Photini Sinnis
- Department of Molecular Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
| | - Carolina Barillas-Mury
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Kassoum Kayentao
- Mali International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, BP 1805, Point G, Bamako, Mali
| | - Aissata Ongoiba
- Mali International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, BP 1805, Point G, Bamako, Mali
| | - Joseph R Francica
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Boubacar Traore
- Mali International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, BP 1805, Point G, Bamako, Mali
| | - Ian A Wilson
- Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA
- The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Robert A Seder
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Peter D Crompton
- Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
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10
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Zou R, Wang Y, Duan M, Guo M, Zhang Q, Zheng H. Dysbiosis of Gut Fungal Microbiota in Children with Autism Spectrum Disorders. J Autism Dev Disord 2021; 51:267-275. [PMID: 32447559 DOI: 10.1007/s10803-020-04543-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In this study, we tested the feces of children with ASD and those of healthy children, and the overall changing of the gut fungal community was observed in ASD children compared with controls. However, there were no abundant fungi populations showed significant variations between the ASD and Control group both at phylum and class level. Among the 507 genera identified, Saccharomyces and Aspergillus showed significant differences between ASD (59.07%) and Control (40.36%), indicating that they may be involved in the abnormal gut fungal community structure of ASD. When analyzed at the species level, a decreased abundance in Aspergillus versicolor was observed while Saccharomyces cerevisiae was increased in children with ASD relative to controls. Overall, this study characterized the fungal microbiota profile of children with ASD and identified potential diagnostic species closely related to the immune response in ASD.
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Affiliation(s)
- Rong Zou
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Basic Medical Sciences, Fudan University, 2140 Xietu road, Xuhui district, Shanghai, China
| | - Yuezhu Wang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China
| | - Mengmeng Duan
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Basic Medical Sciences, Fudan University, 2140 Xietu road, Xuhui district, Shanghai, China
| | - Min Guo
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Basic Medical Sciences, Fudan University, 2140 Xietu road, Xuhui district, Shanghai, China
| | - Qiang Zhang
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Huajun Zheng
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Basic Medical Sciences, Fudan University, 2140 Xietu road, Xuhui district, Shanghai, China.
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11
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Tang J, Xu L, Zeng Y, Gong F. Effect of gut microbiota on LPS-induced acute lung injury by regulating the TLR4/NF-kB signaling pathway. Int Immunopharmacol 2021; 91:107272. [PMID: 33360370 DOI: 10.1016/j.intimp.2020.107272] [Citation(s) in RCA: 250] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023]
Abstract
Acute lung injury (ALI) is a common acute respiratory disease treated in the clinic. Intestinal microflora disorder affect lung diseases through the gut-lung axis. In this study, we explored the regulatory mechanism of the gut flora in the host defense against lipopolysaccharide (LPS)-induced ALI through the TLR4/NF-kB pathway by constructing a gut microflora dysbiosis-model with antibiotic administration and reconstruction of the intestinal microecology. Then, high-throughput sequencing was performed, and the levels of secreted IgA (sIgA), β-defensins, and Muc2 were measured to assess the gut flora and mucosal barrier. The expression of TLR4, NF-kB, TNF-α, IL-1β, oxidative stress and the lung wet/dry (W/D) ratio were evaluated to assess lung damage. Hematoxylin and eosin (HE) staining was performed to evaluate the damage to the gut and lung tissues. Accordingly, gut microbiota imbalance may regulate the TLR4/NF-kB signaling pathway in the lung immune system, activating oxidative stress in the lung and mediating lung injury through the regulation of the gut barrier. However, fecal microbiota transplantation (FMT) impairs the activity of the TLR4/NF-kB signaling pathway in the lung and decreases oxidative stress in animals with ALI by restoring the gut microecology. CONCLUSIONS: Our results indicated the protective effect of gut flora in regulating immunity of LPS-induced ALI by modulating the TLR4/NF-kB signaling pathway which may induce inflammation and oxidative stress.
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Affiliation(s)
- Jia Tang
- Department of Pediatrics, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing 402160, China; Department of Pediatrics, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Lingqi Xu
- Department of Pediatrics, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing 402160, China
| | - Yiwen Zeng
- Department of Pediatrics, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing 402160, China
| | - Fang Gong
- Department of Pediatrics, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing 402160, China.
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12
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Luchetti MM, Ciccia F, Avellini C, Benfaremo D, Rizzo A, Spadoni T, Svegliati S, Marzioni D, Santinelli A, Costantini A, Viola N, Berretta A, Ciferri M, Mattioli Belmonte Cima M, Mosca P, Benedetti A, Gabrielli A. Gut epithelial impairment, microbial translocation and immune system activation in inflammatory bowel disease-associated spondyloarthritis. Rheumatology (Oxford) 2021; 60:92-102. [PMID: 32442267 DOI: 10.1093/rheumatology/keaa164] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/04/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Gut microbiota has been widely reported to be involved in systemic inflammation through microbial translocation and T cell activation in several diseases. In this work we aimed to investigate bacterial infiltration and epithelial impairment in the gut of patients with IBD-associated SpA (SpA-IBD), as well as the relationship of microbial translocation with immune system activation and their putative role in the pathogenesis of joint inflammation in IBD patients. METHODS Tight-junction proteins (TJPs) occludin and claudin-1/-4 and bacteria were assessed by real-time PCR analysis and immunohistochemical staining of the ileum. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPS), soluble CD14 (sCD14), sclerostin and anti-sclerostin antibodies (anti-sclerostin-IgG) were assayed with ELISAs and peripheral mononuclear blood cells with flow cytometry. LPS and sCD14 were used in vitro to stimulate a human osteoblast cell line. RESULTS Compared with IBD, ileal samples from SpA-IBD patients showed bacterial infiltration, epithelial damage and downregulation of TJPs. In sera, they showed higher serum levels of I-FABP, LPS, sCD14 (the latter correlating with sclerostin and anti-sclerostin-IgG) and higher CD80+/CD163+ and lower CD14+ mononuclear cells. In vitro experiments demonstrated that only the LPS and sCD14 synergic action downregulates sclerostin expression in osteoblast cells. CONCLUSION SpA-IBD patients are characterized by gut epithelium impairment with consequent translocation of microbial products into the bloodstream, immune system activation and an increase of specific soluble biomarkers. These findings suggest that gut dysbiosis could be involved in the pathogenesis of SpA-IBD and it could hopefully prompt the use of these biomarkers in the follow-up and management of IBD patients.
