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Boziki M, Theotokis P, Kesidou E, Nella M, Bakirtzis C, Karafoulidou E, Tzitiridou-Chatzopoulou M, Doulberis M, Kazakos E, Deretzi G, Grigoriadis N, Kountouras J. Impact of Mast Cell Activation on Neurodegeneration: A Potential Role for Gut-Brain Axis and Helicobacter pylori Infection. Neurol Int 2024; 16:1750-1778. [PMID: 39728753 DOI: 10.3390/neurolint16060127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/08/2024] [Accepted: 12/03/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND The innate immune response aims to prevent pathogens from entering the organism and/or to facilitate pathogen clearance. Innate immune cells, such as macrophages, mast cells (MCs), natural killer cells and neutrophils, bear pattern recognition receptors and are thus able to recognize common molecular patterns, such as pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), the later occurring in the context of neuroinflammation. An inflammatory component in the pathology of otherwise "primary cerebrovascular and neurodegenerative" disease has recently been recognized and targeted as a means of therapeutic intervention. Activated MCs are multifunctional effector cells generated from hematopoietic stem cells that, together with dendritic cells, represent first-line immune defense mechanisms against pathogens and/or tissue destruction. METHODS This review aims to summarize evidence of MC implication in the pathogenesis of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. RESULTS In view of recent evidence that the gut-brain axis may be implicated in the pathogenesis of neurodegenerative diseases and the characterization of the neuroinflammatory component in the pathology of these diseases, this review also focuses on MCs as potential mediators in the gut-brain axis bi-directional communication and the possible role of Helicobacter pylori, a gastric pathogen known to alter the gut-brain axis homeostasis towards local and systemic pro-inflammatory responses. CONCLUSION As MCs and Helicobacter pylori infection may offer targets of intervention with potential therapeutic implications for neurodegenerative disease, more clinical and translational evidence is needed to elucidate this field.
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Affiliation(s)
- Marina Boziki
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Paschalis Theotokis
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Evangelia Kesidou
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Maria Nella
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Christos Bakirtzis
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Eleni Karafoulidou
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Maria Tzitiridou-Chatzopoulou
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
- Midwifery Department, School of Healthcare Sciences, University of West Macedonia, Koila, 50100 Kozani, Greece
| | - Michael Doulberis
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
- Gastroklinik, Private Gastroenterological Practice, 8810 Horgen, Switzerland
- Division of Gastroenterology and Hepatology, Medical University Department, 5001 Aarau, Switzerland
| | - Evangelos Kazakos
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Georgia Deretzi
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
- Department of Neurology, Papageorgiou General Hospital, 54629 Thessaloniki, Greece
| | - Nikolaos Grigoriadis
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Jannis Kountouras
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
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Baj J, Forma A, Flieger W, Morawska I, Michalski A, Buszewicz G, Sitarz E, Portincasa P, Garruti G, Flieger M, Teresiński G. Helicobacter pylori Infection and Extragastric Diseases-A Focus on the Central Nervous System. Cells 2021; 10:2191. [PMID: 34571840 PMCID: PMC8469861 DOI: 10.3390/cells10092191] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/22/2021] [Accepted: 08/23/2021] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (H. pylori) is most known to cause a wide spectrum of gastrointestinal impairments; however, an increasing number of studies indicates that H. pylori infection might be involved in numerous extragastric diseases such as neurological, dermatological, hematologic, ocular, cardiovascular, metabolic, hepatobiliary, or even allergic diseases. In this review, we focused on the nervous system and aimed to summarize the findings regarding H. pylori infection and its involvement in the induction/progression of neurological disorders. Neurological impairments induced by H. pylori infection are primarily due to impairments in the gut-brain axis (GBA) and to an altered gut microbiota facilitated by H. pylori colonization. Currently, regarding a potential relationship between Helicobacter infection and neurological disorders, most of the studies are mainly focused on H. pylori.
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Affiliation(s)
- Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (G.B.); (M.F.); (G.T.)
| | - Wojciech Flieger
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Izabela Morawska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (A.M.)
| | - Adam Michalski
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (A.M.)
| | - Grzegorz Buszewicz
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (G.B.); (M.F.); (G.T.)
| | - Elżbieta Sitarz
- Chair and I Department of Psychiatry, Psychotherapy, and Early Intervention, Medical University of Lublin, 20-439 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Michał Flieger
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (G.B.); (M.F.); (G.T.)
| | - Grzegorz Teresiński
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (G.B.); (M.F.); (G.T.)
