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Vallejo-Cremades M, Merino J, Carmona R, Córdoba L, Salvador B, Martínez L, Tovar JA, Llamas MÁ, Muñoz-Chápuli R, Fresno M. Toll-like receptors ligand immunomodulators for the treatment congenital diaphragmatic hernia. Orphanet J Rare Dis 2024; 19:386. [PMID: 39425191 PMCID: PMC11487987 DOI: 10.1186/s13023-024-03384-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 09/23/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Congenital diaphragmatic hernia (CDH) is a rare disease that affects the development of the diaphragm, leading to abnormal lung development. Unfortunately, there is no established therapy for CDH. Retinoic acid pathways are implicated in the ethology of CDH and macrophages are known to play a role in repairing organ damage. METHODS We have analyzed the effect of several Toll like receptor (TLR) ligands in the nitrofen-induced CDH model in pregnant rats widely used to study this disease and in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Morphometric and histological studies were carried out. Immune cell infiltration was assayed by immunochemistry and immunofluorescence and retinoic pathway gene expression analyzed in vivo and in vitro in macrophages. RESULTS We found that administering a single dose of atypical TLR2/4 ligands (CS1 or CS2), 3 days after nitrofen, cured diaphragmatic hernia in 73% of the fetuses and repaired the lesion with complete diaphragm closure being on the other hand nontoxic for the mothers or pups. Moreover, these immunomodulators also improved pulmonary hypoplasia and alveolar maturation and vessel hypertrophy, enhancing pulmonary maturity of fetuses. We also found that CS1 treatment rescued the CDH phenotype in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Only 1 out of 11 mutant embryos showed CDH after CS1 administration, whereas CDH prevalence was 70% in untreated mutant embryos. Mechanistically, CS1 stimulated the infiltration of repairing M2 macrophages (CD206+ and Arg1+) into the damaged diaphragm and reduced T cell infiltration. Additionally, those TLR ligands induced retinol pathway genes, including RBP1, RALDH2, RARα, and RARβ, in the affected lungs and the diaphragm and in macrophages in vitro. CONCLUSIONS Our research has shown that TLR ligand immunomodulators that influence anti-inflammatory macrophage activation can be effective in treating CDH, being nontoxic for the mothers or pups suggesting that those TLR ligands are a promising solution for CDH leading to orphan drug designation for CS1. The immune system of the fetus would be responsible for repairing the damage and closure of the hernia in the diaphragm and enhanced proper lung development after CS1 treatment.
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Affiliation(s)
| | - Javier Merino
- Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, Madrid, Spain
| | | | - Laura Córdoba
- Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, Madrid, Spain
| | | | | | | | | | | | - Manuel Fresno
- Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, Madrid, Spain.
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Li R, Li H, Yang X, Hu H, Liu P, Liu H. Crosstalk between dendritic cells and regulatory T cells: Protective effect and therapeutic potential in multiple sclerosis. Front Immunol 2022; 13:970508. [PMID: 36177043 PMCID: PMC9513370 DOI: 10.3389/fimmu.2022.970508] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system related to autoimmunity and is characterized by demyelination, neuroinflammation, and neurodegeneration. Cell therapies mediated by dendritic cells (DCs) and regulatory T cells (Tregs) have gradually become accumulating focusing in MS, and the protective crosstalk mechanisms between DCs and Tregs provide the basis for the efficacy of treatment regimens. In MS and its animal model experimental autoimmune encephalomyelitis, DCs communicate with Tregs to form immune synapses and complete a variety of complex interactions to counteract the unbalanced immune tolerance. Through different co-stimulatory/inhibitory molecules, cytokines, and metabolic enzymes, DCs regulate the proliferation, differentiation and function of Tregs. On the other hand, Tregs inhibit the mature state and antigen presentation ability of DCs, ultimately improving immune tolerance. In this review, we summarized the pivotal immune targets in the interaction between DCs and Tregs, and elucidated the protective mechanisms of DC-Treg cell crosstalk in MS, finally interpreted the complex cell interplay in the manner of inhibitory feedback loops to explore novel therapeutic directions for MS.