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Affiliation(s)
- Michele Maria Luchetti
- Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, Ancona, Italy
| | - Francesco Ciccia
- Dipartimento Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy
| | - Chiara Avellini
- Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, Ancona, Italy
| | - Devis Benfaremo
- Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, Ancona, Italy
| | - Aroldo Rizzo
- Unità di Patologia, Ospedale Cervello, Palermo, Italia
| | - Tatiana Spadoni
- Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, Ancona, Italy
| | - Silvia Svegliati
- Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, Ancona, Italy
| | - Daniela Marzioni
- Dipartimento di Medicina Sperimentale e Clinica, Anatomia Umana, Università Politecnica delle Marche, Ancona, Italy
| | - Alfredo Santinelli
- Anatomia Patologica, Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro, Italy
| | - Andrea Costantini
- Servizio di Immunologia Clinica, Azienda Ospedaliero-Universitaria "Umberto I-G.M. Lancisi-G. Salesi", Ancona, Italy
| | - Nadia Viola
- Servizio di Immunologia Clinica, Azienda Ospedaliero-Universitaria "Umberto I-G.M. Lancisi-G. Salesi", Ancona, Italy
| | - Antonella Berretta
- Servizio di Immunologia Clinica, Azienda Ospedaliero-Universitaria "Umberto I-G.M. Lancisi-G. Salesi", Ancona, Italy
| | - Monia Ciferri
- Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, Ancona, Italy
| | | | - Piergiorgio Mosca
- IBD Unit, Azienda Ospedaliero-Universitaria "Umberto I-G.M. Lancisi-G. Salesi", Ancona, Italy and
| | - Antonio Benedetti
- IBD Unit, Azienda Ospedaliero-Universitaria "Umberto I-G.M. Lancisi-G. Salesi", Ancona, Italy and.,Dipartimento di Scienze Cliniche e Molecolari, Clinica di Gastroenterologia, Università Politecnica delle Marche, Ancona, Italy
| | - Armando Gabrielli
- Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, Ancona, Italy
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13
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Videvall E, Song SJ, Bensch HM, Strandh M, Engelbrecht A, Serfontein N, Hellgren O, Olivier A, Cloete S, Knight R, Cornwallis CK. Early-life gut dysbiosis linked to juvenile mortality in ostriches. MICROBIOME 2020; 8:147. [PMID: 33046114 PMCID: PMC7552511 DOI: 10.1186/s40168-020-00925-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 09/20/2020] [Indexed: 05/23/2023]
Abstract
BACKGROUND Imbalances in the gut microbial community (dysbiosis) of vertebrates have been associated with several gastrointestinal and autoimmune diseases. However, it is unclear which taxa are associated with gut dysbiosis, and if particular gut regions or specific time periods during ontogeny are more susceptible. We also know very little of this process in non-model organisms, despite an increasing realization of the general importance of gut microbiota for health. METHODS Here, we examine the changes that occur in the microbiome during dysbiosis in different parts of the gastrointestinal tract in a long-lived bird with high juvenile mortality, the ostrich (Struthio camelus). We evaluated the 16S rRNA gene composition of the ileum, cecum, and colon of 68 individuals that died of suspected enterocolitis during the first 3 months of life (diseased individuals), and of 50 healthy individuals that were euthanized as age-matched controls. We combined these data with longitudinal environmental and fecal sampling to identify potential sources of pathogenic bacteria and to unravel at which stage of development dysbiosis-associated bacteria emerge. RESULTS Diseased individuals had drastically lower microbial alpha diversity and differed substantially in their microbial beta diversity from control individuals in all three regions of the gastrointestinal tract. The clear relationship between low diversity and disease was consistent across all ages in the ileum, but decreased with age in the cecum and colon. Several taxa were associated with mortality (Enterobacteriaceae, Peptostreptococcaceae, Porphyromonadaceae, Clostridium), while others were associated with health (Lachnospiraceae, Ruminococcaceae, Erysipelotrichaceae, Turicibacter, Roseburia). Environmental samples showed no evidence of dysbiosis-associated bacteria being present in either the food, water, or soil substrate. Instead, the repeated fecal sampling showed that pathobionts were already present shortly after hatching and proliferated in individuals with low microbial diversity, resulting in high mortality several weeks later. CONCLUSIONS Identifying the origins of pathobionts in neonates and the factors that subsequently influence the establishment of diverse gut microbiota may be key to understanding dysbiosis and host development. Video Abstract.
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Affiliation(s)
- Elin Videvall
- Department of Biology, Lund University, Lund, Sweden.
- Center for Conservation Genomics, Smithsonian Conservation Biology Institute, Washington, DC, USA.
| | - Se Jin Song
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
| | | | - Maria Strandh
- Department of Biology, Lund University, Lund, Sweden
| | - Anel Engelbrecht
- Western Cape Department of Agriculture, Directorate Animal Sciences, Elsenburg, South Africa
| | - Naomi Serfontein
- Western Cape Agricultural Research Trust, Elsenburg, South Africa
| | - Olof Hellgren
- Department of Biology, Lund University, Lund, Sweden
| | - Adriaan Olivier
- South African Ostrich Business Chamber, Oudtshoorn, South Africa
| | - Schalk Cloete
- Western Cape Department of Agriculture, Directorate Animal Sciences, Elsenburg, South Africa
- Department of Animal Sciences, Stellenbosch University, Matieland, South Africa
| | - Rob Knight
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
- Department of Computer Science & Engineering, University of California San Diego, La Jolla, CA, USA
- Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
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14
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Kappler K, Hennet T. Emergence and significance of carbohydrate-specific antibodies. Genes Immun 2020; 21:224-239. [PMID: 32753697 PMCID: PMC7449879 DOI: 10.1038/s41435-020-0105-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/14/2020] [Accepted: 07/22/2020] [Indexed: 12/14/2022]
Abstract
Carbohydrate-specific antibodies are widespread among all classes of immunoglobulins. Despite their broad occurrence, little is known about their formation and biological significance. Carbohydrate-specific antibodies are often classified as natural antibodies under the assumption that they arise without prior exposure to exogenous antigens. On the other hand, various carbohydrate-specific antibodies, including antibodies to ABO blood group antigens, emerge after the contact of immune cells with the intestinal microbiota, which expresses a vast diversity of carbohydrate antigens. Here we explore the development of carbohydrate-specific antibodies in humans, addressing the definition of natural antibodies and the production of carbohydrate-specific antibodies upon antigen stimulation. We focus on the significance of the intestinal microbiota in shaping carbohydrate-specific antibodies not just in the gut, but also in the blood circulation. The structural similarity between bacterial carbohydrate antigens and surface glycoconjugates of protists, fungi and animals leads to the production of carbohydrate-specific antibodies protective against a broad range of pathogens. Mimicry between bacterial and human glycoconjugates, however, can also lead to the generation of carbohydrate-specific antibodies that cross-react with human antigens, thereby contributing to the development of autoimmune disorders.
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Affiliation(s)
| | - Thierry Hennet
- Institute of Physiology, University of Zurich, Zurich, Switzerland.