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Kountouras J, Papaefthymiou A, Gavalas E, Polyzos SA, Boziki M, Kyriakou P, Katsinelos P, Zavos C, Liatsos C, Tzivras D, Tzitiridou-Chatzopoulou M, Dardiotis E, Deretzi G, Vardaka E, Doulberis M. Helicobacter pylori infection as a potential risk factor for multiple sclerosis. Med Hypotheses 2020; 143:110135. [DOI: 10.1016/j.mehy.2020.110135] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/28/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023]
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Association between Active Helicobacter pylori Infection and Glaucoma: A Systematic Review and Meta-Analysis. Microorganisms 2020; 8:microorganisms8060894. [PMID: 32545826 PMCID: PMC7355761 DOI: 10.3390/microorganisms8060894] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Glaucoma is the second most common cause of blindness worldwide affecting almost 70 million individuals. Helicobacter pylori (H. pylori) is a widespread pathogen with systematic pathogenicity. This meta-analysis aimed to estimate the contradictory data regarding a potential association between active H. pylori infection and glaucoma. Materials and Methods: A research in MEDLINE/PubMed and Google Scholar was conducted and original studies investigating the relationship between H. pylori infection and glaucoma were included. Analysis was performed with random effects model. The main outcome was the odds ratio (OR) with 95% confidence intervals (CI) of H. pylori infection as a risk factor for glaucoma. A parallel analysis studied the role of active infection as indicated by histology and the titer of anti-H. pylori antibodies. For the anti-H. pylori antibody titers, weighted mean differences (WMD) were estimated between patients and controls. Results: Fifteen studies were included, with 2664 participants (872 patients with glaucoma and 1792 controls), divided into primary open-angle glaucoma (POAG), normal tension glaucoma (NTG) and pseudo-exfoliation glaucoma (PEG). The association between H. pylori infection and overall glaucoma was significant (OR = 2.08, CI 95% 1.48–2.93) with moderate heterogeneity (I2 = 61.54%). After stratification by glaucoma subtype, heterogeneity was eliminated in the NTG subgroup. Studies with healthy controls, and controls with anemia yielded very low or no heterogeneity, respectively. Gastric biopsy to document active H. pylori infection yielded the highest OR (5.4, CI: 3.17–9.2, p < 0.001) and null heterogeneity. For anti-H. pylori antibody titers, there was a significant difference in WMD between patients and controls (WMD 15.98 IU/mL; 95% CI: 4.09–27.87; p = 0.008); values were greater in glaucoma patients, with high heterogeneity (I2: 93.8%). Meta-regression analysis showed that mean age had a significant impact on glaucoma (p = 0.037). Conclusions: Active H. pylori infection may be associated with glaucoma with null heterogeneity, as, beyond histology, quantified by anti-H. pylori titers and increases with age.
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Dardiotis E, Sokratous M, Tsouris Z, Siokas V, Mentis AFA, Aloizou AM, Michalopoulou A, Bogdanos DP, Xiromerisiou G, Deretzi G, Kountouras J, Hadjigeorgiou GM. Association between Helicobacter pylori infection and Guillain-Barré Syndrome: A meta-analysis. Eur J Clin Invest 2020; 50:e13218. [PMID: 32124432 DOI: 10.1111/eci.13218] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/31/2020] [Accepted: 02/27/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Helicobacter pylori (H pylori) is a Gram-negative bacterium, considered to trigger autoimmune gastrointestinal disorders. This pathogen has also been linked to the autoimmune sequelae in extra-gastrointestinal diseases and peripheral neuropathies. Guillain-Barré syndrome (GBS) is a serious autoimmune demyelinating disorder of peripheral nerves, usually with a post-infectious onset. About 30% of cases of GBS attributed to by Campylobacter jejuni, so, H pylori, could be also involved. Growing evidence suggests the likely involvement of H pylori infection in the development of GBS. The aim of the current study was to therefore estimate the prevalence of H pylori antibodies in GBS. METHODS A search of the literature was performed, using the PUBMED database, until December 2018. Data were extracted from six case-control studies, and a stratification analysis was conducted according to cerebrospinal fluid (CSF) or serum detection material. RESULTS Among 29 records found, 6 studies met in the inclusion criteria for the meta-analysis. In the CSF subgroup, 105 participants were involved (40 GBS patients and 65 controls), while the serum subgroup included 325 participants (152 GBS and 173 controls). Data were combined using a fixed-effects model. Anti-H pylori IgG were significantly more prevalent in GBS patients compared to controls, in both CSF (95% CI: 9.66-186.56, OR: 42.45, Pz < .00001) and serum (95% CI: 1.30-4.11, OR: 2.31, Pz: .004) subgroups. CONCLUSION The present meta-analysis showed a strong association between GBS and the presence of H pylori antibodies, especially in CSF, thereby suggesting a role of H pylori infection in the pathophysiology of GBS.