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Affiliation(s)
- Ruoyu Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hui Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyan Yang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huiru Hu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Peidong Liu
- Department of Neurosurgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Translational Medicine Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hongbo Liu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Translational Medicine Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Hongbo Liu,
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Chienwichai P, Nogrado K, Tipthara P, Tarning J, Limpanont Y, Chusongsang P, Chusongsang Y, Tanasarnprasert K, Adisakwattana P, Reamtong O. Untargeted serum metabolomic profiling for early detection of Schistosoma mekongi infection in mouse model. Front Cell Infect Microbiol 2022; 12:910177. [PMID: 36061860 PMCID: PMC9433908 DOI: 10.3389/fcimb.2022.910177] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
Mekong schistosomiasis is a parasitic disease caused by blood flukes in the Lao People’s Democratic Republic and in Cambodia. The standard method for diagnosis of schistosomiasis is detection of parasite eggs from patient samples. However, this method is not sufficient to detect asymptomatic patients, low egg numbers, or early infection. Therefore, diagnostic methods with higher sensitivity at the early stage of the disease are needed to fill this gap. The aim of this study was to identify potential biomarkers of early schistosomiasis using an untargeted metabolomics approach. Serum of uninfected and S. mekongi-infected mice was collected at 2, 4, and 8 weeks post-infection. Samples were extracted for metabolites and analyzed with a liquid chromatography-tandem mass spectrometer. Metabolites were annotated with the MS-DIAL platform and analyzed with Metaboanalyst bioinformatic tools. Multivariate analysis distinguished between metabolites from the different experimental conditions. Biomarker screening was performed using three methods: correlation coefficient analysis; feature important detection with a random forest algorithm; and receiver operating characteristic (ROC) curve analysis. Three compounds were identified as potential biomarkers at the early stage of the disease: heptadecanoyl ethanolamide; picrotin; and theophylline. The levels of these three compounds changed significantly during early-stage infection, and therefore these molecules may be promising schistosomiasis markers. These findings may help to improve early diagnosis of schistosomiasis, thus reducing the burden on patients and limiting spread of the disease in endemic areas.
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Affiliation(s)
- Peerut Chienwichai
- Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Kathyleen Nogrado
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Phornpimon Tipthara
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Joel Tarning
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
| | - Yanin Limpanont
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Phiraphol Chusongsang
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Yupa Chusongsang
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Kanthi Tanasarnprasert
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Poom Adisakwattana
- Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Onrapak Reamtong
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- *Correspondence: Onrapak Reamtong,
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Regulatory significance of CULLIN2 in neuronal differentiation and regeneration. Neurochem Int 2022; 159:105386. [PMID: 35803325 DOI: 10.1016/j.neuint.2022.105386] [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: 12/18/2021] [Revised: 05/05/2022] [Accepted: 06/27/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Scaffold proteins coordinate multiple signalling pathways by integrating various proteins but the role of these proteins in neuronal pathways remains to be elucidated. The present study focused to evaluate the expression of the scaffold protein CULLIN2 in neuronal cells. METHODS The neuronal precursor cell line N2A was differentiated to neurons in-vitro with retinoic acid and biochemical assays were used to understand the gene expression profiling of CULLIN2. Moreover, neddylation inhibitor MLN4924 was used to inhibit the activity of CULLIN2 and the downstream substrates were validated. Finally, the role of CULLIN2 in nerve regeneration was evaluated in an in vivo zebrafish model. RESULTS Experimental data showed that the neuronal cells N2A have lower expression of CULLIN2 compared to skin cell lines (HaCaT and A431) and inactivation with the neddylation inhibitor resulted in cell death. Furthermore differentiating the neural precursor cell line into neurons with retinoic acid enhanced the expression of CULLIN2. Examining downstream signalling molecules with the neddylation inhibitor illuminates that MLN4924 treatment influences the cytokine signalling cascade (JAK-STAT) in neuronal cells. Moreover, for the first time, we show that the ubiquitin ligase protein CULLIN2 is perturbed in neural regeneration. Expression profile of CULLIN2 was significantly decreased in response to a nerve injury in Zebra fish and as the nerve regenerates there is corresponding reduction in the mRNA levels. CONCLUSION During differentiation CULLIN2 is upregulated whereas during regeneration there is significant downregulation. Thus, our findings reveal a crucial role of the scaffold protein CULLIN2 in nerve differentiation and regeneration which can be vital for the treatment of nerve injury.
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Moulson AJ, Av-Gay Y. BCG immunomodulation: From the 'hygiene hypothesis' to COVID-19. Immunobiology 2021; 226:152052. [PMID: 33418320 PMCID: PMC7833102 DOI: 10.1016/j.imbio.2020.152052] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/07/2020] [Accepted: 12/17/2020] [Indexed: 12/23/2022]
Abstract
The century-old tuberculosis vaccine BCG has been the focus of renewed interest due to its well-documented ability to protect against various non-TB pathogens. Much of these broad spectrum protective effects are attributed to trained immunity, the epigenetic and metabolic reprogramming of innate immune cells. As BCG vaccine is safe, cheap, widely available, amendable to use as a recombinant vector, and immunogenic, it has immense potential for use as an immunotherapeutic agent for various conditions including autoimmune, allergic, neurodegenerative, and neoplastic diseases as well as a preventive measure against infectious agents. Of particular interest is the use of BCG vaccination to counteract the increasing prevalence of autoimmune and allergic conditions in industrialized countries attributable to reduced infectious burden as described by the 'hygiene hypothesis.' Furthermore, BCG vaccination has been proposed as a potential therapy to mitigate spread and disease burden of COVID-19 as a bridge to development of a specific vaccine and recombinant BCG expression vectors may prove useful for the introduction of SARS-CoV-2 antigens (rBCG-SARS-CoV-2) to induce long-term immunity. Understanding the immunomodulatory effects of BCG vaccine in these disease contexts is therefore critical. To that end, we review here BCG-induced immunomodulation focusing specifically on BCG-induced trained immunity and how it relates to the 'hygiene hypothesis' and COVID-19.