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15
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Paun A, Yau C, Meshkibaf S, Daigneault MC, Marandi L, Mortin-Toth S, Bar-Or A, Allen-Vercoe E, Poussier P, Danska JS. Association of HLA-dependent islet autoimmunity with systemic antibody responses to intestinal commensal bacteria in children. Sci Immunol 2020; 4:4/32/eaau8125. [PMID: 30709843 DOI: 10.1126/sciimmunol.aau8125] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 12/13/2018] [Indexed: 12/11/2022]
Abstract
Microbiome sequence analyses have suggested that changes in gut bacterial composition are associated with autoimmune disease in humans and animal models. However, little is known of the mechanisms through which the gut microbiota influences autoimmune responses to distant tissues. Here, we evaluated systemic antibody responses against cultured human gut bacterial strains to determine whether observed patterns of anticommensal antibody (ACAb) responses are associated with type 1 diabetes (T1D) in two cohorts of pediatric study participants. In the first cohort, ACAb responses in sera collected from participants within 6 months of T1D diagnosis were compared with age-matched healthy controls and also with patients with recent onset Crohn's disease. ACAb responses against multiple bacterial species discriminated among these three groups. In the second cohort, we asked whether ACAb responses present before diagnosis were associated with later T1D development and with HLA genotype in participants who were discordant for subsequent progression to diabetes. Serum IgG2 antibodies against Roseburia faecis and against a bacterial consortium were associated with future T1D diagnosis in an HLA DR3/DR4 haplotype-dependent manner. These analyses reveal associations between antibody responses to intestinal microbes and HLA-DR genotype and islet autoantibody specificity and with a future diagnosis of T1D. Further, we present a platform to investigate antibacterial antibodies in biological fluids that is applicable to studies of autoimmune diseases and responses to therapeutic interventions.
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Affiliation(s)
- Alexandra Paun
- Hospital for Sick Children, Toronto, ON, Canada. .,Department of Immunology, University of Toronto, Faculty of Medicine, Toronto, ON, Canada
| | - Christopher Yau
- Hospital for Sick Children, Toronto, ON, Canada. .,Department of Immunology, University of Toronto, Faculty of Medicine, Toronto, ON, Canada
| | | | - Michelle C Daigneault
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | | | | | - Amit Bar-Or
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada.,Department of Neurology, Perelman Center for Advanced Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, U.S.A
| | - Emma Allen-Vercoe
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Philippe Poussier
- Department of Immunology, University of Toronto, Faculty of Medicine, Toronto, ON, Canada.,Sunnybrook Research Institute, Toronto, ON Canada
| | - Jayne S Danska
- Hospital for Sick Children, Toronto, ON, Canada. .,Department of Immunology, University of Toronto, Faculty of Medicine, Toronto, ON, Canada.,Department of Medical Biophysics, University of Toronto, Faculty of Medicine, Toronto, ON, Canada
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16
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MacDonald ES, Barrett JG. The Potential of Mesenchymal Stem Cells to Treat Systemic Inflammation in Horses. Front Vet Sci 2020; 6:507. [PMID: 32039250 PMCID: PMC6985200 DOI: 10.3389/fvets.2019.00507] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/20/2019] [Indexed: 12/13/2022] Open
Abstract
One hallmark of mesenchymal stem cells (MSCs) is the ability to differentiate into multiple tissue types which assists in tissue regeneration. Another hallmark of MSCs is their potent anti-inflammatory and immunomodulatory properties and the potential to treat inflammatory, immune-mediated, and ischemic conditions. In equine practice, MSCs have shown efficacy in the treatment of musculoskeletal disorders such as tendinopathy, meniscal tears and cartilage injury. However, there are many equine disease processes and conditions that may benefit from the immunomodulatory properties of MSCs. Examples include conditions associated with overwhelming acute inflammatory response such as systemic inflammatory response syndrome to chronic diseases characterized by a prolonged low level of inflammation such as equine asthma and recurrent uveitis. For the acute inflammatory response processes, there is often high morbidity and mortality with no effective immunomodulatory treatment to prevent the overwhelming synthesis of proinflammatory mediators. For chronic inflammatory disease processes, frequently long-term corticosteroid treatment is the therapeutic mainstay, with serious potential complications. Thus, there is an unmet need for alternative anti-inflammatory treatments for both acute and chronic illnesses in horses. While MSCs show promise for such conditions, much research is needed before a clinically safe and effective treatment will be available. Optimal MSC tissue source, patient vs. donor source (autologous vs. allogeneic) and cell growth conditions need to be determined for each problem. For immediate use, allogeneic MSC treatments is preferable, but immune tolerance and adequate safety require further study. MSC collection and cryopreservation from horses before they are injured or ill, whether from umbilical cord tissue, bone marrow or adipose might become more widespread. Once these fundamental approaches to treating specific diseases with MSCs are determined, the route of administration, dose and timing of administration also need to be studied. To provide a framework for development of MSC immunomodulatory treatments, this article reviews the current understanding of equine MSC anti-inflammatory and immunomodulatory properties and proposes how MSC therapy may be further developed to treat acute onset systemic inflammatory processes and chronic inflammatory diseases.
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Affiliation(s)
- Elizabeth S MacDonald
- Marion duPont Scott Equine Medical Center, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, United States
| | - Jennifer G Barrett
- Marion duPont Scott Equine Medical Center, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, United States
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17
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Amadou Amani S, Lang ML. Bacteria That Cause Enteric Diseases Stimulate Distinct Humoral Immune Responses. Front Immunol 2020; 11:565648. [PMID: 33042146 PMCID: PMC7524877 DOI: 10.3389/fimmu.2020.565648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 08/18/2020] [Indexed: 12/12/2022] Open
Abstract
Bacterial enteric pathogens individually and collectively represent a serious global health burden. Humoral immune responses following natural or experimentally-induced infections are broadly appreciated to contribute to pathogen clearance and prevention of disease recurrence. Herein, we have compared observations on humoral immune mechanisms following infection with Citrobacter rodentium, the model for enteropathogenic Escherichia coli, Vibrio cholerae, Shigella species, Salmonella enterica species, and Clostridioides difficile. A comparison of what is known about the humoral immune responses to these pathogens reveals considerable variance in specific features of humoral immunity including establishment of high affinity, IgG class-switched memory B cell and long-lived plasma cell compartments. This article suggests that such variance could be contributory to persistent and recurrent disease.