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Affiliation(s)
- Efthimios Dardiotis
- Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Maria Sokratous
- Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Zisis Tsouris
- Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Vasileios Siokas
- Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Alexios-Fotios A Mentis
- Department of Microbiology, University Hospital of Larissa, University of Thessaly, Larissa, Greece.,Public Health Laboratories, Hellenic Pasteur Institute, Athens, Greece
| | - Athina-Maria Aloizou
- Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Amalia Michalopoulou
- Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.,Cellular Immunotherapy & Molecular Immunodiagnostics, Biomedical Section, Centre for Research and Technology-Hellas (CERTH)-Institute for Research and Technology-Thessaly (IRETETH), Larissa, Greece
| | - Georgia Xiromerisiou
- Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Georgia Deretzi
- Department of Neurology, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Jannis Kountouras
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
| | - Georgios M Hadjigeorgiou
- Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece.,Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus
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Papaefthymiou A, Doulberis M, Katsinelos P, Liatsos C, Polyzos SA, Kotronis G, Papanikolaou K, Kountouras J. Impact of nitric oxide's bidirectional role on glaucoma: focus onHelicobacter pylori–related nitrosative stress. Ann N Y Acad Sci 2020; 1465:10-28. [DOI: 10.1111/nyas.14253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 09/07/2019] [Accepted: 09/17/2019] [Indexed: 12/12/2022]
Affiliation(s)
| | - Michael Doulberis
- Department of Gastroenterology and HepatologyUniversity of Zurich Zurich Switzerland
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
| | - Panagiotis Katsinelos
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
| | - Christos Liatsos
- Department of Gastroenterology401 General Military Hospital of Athens Athens Greece
| | - Stergios A. Polyzos
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
- First Department of Pharmacology, School of MedicineAristotle University of Thessaloniki Thessaloniki Macedonia Greece
| | - Georgios Kotronis
- Department of Internal MedicineAgios Pavlos General Hospital Thessaloniki Macedonia Greece
| | - Katerina Papanikolaou
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
| | - Jannis Kountouras
- Department of Internal Medicine, Second Medical Clinic, Ippokration HospitalAristotle University of Thessaloniki Thessaloniki Macedonia Greece
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Doulberis M, Kotronis G, Thomann R, Polyzos SA, Boziki M, Gialamprinou D, Deretzi G, Katsinelos P, Kountouras J. Review: Impact of Helicobacter pylori on Alzheimer's disease: What do we know so far? Helicobacter 2018; 23. [PMID: 29181894 DOI: 10.1111/hel.12454] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Helicobacter pylori has changed radically gastroenterologic world, offering a new concept in patients' management. Over time, more medical data gave rise to diverse distant, extragastric manifestations and interactions of the "new" discovered bacterium. Special interest appeared within the field of neurodegenerative diseases and particularly Alzheimer's disease, as the latter and Helicobacter pylori infection are associated with a large public health burden and Alzheimer's disease ranks as the leading cause of disability. However, the relationship between Helicobacter pylori infection and Alzheimer's disease remains uncertain. METHODS We performed a narrative review regarding a possible connection between Helicobacter pylori and Alzheimer's disease. All accessible relevant (pre)clinical studies written in English were included. Both affected pathologies were briefly analyzed, and relevant studies are discussed, trying to focus on the possible pathogenetic role of this bacterium in Alzheimer's disease. RESULTS Data stemming from both epidemiologic studies and animal experiments seem to be rather encouraging, tending to confirm the hypothesis that Helicobacter pylori infection might influence the course of Alzheimer's disease pleiotropically. Possible main mechanisms may include the bacterium's access to the brain via the oral-nasal-olfactory pathway or by circulating monocytes (infected with Helicobacter pylori due to defective autophagy) through disrupted blood-brain barrier, thereby possibly triggering neurodegeneration. CONCLUSIONS Current data suggest that Helicobacter pylori infection might influence the pathophysiology of Alzheimer's disease. However, further large-scale randomized controlled trials are mandatory to clarify a possible favorable effect of Helicobacter pylori eradication on Alzheimer's disease pathophysiology, before the recommendation of short-term and cost-effective therapeutic regimens against Helicobacter pylori-related Alzheimer's disease.