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Bello-Gil D, Audebert C, Olivera-Ardid S, Pérez-Cruz M, Even G, Khasbiullina N, Gantois N, Shilova N, Merlin S, Costa C, Bovin N, Mañez R. The Formation of Glycan-Specific Natural Antibodies Repertoire in GalT-KO Mice Is Determined by Gut Microbiota. Front Immunol 2019; 10:342. [PMID: 30891034 PMCID: PMC6411795 DOI: 10.3389/fimmu.2019.00342] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 02/11/2019] [Indexed: 12/19/2022] Open
Abstract
Gut commensal bacteria are known to have a significant role in regulating the innate and adaptive immune homeostasis. Alterations in the intestinal microbial composition have been associated with several disease states, including autoimmune and inflammatory conditions. However, it is not entirely clear how commensal gut microbiota modulate and contribute to the systemic immunity, and whether circulating elements of the host immune system could regulate the microbiome. Thus, we have studied the diversity and abundance of specific taxons in the gut microbiota of inbred GalT-KO mice during 7 months of animal life by metagenetic high-throughput sequencing (16S rRNA gene, variable regions V3-V5). The repertoire of glycan-specific natural antibodies, obtained by printed glycan array technology, was then associated with the microbial diversity for each animal by metagenome-wide association studies (MWAS). Our data show that the orders clostridiales (most abundant), bacteriodales, lactobacillales, and deferribacterales may be associated with the development of the final repertoire of natural anti-glycan antibodies in GalT-KO mice. The main changes in microbiota diversity (month-2 and month-3) were related to important changes in levels and repertoire of natural anti-glycan antibodies in these mice. Additionally, significant positive and negative associations were found between the gut microbiota and the pattern of specific anti-glycan antibodies. Regarding individual features, the gut microbiota and the corresponding repertoire of natural anti-glycan antibodies showed differences among the examined animals. We also found redundancy in different taxa associated with the development of specific anti-glycan antibodies. Differences in microbial diversity did not, therefore, necessarily influence the overall functional output of the gut microbiome of GalT-KO mice. In summary, the repertoire of natural anti-carbohydrate antibodies may be partially determined by the continuous antigenic stimulation produced by the gut bacterial population of each GalT-KO mouse. Small differences in gut microbiota diversity could determine different repertoire and levels of natural anti-glycan antibodies and consequently might induce different immune responses to pathogens or other potential threats.
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Affiliation(s)
- Daniel Bello-Gil
- Infectious Pathology and Transplantation Division, Institut d'Investigació Biomèdica de Bellvitge, Barcelona, Spain
| | - Christophe Audebert
- Genes Diffusion, Douai, France.,PEGASE-Biosciences, Institut Pasteur de Lille, Lille, France
| | - Sara Olivera-Ardid
- Infectious Pathology and Transplantation Division, Institut d'Investigació Biomèdica de Bellvitge, Barcelona, Spain
| | - Magdiel Pérez-Cruz
- CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Université de Lille, Lille, France
| | - Gaël Even
- Genes Diffusion, Douai, France.,PEGASE-Biosciences, Institut Pasteur de Lille, Lille, France
| | | | - Nausicaa Gantois
- Lille University, CNRS, Inserm, Lille University Hospital, Pasteur Institute of Lille, U1019 -UMR 8204 -CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France
| | - Nadezhda Shilova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Sophie Merlin
- Genes Diffusion, Douai, France.,PEGASE-Biosciences, Institut Pasteur de Lille, Lille, France
| | - Cristina Costa
- Infectious Pathology and Transplantation Division, Institut d'Investigació Biomèdica de Bellvitge, Barcelona, Spain
| | - Nicolai Bovin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Rafael Mañez
- Infectious Pathology and Transplantation Division, Institut d'Investigació Biomèdica de Bellvitge, Barcelona, Spain.,Intensive Care Department, Bellvitge University Hospital, Barcelona, Spain
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19
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Sorini C, Cardoso RF, Gagliani N, Villablanca EJ. Commensal Bacteria-Specific CD4 + T Cell Responses in Health and Disease. Front Immunol 2018; 9:2667. [PMID: 30524431 PMCID: PMC6256970 DOI: 10.3389/fimmu.2018.02667] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 10/29/2018] [Indexed: 12/14/2022] Open
Abstract
Over the course of evolution, mammalian body surfaces have adapted their complex immune system to allow a harmless coexistence with the commensal microbiota. The adaptive immune response, in particular CD4+ T cell-mediated, is crucial to maintain intestinal immune homeostasis by discriminating between harmless (e.g., dietary compounds and intestinal microbes) and harmful stimuli (e.g., pathogens). To tolerate food molecules and microbial components, CD4+ T cells establish a finely tuned crosstalk with the environment whereas breakdown of these mechanisms might lead to chronic disease associated with mucosal barriers and beyond. How commensal-specific immune responses are regulated and how these molecular and cellular mechanisms can be manipulated to treat chronic disorders is yet poorly understood. In this review, we discuss current knowledge of the regulation of commensal bacteria-specific CD4+ T cells. We place particular focus on the key role of commensal-specific CD4+ T cells in maintaining tolerance while efficiently eradicating local and systemic infections, with a focus on factors that trigger their aberrant activation.
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Affiliation(s)
- Chiara Sorini
- Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
| | - Rebeca F. Cardoso
- Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
| | - Nicola Gagliani
- Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eduardo J. Villablanca
- Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
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20
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Janket SJ, Nunn ME, Salih E, Baird AE. Evidence-Based Approach in Translational Dental Research. TRANSLATIONAL ORAL HEALTH RESEARCH 2018:81-101. [DOI: 10.1007/978-3-319-78205-8_8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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21
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Hughes HK, Ashwood P. Anti- Candida albicans IgG Antibodies in Children With Autism Spectrum Disorders. Front Psychiatry 2018; 9:627. [PMID: 30534090 PMCID: PMC6275220 DOI: 10.3389/fpsyt.2018.00627] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 11/05/2018] [Indexed: 12/20/2022] Open
Abstract
The gut microbiota are known to have a profound influence on both mucosal and systemic immunity and are important for gastrointestinal (GI) function. In addition, new evidence shows that the microbiota significantly influence neurodevelopment and behavior. Immune dysfunction and GI distress are extremely common in individuals with autism spectrum disorders (ASD). A growing body of evidence suggests that individuals with ASD have significant aberrations in the composition of their gut microbiota, known as dysbiosis. However, these studies have focused on the bacterial components of the microbiota, leaving the fungal microbiota in ASD poorly studied. Increases in fungal species such as Candida albicans are associated with inflammatory bowel disorders, and have recently been implicated in several neurological disorders including schizophrenia. We aimed to determine if children with ASD exhibit elevations in antibodies that target C. albicans, indicating current or previous overgrowth of this fungal species. We measured anti-C. albicans immunoglobulin (IgG) in plasma from 80 children enrolled in the UC Davis MIND Institute CHARGE study. Measurements were acquired using a commercial ELISA kit. Plasma anti-C. albicans antibody positivity was found in 36.5% (19/52) of children with ASD. Anti-C. albicans antibodies in typically developing controls was (14.3%; 4/28). Overall, ASD children had a higher rate of high-positive values compared to typically developed children with an unadjusted odds ratio of 3.45 (95% confidence interval, 1.0409 to 11.4650; p = 0.041, two-tailed). GI dysfunction was found in about half of the ASD children who were positive for anti-Candida IgG. This study provides evidence of a new microbial risk factor for ASD.
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Affiliation(s)
- Heather K Hughes
- Department of Medical Microbiology and Immunology, and The Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis, Davis, CA, United States
| | - Paul Ashwood
- Department of Medical Microbiology and Immunology, and The Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis, Davis, CA, United States
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22
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Hel Z, Xu J, Denning WL, Helton ES, Huijbregts RPH, Heath SL, Overton ET, Christmann BS, Elson CO, Goepfert PA, Mestecky J. Dysregulation of Systemic and Mucosal Humoral Responses to Microbial and Food Antigens as a Factor Contributing to Microbial Translocation and Chronic Inflammation in HIV-1 Infection. PLoS Pathog 2017; 13:e1006087. [PMID: 28125732 PMCID: PMC5268400 DOI: 10.1371/journal.ppat.1006087] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 11/23/2016] [Indexed: 01/25/2023] Open
Abstract
HIV-1 infection is associated with an early and profound depletion of mucosal memory CD4+ T cells, a population that plays an indispensable role in the regulation of isotype switching and transepithelial transport of antibodies. In this study, we addressed whether the depletion of CD4+ T cell in HIV-1-infected individuals results in altered humoral responses specific to antigens encountered at mucosal surfaces. Comprehensive protein microarray of systemic humoral responses to intestinal microbiota demonstrated reduced IgG responses to antigens derived from Proteobacteria and Firmicutes but not Bacteroidetes. Importantly, intestinal secretions of antiretroviral therapy-treated HIV-1-infected individuals exhibited a significant elevation of IgM levels and decreased IgA/IgM and IgG/IgM ratios of antibodies specific to a variety of microbial and food antigens. The presented findings indicate reduced competence of mucosal B cells for class switch recombination from IgM to other isotypes limiting their capacity to react to changing antigenic variety in the gut lumen. Decreased availability of microbiota-specific IgA and IgG may be an important factor contributing to the translocation of microbial antigens across the intestinal mucosal barrier and their systemic dissemination that drives chronic inflammation in HIV-1-infected individuals.
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Affiliation(s)
- Zdenek Hel
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jun Xu
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Warren L. Denning
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - E. Scott Helton
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Richard P. H. Huijbregts
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Sonya L. Heath
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - E. Turner Overton
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Benjamin S. Christmann
- Department of Natural Science and Mathematics, Lee University, Cleveland, Tennessee, United States of America
| | - Charles O. Elson
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Paul A. Goepfert
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jiri Mestecky
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Institute of Immunology and Microbiology, 1 School of Medicine, Charles University, Prague, Czech Republic
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23
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Kamdar K, Khakpour S, Chen J, Leone V, Brulc J, Mangatu T, Antonopoulos DA, Chang EB, Kahn SA, Kirschner BS, Young G, DePaolo RW. Genetic and Metabolic Signals during Acute Enteric Bacterial Infection Alter the Microbiota and Drive Progression to Chronic Inflammatory Disease. Cell Host Microbe 2016; 19:21-31. [PMID: 26764594 DOI: 10.1016/j.chom.2015.12.006] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/20/2015] [Accepted: 12/21/2015] [Indexed: 12/18/2022]
Abstract
Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals.
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Affiliation(s)
- Karishma Kamdar
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90089, USA
| | - Samira Khakpour
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA
| | - Jingyu Chen
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; Department of Food Science and Technology, University of California, Davis, Davis, CA 95616, USA
| | - Vanessa Leone
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA
| | | | - Thomas Mangatu
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics Section of Pediatric Gastroenterology, Hepatology, & Nutrition, University of Chicago, Chicago, IL 60637, USA
| | - Dionysios A Antonopoulos
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Argonne National Laboratory, Argonne, IL 60439, USA
| | - Eugene B Chang
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA
| | - Stacy A Kahn
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics Section of Pediatric Gastroenterology, Hepatology, & Nutrition, University of Chicago, Chicago, IL 60637, USA
| | - Barbara S Kirschner
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics Section of Pediatric Gastroenterology, Hepatology, & Nutrition, University of Chicago, Chicago, IL 60637, USA
| | - Glenn Young
- Department of Food Science and Technology, University of California, Davis, Davis, CA 95616, USA
| | - R William DePaolo
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90089, USA.
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24
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Ulsemer P, Toutounian K, Kressel G, Goletz C, Schmidt J, Karsten U, Hahn A, Goletz S. Impact of oral consumption of heat-treated Bacteroides xylanisolvens DSM 23964 on the level of natural TFα-specific antibodies in human adults. Benef Microbes 2016; 7:485-500. [DOI: 10.3920/bm2015.0143] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
It is now generally accepted that the human body exists in close synergy with the gut microbiome and that this cross-talk plays an essential role in human health and disease. One facet from the many interactions between the microbiome and the immune system is the induction of natural antibodies to commensal bacterial glycans, such as blood group antigens, the alpha-Gal epitope or the Thomsen-Friedenreich (TFα) antigen. Since we have observed that certain species of the commensal genus Bacteroides express the TFα antigen, we examined whether the oral dietary supplementation of a pasteurised Bacteroides xylanisolvens strain might be able to enhance the level of natural anti-TFα antibodies in healthy adults. The data obtained from a double-blind, placebo-controlled study involving 140 healthy volunteers and lasting 8 weeks revealed that the oral uptake of this strain was indeed able to increase the level of TFα-specific immunoglobulin M serum antibodies. The effect was dose-dependent but remained – at any doses – within the physiological range determined before intervention. Furthermore, the effect reverted after stopping the intake. The results support the idea of the microbiome inducing the generation of systemic antigen-specific antibodies against sugar epitopes. They also demonstrate the possibility to modulate essential regulatory or defence processes through dietary supplementation of selected commensal bacteria with the aim to assist human health.
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Affiliation(s)
- P. Ulsemer
- Avitop GmbH, Robert-Roessler-Str. 10, 13125 Berlin, Germany
| | - K. Toutounian
- Avitop GmbH, Robert-Roessler-Str. 10, 13125 Berlin, Germany
| | - G. Kressel
- Leibniz University of Hannover, Institute of Food Science and Human Nutrition, Am Kleinen Felde 30, 30163 Hannover, Germany
| | - C. Goletz
- Glycotope GmbH, Robert-Roessle-Str. 10, 13125 Berlin, Germany
| | - J. Schmidt
- Avitop GmbH, Robert-Roessler-Str. 10, 13125 Berlin, Germany
| | - U. Karsten
- Glycotope GmbH, Robert-Roessle-Str. 10, 13125 Berlin, Germany
| | - A. Hahn
- Leibniz University of Hannover, Institute of Food Science and Human Nutrition, Am Kleinen Felde 30, 30163 Hannover, Germany
| | - S. Goletz
- Glycotope GmbH, Robert-Roessle-Str. 10, 13125 Berlin, Germany
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25
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Lemke A, Kraft M, Roth K, Riedel R, Lammerding D, Hauser AE. Long-lived plasma cells are generated in mucosal immune responses and contribute to the bone marrow plasma cell pool in mice. Mucosal Immunol 2016; 9:83-97. [PMID: 25943272 DOI: 10.1038/mi.2015.38] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 03/24/2015] [Indexed: 02/04/2023]
Abstract
During systemic immune responses, plasma blasts are generated in secondary lymphoid organs and migrate to the bone marrow, where they can become long-lived, being responsible for the maintenance of long-term antibody titers. Plasma blasts generated in mucosal immune responses of the small intestine home to the lamina propria (LP), producing mainly immunoglobulin A. The migration of these antibody-secreting cells is well characterized during acute immune responses. Less is known about their lifetime and contribution to the long-lived bone marrow compartment. Here we investigate the lifetime of plasma cells (PCs) and the relationship between the PC compartments of the gut and bone marrow after oral immunization. Our findings indicate that PCs in the LP can survive for extended time periods. PCs specific for orally administered antigens can be detected in the bone marrow for at least 9 months after immunization, indicating that the mucosal PC compartment can contribute to the long-lived PC pool in this organ, independent of the participation of splenic B cells. Our findings suggest that the compartmentalization between mucosal and systemic PC pools is less strict than previously thought. This may have implications for the development of vaccines as well as for autoantibody-mediated diseases.