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Affiliation(s)
- Michael Doulberis
- Department of Internal Medicine, Bürgerspital Hospital, Solothurn, Switzerland
| | - Georgios Kotronis
- Department of Internal Medicine, Agios Pavlos General Hospital, Thessaloniki, Macedonia, Greece
| | - Robert Thomann
- Department of Internal Medicine, Bürgerspital Hospital, Solothurn, Switzerland
| | - Stergios A Polyzos
- Department of Internal Medicine, Ippokration Hospital, Second Medical Clinic, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Marina Boziki
- Department of Internal Medicine, Ippokration Hospital, Second Medical Clinic, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Dimitra Gialamprinou
- Department of Pediatrics, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Georgia Deretzi
- Department of Neurology, Papageorgiou General Hospital, Multiple Sclerosis Unit, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Panagiotis Katsinelos
- Department of Internal Medicine, Ippokration Hospital, Second Medical Clinic, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Jannis Kountouras
- Department of Internal Medicine, Ippokration Hospital, Second Medical Clinic, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
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8
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Obesity and the nervous system: more questions. Lancet Neurol 2017; 16:772-773. [DOI: 10.1016/s1474-4422(17)30291-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 08/23/2017] [Indexed: 12/12/2022]
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Kountouras J, Deretzi G, Gavalas E, Zavos C, Boziki M, Tsiaousi E, Stergiopoulos C, Romiopoulos I, Giorgakis N, Michael S, Tantsi N, Kotsani M. Aquaporin 4, Helicobacter pylori and potential implications for neuromyelitis optica. J Neuroimmunol 2013; 263:162-3. [DOI: 10.1016/j.jneuroim.2013.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Revised: 06/06/2013] [Accepted: 06/10/2013] [Indexed: 10/26/2022]
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Zheng P, Chang X, Lu Q, Liu Y. Cytopenia and autoimmune diseases: a vicious cycle fueled by mTOR dysregulation in hematopoietic stem cells. J Autoimmun 2013; 41:182-7. [PMID: 23375848 DOI: 10.1016/j.jaut.2012.12.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 12/13/2012] [Indexed: 12/24/2022]
Abstract
A long-standing but poorly understood defect in autoimmune diseases is dysfunction of the hematopoietic cells. Leukopenia is often associated with systemic lupus erythematous (SLE) and other autoimmune diseases. In addition, homeostatic proliferation of T cells, which is a host response to T-cell lymphopenia, has been implicated as potential cause of rheumatoid arthritis (RA) in human and experimental models of autoimmune diabetes in the NOD mice and the BB rats. Conversely, successful treatments of aplastic anemia by immune suppression suggest that the hematologic abnormality may have a root in autoimmune diseases. Traditionally, the link between autoimmune diseases and defects in hematopoietic cells has been viewed from the prism of antibody-mediated hemolytic cytopenia. While autoimmune destruction may well be part of pathogenesis of defects in hematopoietic system, it is worth considering the hypothesis that either leukopenia or pancytopenia may also result directly from defective hematopoietic stem cells (HSC). We have recently tested this hypothesis in the autoimmune Scurfy mice which has mutation Foxp3, the master regulator of regulatory T cells. Our data demonstrated that due to hyperactivation of mTOR, the HSC in the Scurfy mice are extremely poor in hematopoiesis. Moreover, rapamycin, an mTOR inhibitor rescued HSC defects and prolonged survival of the Scurfy mice. Our data raised the intriguing possibility that targeting mTOR dysregulation in the HSC may help to break the vicious cycle between cytopenia and autoimmune diseases.