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Affiliation(s)
- A Lemke
- Deutsches Rheuma Forschungszentrum (DRFZ), a Leibniz Institute, Berlin, Germany
| | - M Kraft
- Deutsches Rheuma Forschungszentrum (DRFZ), a Leibniz Institute, Berlin, Germany.,Charité Universitätsmedizin, Charitéplatz 1, Berlin, Germany
| | - K Roth
- Deutsches Rheuma Forschungszentrum (DRFZ), a Leibniz Institute, Berlin, Germany
| | - R Riedel
- Deutsches Rheuma Forschungszentrum (DRFZ), a Leibniz Institute, Berlin, Germany
| | - D Lammerding
- Deutsches Rheuma Forschungszentrum (DRFZ), a Leibniz Institute, Berlin, Germany.,Charité Universitätsmedizin, Charitéplatz 1, Berlin, Germany
| | - A E Hauser
- Deutsches Rheuma Forschungszentrum (DRFZ), a Leibniz Institute, Berlin, Germany.,Charité Universitätsmedizin, Charitéplatz 1, Berlin, Germany
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26
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Ben Ya'acov A, Lichtenstein Y, Zolotarov L, Ilan Y. The gut microbiome as a target for regulatory T cell-based immunotherapy: induction of regulatory lymphocytes by oral administration of anti-LPS enriched colostrum alleviates immune mediated colitis. BMC Gastroenterol 2015; 15:154. [PMID: 26518263 PMCID: PMC4628342 DOI: 10.1186/s12876-015-0388-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 10/25/2015] [Indexed: 02/07/2023] Open
Abstract
Background Gut-derived bacterial endotoxin is an important cofactor in the pathogenesis of IBD. Regulatory T cells (Tregs) are essential for maintenance of peripheral tolerance and can prevent and alleviate IBD. To determine the immune modulatory effect of anti-LPS enriched hyperimmune colostrum, its ability to induce Tregs and alleviate immune mediated colitis. Methods Immune-mediated colitis was induced in mice by intra-colonic instillation of Trinitrobenzene Sulfonate (TNBS). Four groups of mice were orally administered with two dosages of IgG-enriched colostrum fractions. The fractions were harvested from cows immunized against LPS derived from intestinal Escherichia coli bacteria (Imm124E). Control mice received non-immunized colostrum or vehicle (PBS). Treatment was administered one day following sensitization and four additional days following the administration of TNBS. The following parameters in the mice were tracked: body weight, bowel histology, serum cytokine levels and regulatory T cells. Results Oral administration of Imm124E hyperimmune colostrum ameliorated immune-mediated colitis. Significant amelioration of weight reduction was noted in treated mice. Oral administration of Imm124E improved bowel histology. Both the extent of the disease, inflammation score, and colitis damage and regeneration scores decreased in Imm-124E treated animals. These effects were associated with an increase in serum IL10 anti inflammatory cytokine levels, and an increase in CD4 + CD25+ and CD4 + Foxp3+ Tregs. Conclusions Oral administration of Imm124E promoted Tregs and alleviated bowel inflammation in immune mediated colitis. The present data suggests that the microbiome may serve as a target for Tregs-based immunotherapy. Electronic supplementary material The online version of this article (doi:10.1186/s12876-015-0388-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ami Ben Ya'acov
- Gastroenterology and liver Unit, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
| | - Yoav Lichtenstein
- Gastroenterology and liver Unit, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
| | - Lidya Zolotarov
- Gastroenterology and liver Unit, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
| | - Yaron Ilan
- Gastroenterology and liver Unit, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
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27
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Zimmermann K, Bastidas S, Knecht L, Kuster H, Vavricka SR, Günthard HF, Oxenius A. Gut commensal microbes do not represent a dominant antigenic source for continuous CD4+ T-cell activation during HIV-1 infection. Eur J Immunol 2015; 45:3107-13. [PMID: 26345361 DOI: 10.1002/eji.201545940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 08/20/2015] [Accepted: 09/08/2015] [Indexed: 11/06/2022]
Abstract
Chronic immune activation is a hallmark of HIV-1 infection; specifically, the activation of T cells has predictive value for progression to AIDS. The majority of hyperactivated T cells are not HIV-specific and their antigenic specificities remain poorly understood. Translocation of gut luminal microbial products to systemic sites contributes to chronic immune activation during HIV-1 infection, but how it affects (TCR-dependent) immune activation remains elusive. We hypothesized that gut luminal antigens foster activation of CD4(+) T cells with specificities for commensal bacterial antigens, thereby contributing to the pool of activated CD4(+) T cells in the circulation of HIV-1 infected individuals. To test this hypothesis, we quantified the frequencies of gut microbe-specific CD4(+) T cells by cytokine production upon restimulation with selected gut commensal microbial antigens. Contrary to our hypothesis, we did not observe increased but rather decreased frequencies of gut microbe-specific CD4(+) T cells in HIV-1 infected individuals compared to healthy controls. We conclude that the increased activation status of circulating CD4(+) T cells in HIV-1 infected individuals is not driven by CD4(+) T cells with specificities for commensal bacterial antigens.
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Affiliation(s)
| | - Sonia Bastidas
- Institute of Microbiology, ETH Zurich, Zurich, Switzerland
| | - Leandra Knecht
- Institute of Microbiology, ETH Zurich, Zurich, Switzerland
| | - Herbert Kuster
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Stephan R Vavricka
- Division of Gastroenterology and Hepatology, Triemli Hospital, Zurich, Switzerland
| | - Huldrych F Günthard
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Institute of Medical Virology, University of Zurich, Zurich, Switzerland
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28
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Harnessing the Microbiome to Enhance Cancer Immunotherapy. J Immunol Res 2015; 2015:368736. [PMID: 26101781 PMCID: PMC4458560 DOI: 10.1155/2015/368736] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 05/10/2015] [Indexed: 12/20/2022] Open
Abstract
The microbiota plays a key role in regulating the innate and adaptive immune system. Herein, we review the immunological aspects of the microbiota in tumor immunity in mice and man, with a focus on toll-like receptor (TLR) agonists, vaccines, checkpoint modulators, chemotherapy, and adoptive T cell transfer (ACT) therapies. We propose innovative treatments that may safely harness the microbiota to enhance T cell-based therapies in cancer patients. Finally, we highlight recent developments in tumor immunotherapy, particularly novel ways to modulate the microbiome and memory T cell responses to human malignancies.
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29
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Stipić F, Pletikapić G, Jakšić Ž, Frkanec L, Zgrablić G, Burić P, Lyons DM. Application of Functionalized Lanthanide-Based Nanoparticles for the Detection of Okadaic Acid-Specific Immunoglobulin G. J Phys Chem B 2015; 119:1259-64. [DOI: 10.1021/jp506382w] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Filip Stipić
- Center
for Marine Research, Ruđer Bošković Institute, G. Paliaga
5, 52210 Rovinj, Croatia
| | | | - Željko Jakšić
- Center
for Marine Research, Ruđer Bošković Institute, G. Paliaga
5, 52210 Rovinj, Croatia
| | | | - Goran Zgrablić
- Time
Resolved X-ray Spectroscopy Laboratory, Elettra-Sincrotrone Trieste, 34149 Basovizza, Italy
| | - Petra Burić
- Center
for Marine Research, Ruđer Bošković Institute, G. Paliaga
5, 52210 Rovinj, Croatia
| | - Daniel M. Lyons
- Center
for Marine Research, Ruđer Bošković Institute, G. Paliaga
5, 52210 Rovinj, Croatia
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Abstract
There is growing evidence that the commensal bacteria in the gastrointestinal tract (the gut microbiota) influence the development of autoimmunity in rodent models. Since humans have co-evolved with commensals for millennia, it is likely that people, who are genetically predisposed to autoimmunity, harbor gut microbial communities that similarly influence the onset and/or severity of disease. Beyond the current efforts to identify such disease-promoting or -preventing commensals ("pathobionts" or "symbionts"), it will be important to determine what factors modulate them. Dietary changes are known to affect both the composition and function of the gut microbial communities, which in turn can alter the innate and adaptive immune system. In this review, we focus on the relationships between diet, microbiota, and autoimmune diseases. We hypothesize that the beneficial and life-prolonging effects of caloric restriction on a variety of autoimmune models including lupus might partly be mediated by its effects on the gut microbiome and associated virome, the collection of all viruses in the gut. We give recent examples of the immunomodulatory potential of select gut commensals and their products or diet-derived metabolites in murine models of arthritis, multiple sclerosis, and type 1 diabetes. Lastly, we summarize the published phenotypes of germ-free mouse models of lupus and speculate on any role of the diet-sensitive microbiome and virome in systemic lupus and the related antiphospholipid syndrome.
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Decreased frequencies of circulating follicular helper T cell counterparts and plasmablasts in ankylosing spondylitis patients Naïve for TNF blockers. PLoS One 2014; 9:e107086. [PMID: 25203742 PMCID: PMC4159293 DOI: 10.1371/journal.pone.0107086] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 08/06/2014] [Indexed: 12/19/2022] Open
Abstract
Follicular helper T cells (Tfh), localized in lymphoid organs, promote B cell differentiation and function. Circulating CD4 T cells expressing CXCR5, ICOS and/or PD-1 are counterparts of Tfh. Three subpopulations of circulating CD4+CXCR5+ cells have been described: CXCR3+CCR6- (Tfh-Th1), CXCR3-CCR6+ (Tfh-Th17), and CXCR3-CCR6- (Tfh-Th2). Only Tfh-Th17 and Tfh-Th2 function as B cell helpers. Our objective was to study the frequencies of circulating Tfh (cTfh), cTfh subsets and plasmablasts (CD19+CD20-CD27+CD38high cells), and the function of cTfh cells, in patients with Ankylosing Spondylitis (AS). To this end, peripheral blood was drawn from healthy controls (HC) (n = 50), AS patients naïve for TNF blockers (AS/nb) (n = 25) and AS patients treated with TNF blockers (AS/b) (n = 25). The frequencies of cTfh and plasmablasts were determined by flow cytometry. Cocultures of magnetically sorted CD4+CXCR5+ T cells with autologous CD19+CD27- naïve B cells were established from 3 AS/nb patients and 3 HC, and concentrations of IgG, A and M were measured in supernatants. We obseved that AS/nb but not AS/b patients, demonstrated decreased frequencies of circulating CD4+CXCR5+ICOS+PD-1+ cells and plasmablasts, together with a decreased (Tfh-Th17+Tfh-Th2)/Tfh-Th1 ratio. The amounts of IgG and IgA produced in cocultures of CD4+CXCR5+ T cells with CD19+CD27- B cells of AS/nb patients were significantly lower than observed in cocultures established from HC. In summary, AS/nb but not AS/b patients, demonstrate a decreased frequency of cTfh and plasmablasts, and an underrepresentation of cTfh subsets bearing a B helper phenotype. In addition, peripheral blood CD4+CXCR5+ T cells of AS/nb patients showed a decreased capacity to help B cells ex vivo.
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Toxicological effects of nickel chloride on IgA+ B Cells and sIgA, IgA, IgG, IgM in the intestinal mucosal immunity in broilers. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2014; 11:8175-92. [PMID: 25116637 PMCID: PMC4143856 DOI: 10.3390/ijerph110808175] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/15/2014] [Accepted: 07/25/2014] [Indexed: 11/17/2022]
Abstract
The objective of this study was to investigate the toxicological effects of dietary NiCl2 on IgA+ B cells and the immunoglobulins including sIgA, IgA, IgG and IgM in the small intestine and cecal tonsil of broilers by the methods of immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Two hundred and forty one-day-old avian broilers were randomly divided into four groups and fed on a control diet and three experimental diets supplemented with 300, 600, and 900 mg/kg NiCl2 for 42 days. Compared with the control group, the IgA+ B cell number and the sIgA, IgA, IgG, and IgM contents in the NiCl2-treated groups were significantly decreased (p < 0.05 or p < 0.01). It was concluded that dietary NiCl2 in the excess of 300 mg/kg had negative effects on the IgA+ B cell number and the above mentioned immunoglobulin contents in the small intestine and the cecal tonsil. NiCl2-reduced sIgA, IgA, IgG and IgM contents is due to decrease in the population and/or the activation of B cell. The results suggest that NiCl2 at high levels has intestinal mucosal humoral immunotoxicity in animals.
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33
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Abstract
The adaptive immune system provides critical defense against pathogenic bacteria. Commensal bacteria have begun to receive much attention in recent years, especially in the gut where there is growing evidence of complex interactions with the adaptive immune system. In the present study, we observed that commensal skin bacteria are recognized by major populations of T cells in skin-draining lymph nodes of mice. Recombination activating gene 1 (Rag1)(-/-) mice, which lack adaptive immune cells, contained living skin-derived bacteria and bacterial sequences, especially mycobacteria, in their skin-draining lymph nodes. T cells from skin-draining lymph nodes of normal mice were shown, in vitro, to specifically recognize bacteria of several species that were grown from Rag1(-/-) lymph nodes. T cells from skin-draining lymph nodes, transferred into Rag1(-/-) mice proliferated in skin-draining lymph nodes, expressed a restricted T-cell receptor spectrotype and produced cytokines. Transfer of T cells into Rag1(-/-) mice had the effect of reducing bacterial sequences in skin-draining lymph nodes and in skin itself. Antibacterial effects of transferred T cells were dependent on IFNγ and IL-17A. These studies suggest a previously unrecognized role for T cells in controlling skin commensal bacteria and provide a mechanism to account for cutaneous infections and mycobacterial infections in T-cell-deficient patients.