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Affiliation(s)
- Pan Zheng
- Department of Surgery, University of Michigan, School of Medicine, Ann Arbor, MI 48109, USA.
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Kountouras J, Zavos C, Gavalas E, Deretzi G, Tsona A, Katsinelos P, Grigoriadis S, Pilpilidis I, Tzilves D, Vardaka E, Mantzoukis K, Polyzos SA. A rebuttal to the potential anti-tumour benefit of Helicobacter pylori-induced neutrophil-activating protein. Cancer Immunol Immunother 2012; 61:445-6; discussion 447-51. [PMID: 22065048 PMCID: PMC11028557 DOI: 10.1007/s00262-011-1142-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 10/21/2011] [Indexed: 12/28/2022]
Affiliation(s)
- Jannis Kountouras
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Christos Zavos
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Emmanuel Gavalas
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Georgia Deretzi
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Afroditi Tsona
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Panagiotis Katsinelos
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Savas Grigoriadis
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Ioannis Pilpilidis
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Dimitrios Tzilves
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Elizabeth Vardaka
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Konstantinos Mantzoukis
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
| | - Stergios A. Polyzos
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece
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Kountouras J, Zavos C, Deretzi G, Gavalas E, Chatzopoulos D, Katsinelos P, Tsiaousi E, Gagalis S, Polyzos SA, Venizelos I. Potential implications of Helicobacter pylori-related neutrophil-activating protein. World J Gastroenterol 2012; 18:489-90. [PMID: 22346256 PMCID: PMC3270508 DOI: 10.3748/wjg.v18.i5.489] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Revised: 08/18/2011] [Accepted: 08/27/2011] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) virulence factors promote the release of various chemoattractants/inflammatory mediators, including mainly the neutrophil-attractant chemokine interleukin-8 and neutrophil-activating protein (NAP), involved in H. pylori-induced gastric pathologies. Co-administration of Chios mastic gum (CMG), which inhibits H. pylori NAP, with an H. pylori eradication regimen might add clinical benefits against H. pylori-related gastric pathologies, but possibly not CMG as main therapy. Although H. pylori NAP and other H. pylori-related cytotoxins [i.e., vaculating cytotoxin (VacA)] appear to play a major role in generating and maintaining the H. pylori-associated gastric inflammatory response and H. pylori NAP is a promising vaccine candidate against H. pylori infection (H. pylori-I), concerns regarding its potential drawbacks, particularly neurogenic ones, due to possible cross-mimicry, should be considered. Possible cross-mimicry between H. pylori NAP and/or bacterial aquaporin (AQP) and neural tissues may be associated with the anti-AQP-4 antibody-related neural damage in multiple sclerosis (MS)/neuromyelitis optica patients. Moreover, the sequence homology found between H. pylori VacA and human Na+/K+-ATPase A subunit suggests that antibodies to VacA involve ion channels in abaxonal Schwann cell plasmalemma resulting in demyelination in some patients. A series of factors have been implicated in inducing blood-brain barrier (BBB) disruption, including inflammatory mediators (e.g., cytokines and chemokines induced by H. pylori-I) and oxidative stress. BBB disruption permits access of AQP4-specific antibodies and T lymphocytes to the central nervous system, thereby playing a major role in multiple sclerosis pathogenesis. Relative studies show a strong association between H. pylori-I and MS. H. pylori-I induces humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of nerves, thereby contributing and perpetuating neural tissue damage. Finally, H. pylori NAP also plays a possible pathogenetic role in both gastric and colon oncogenesis.