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Chai JN, Zhou YW, Hsieh CS. T cells and intestinal commensal bacteria--ignorance, rejection, and acceptance. FEBS Lett 2014; 588:4167-75. [PMID: 24997344 DOI: 10.1016/j.febslet.2014.06.040] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Revised: 06/23/2014] [Accepted: 06/24/2014] [Indexed: 02/01/2023]
Abstract
Trillions of commensal bacteria cohabit our bodies to mutual benefit. In the past several years, it has become clear that the adaptive immune system is not ignorant of intestinal commensal bacteria, but is constantly interacting with them. For T cells, the response to commensal bacteria does not appear uniform, as certain commensal bacterial species appear to trigger effector T cells to reject and control them, whereas other species elicit Foxp3(+) regulatory T (Treg) cells to accept and be tolerant of them. Here, we review our current knowledge of T cell differentiation in response to commensal bacteria, and how this process leads to immune homeostasis in the intestine.
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Affiliation(s)
- Jiani N Chai
- Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63132, United States
| | - You W Zhou
- Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63132, United States
| | - Chyi-Song Hsieh
- Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63132, United States.
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Kol A, Foutouhi S, Walker NJ, Kong NT, Weimer BC, Borjesson DL. Gastrointestinal microbes interact with canine adipose-derived mesenchymal stem cells in vitro and enhance immunomodulatory functions. Stem Cells Dev 2014; 23:1831-43. [PMID: 24803072 DOI: 10.1089/scd.2014.0128] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are somatic, multipotent stromal cells with potent immunomodulatory and regenerative properties. Although MSCs have pattern recognition receptors and are modulated by Toll-like receptor ligands, MSC-microbial interactions are poorly defined. The objectives of this study were to determine the effect of bacterial association on MSC function. We hypothesized that gastrointestinal bacteria associate with MSCs and alter their immunomodulatory properties. The effect of MSC-microbial interactions on MSC morphology, viability, proliferation, migration, and immunomodulatory functions was investigated. MSCs associated with a remarkable array of enteric pathogens and commensal bacteria. MSC interactions with two model organisms, the pathogen Salmonella typhimurium and the probiotic Lactobacillus acidophilus, were further investigated. While ST readily invaded MSCs, LB adhered to the MSC plasma membrane. Neither microbe induced MSC death, degeneration, or diminished proliferation. Microbial association did not upregulate MHC-II, CD80/86, or CD1 expression. MSC-microbial interaction significantly increased transcription of key immunomodulatory genes, including COX2, IL6, and IL8, coupled with significantly increased prostaglandin E2 (PGE2), interleukin (IL)6, and IL8 secretion. MSC-ST coincubation resulted in increased MSC expression of CD54, and significant augmentation of MSC inhibition of mitogen-induced T-cell proliferation. T-cell proliferation was partially restored when PGE2 secretion was blocked from ST-primed MSCs. MSC-microbe interactions have a profound effect on MSC function and may be pivotal in a variety of clinical settings where MSCs are being explored as potential therapeutics in the context of microbial communities, such as Crohn's disease, chronic nonhealing wounds, and sepsis.
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Affiliation(s)
- Amir Kol
- 1 Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California , Davis, California
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36
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Moyat M, Velin D. Immune responses to Helicobacter pylori infection. World J Gastroenterol 2014; 20:5583-5593. [PMID: 24914318 PMCID: PMC4024767 DOI: 10.3748/wjg.v20.i19.5583] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/13/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is one of the most common infections in human beings worldwide. H. pylori express lipopolysaccharides and flagellin that do not activate efficiently Toll-like receptors and express dedicated effectors, such as γ-glutamyl transpeptidase, vacuolating cytotoxin (vacA), arginase, that actively induce tolerogenic signals. In this perspective, H. pylori can be considered as a commensal bacteria belonging to the stomach microbiota. However, when present in the stomach, H. pylori reduce the overall diversity of the gastric microbiota and promote gastric inflammation by inducing Nod1-dependent pro-inflammatory program and by activating neutrophils through the production of a neutrophil activating protein. The maintenance of a chronic inflammation in the gastric mucosa and the direct action of virulence factors (vacA and cytotoxin-associated gene A) confer pro-carcinogenic activities to H. pylori. Hence, H. pylori cannot be considered as symbiotic bacteria but rather as part of the pathobiont. The development of a H. pylori vaccine will bring health benefits for individuals infected with antibiotic resistant H. pylori strains and population of underdeveloped countries.
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Mavrommatis B, Young GR, Kassiotis G. Counterpoise between the microbiome, host immune activation and pathology. Curr Opin Immunol 2013; 25:456-62. [PMID: 23743081 DOI: 10.1016/j.coi.2013.05.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 05/03/2013] [Accepted: 05/08/2013] [Indexed: 12/13/2022]
Abstract
The role of the mammalian intestinal microbiota in health and disease of the host has long been recognized and extensively studied. Largely, these studies have focused on the bacterial component of the microbiota. However, recent technological advances have shed new light on the microbiome at distinct anatomical locations and uncovered the role of additional microbial symbionts, including the virome and endogenous retroelements. Together, they have revealed interactions more intricate than previously recognized. Here, we review recent advances in our knowledge of this collective microbiome and the interactions with the immune system of their host.
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Affiliation(s)
- Bettina Mavrommatis
- Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK
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38
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Belkaid Y, Bouladoux N, Hand TW. Effector and memory T cell responses to commensal bacteria. Trends Immunol 2013; 34:299-306. [PMID: 23643444 PMCID: PMC3733441 DOI: 10.1016/j.it.2013.03.003] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 03/18/2013] [Accepted: 03/18/2013] [Indexed: 02/08/2023]
Abstract
Barrier surfaces are home to a vast population of commensal organisms that together encode millions of proteins; each of them possessing several potential foreign antigens. Regulation of immune responses to this enormous antigenic load represents a tremendous challenge for the immune system. Tissues exposed to commensals have developed elaborate systems of regulation including specialized populations of resident lymphocytes that maintain barrier function and limit potential responses to commensal antigens. However, in settings of infection and inflammation these regulatory mechanisms are compromised and specific effector responses against commensal bacteria can develop. This review discusses the circumstances controlling the fate of commensal specific T cells and how dysregulation of these responses could lead to severe pathological outcomes.
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Affiliation(s)
- Yasmine Belkaid
- Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, NIH, Bethesda 20892, USA.
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