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Codolo G, Fassan M, D’Elios MM, de Bernard M. HP-NAP new therapy for bladder cancer: numquam periculum sine periculo vincitur. Cancer Immunol Immunother 2011; 61:447-448. [PMCID: PMC11029137 DOI: 10.1007/s00262-011-1145-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Accepted: 10/23/2011] [Indexed: 10/15/2022]
Affiliation(s)
- Gaia Codolo
- Department of Biology, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy
- Venetian Institute of Molecular Medicine, V. Orus 2, 35129 Padua, Italy
| | - Matteo Fassan
- Department of Medical Diagnostic Sciences and Special Therapies, Surgical Pathology and Cytopathology Unit, University of Padua, Via A. Gabelli 61, 35121 Padua, Italy
| | - Mario M. D’Elios
- Department of Internal Medicine, University of Firenze, Viale Morgagni 85, 50134 Florence, Italy
| | - Marina de Bernard
- Department of Biology, University of Padua, Via U. Bassi 58/B, 35121 Padua, Italy
- Venetian Institute of Molecular Medicine, V. Orus 2, 35129 Padua, Italy
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Helicobacter pylori and the Guillain-Barré syndrome: The evidence is lacking. J Neurol Sci 2011. [DOI: 10.1016/j.jns.2011.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Kountouras J, Zavos C, Deretzi G, Polyzos SA, Gavalas E, Tsiaousi E, Giartza-Taxidou E, Chatzopoulos D, Michael S, Tsarouchas G. Neuroprotection in glaucoma: Is there a future role of Helicobacter pylori eradication? Exp Eye Res 2011; 92:436-8. [DOI: 10.1016/j.exer.2011.02.017] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Revised: 02/15/2011] [Accepted: 02/24/2011] [Indexed: 11/28/2022]
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Kountouras J, Deretzi G, Zavos C, Tsiptsios D, Gavalas E, Vardaka E, Polyzos SA, Klonizakis P, Kyriakou P. Helicobacter pylori infection may trigger Guillain-Barré syndrome, Fisher syndrome and Bickerstaff brainstem encephalitis. J Neurol Sci 2011; 305:167-8; author reply 169. [PMID: 21440259 DOI: 10.1016/j.jns.2011.03.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Accepted: 03/03/2011] [Indexed: 01/26/2023]
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Kountouras J, Gavalas E, Deretzi G, Boziki M, Zavos C, Chatzopoulos D, Katsinelos P, Giartza-Taxidou E, Grigoriadis N, Venizelos I. Helicobacter pylori with or without its neutrophil-activating protein may be the common denominator associated with multiple sclerosis and neuromyelitis optica. Mult Scler 2010; 16:376-7; author reply 378-9. [PMID: 20203152 DOI: 10.1177/1352458509360550] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Pithadia AB, Kakadia N. Guillain-Barré syndrome (GBS). Pharmacol Rep 2010; 62:220-32. [PMID: 20508277 DOI: 10.1016/s1734-1140(10)70261-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2009] [Revised: 10/20/2009] [Indexed: 10/25/2022]
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Deretzi G, Kountouras J, Grigoriadis N, Zavos C, Chatzigeorgiou S, Koutlas E, Tsiptsios I. From the "little brain" gastrointestinal infection to the "big brain" neuroinflammation: a proposed fast axonal transport pathway involved in multiple sclerosis. Med Hypotheses 2009; 73:781-7. [PMID: 19467574 DOI: 10.1016/j.mehy.2009.04.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2009] [Revised: 04/04/2009] [Accepted: 04/08/2009] [Indexed: 12/14/2022]
Abstract
The human central nervous system (CNS) is targeted by different pathogens which, apart from pathogens' intranasal inoculation or trafficking into the brain through infected blood cells, may use a distinct pathway to bypass the blood-brain barrier by using the gastrointestinal tract (GIT) retrograde axonal transport through sensory or motor fibres. The recent findings regarding the enteric nervous system (often called the "little brain") similarities with CNS and GIT axonal transport of infections resulting in CNS neuroinflammation are mainly reviewed in this article. We herein propose that the GIT is the vulnerable area through which pathogens (such as Helicobacter pylori) may influence the brain and induce multiple sclerosis pathologies, mainly via the fast axonal transport by the afferent neurones connecting the GIT to brain.
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Affiliation(s)
- Georgia Deretzi
- Department of Neurology, Papageorgiou Regional General Hospital, Thessaloniki, Greece
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Eradication of Helicobacter pylori may be beneficial in the management of Alzheimer’s disease. J Neurol 2009; 256:758-67. [DOI: 10.1007/s00415-009-5011-z] [Citation(s) in RCA: 136] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2008] [Revised: 11/26/2008] [Accepted: 12/10/2008] [Indexed: 12/13/2022]
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