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Affiliation(s)
- Aaron J Moulson
- Faculty of Medicine, University of British Columbia, Vancouver, Canada.
| | - Yossef Av-Gay
- Faculty of Medicine, University of British Columbia, Vancouver, Canada; Division of Infectious Disease, University of British Columbia, Vancouver, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
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Ruiter B, Smith NP, Fleming E, Patil SU, Hurlburt BK, Maleki SJ, Shreffler WG. Peanut protein acts as a T H2 adjuvant by inducing RALDH2 in human antigen-presenting cells. J Allergy Clin Immunol 2020; 148:182-194.e4. [PMID: 33378690 DOI: 10.1016/j.jaci.2020.11.047] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/26/2020] [Accepted: 11/26/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Peanut is a potent inducer of proallergenic TH2 responses in susceptible individuals. Antigen-presenting cells (APCs) including dendritic cells and monocytes instruct naive T cells to differentiate into various effector cells, determining immune responses such as allergy and tolerance. OBJECTIVE We sought to detect peanut protein (PN)-induced changes in gene expression in human myeloid dendritic cells (mDCs) and monocytes, identify signaling receptors that mediate these changes, and assess how PN-induced genes in mDCs impact their ability to promote T-cell differentiation. METHODS mDCs, monocytes, and naive CD4+ T cells were isolated from blood bank donors and peanut-allergic patients. APCs were incubated with PN and other stimulants, and gene expression was measured using microarray and RT quantitative PCR. To assess T-cell differentiation, mDCs were cocultured with naive TH cells. RESULTS PN induced a unique gene expression profile in mDCs, including the gene that encodes retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in the retinoic acid (RA)-producing pathway. Stimulation of mDCs with PN also induced a 7-fold increase in the enzymatic activity of RALDH2. Blocking antibodies against Toll-like receptor (TLR)1/TLR2, as well as small interfering RNA targeting TLR1/TLR2, reduced the expression of RALDH2 in PN-stimulated APCs by 70%. Naive TH cells cocultured with PN-stimulated mDCs showed an RA-dependent 4-fold increase in production of IL-5 and expression of integrin α4β7. CONCLUSIONS PN induces RALDH2 in human APCs by signaling through the TLR1/TLR2 heterodimer. This leads to production of RA, which acts on TH cells to induce IL-5 and gut-homing integrin. RALDH2 induction by PN in APCs and RA-promoted TH2 differentiation could be an important factor determining allergic responses to peanut.
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Affiliation(s)
- Bert Ruiter
- Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, Mass; Harvard Medical School, Boston, Mass.
| | - Neal P Smith
- Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, Mass
| | - Elizabeth Fleming
- Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, Mass
| | - Sarita U Patil
- Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, Mass; Harvard Medical School, Boston, Mass; Food Allergy Center, Massachusetts General Hospital, Boston, Mass
| | - Barry K Hurlburt
- US Department of Agriculture, Agricultural Research Service, New Orleans, La
| | - Soheila J Maleki
- US Department of Agriculture, Agricultural Research Service, New Orleans, La
| | - Wayne G Shreffler
- Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, Mass; Harvard Medical School, Boston, Mass; Food Allergy Center, Massachusetts General Hospital, Boston, Mass
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Vanhamme L, Souopgui J, Ghogomu S, Ngale Njume F. The Functional Parasitic Worm Secretome: Mapping the Place of Onchocerca volvulus Excretory Secretory Products. Pathogens 2020; 9:pathogens9110975. [PMID: 33238479 PMCID: PMC7709020 DOI: 10.3390/pathogens9110975] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 01/15/2023] Open
Abstract
Nematodes constitute a very successful phylum, especially in terms of parasitism. Inside their mammalian hosts, parasitic nematodes mainly dwell in the digestive tract (geohelminths) or in the vascular system (filariae). One of their main characteristics is their long sojourn inside the body where they are accessible to the immune system. Several strategies are used by parasites in order to counteract the immune attacks. One of them is the expression of molecules interfering with the function of the immune system. Excretory-secretory products (ESPs) pertain to this category. This is, however, not their only biological function, as they seem also involved in other mechanisms such as pathogenicity or parasitic cycle (molting, for example). We will mainly focus on filariae ESPs with an emphasis on data available regarding Onchocerca volvulus, but we will also refer to a few relevant/illustrative examples related to other worm categories when necessary (geohelminth nematodes, trematodes or cestodes). We first present Onchocerca volvulus, mainly focusing on the aspects of this organism that seem relevant when it comes to ESPs: life cycle, manifestations of the sickness, immunosuppression, diagnosis and treatment. We then elaborate on the function and use of ESPs in these aspects.
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Affiliation(s)
- Luc Vanhamme
- Department of Molecular Biology, Institute of Biology and Molecular Medicine, IBMM, Université Libre de Bruxelles, Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium; (J.S.); (F.N.N.)
- Correspondence:
| | - Jacob Souopgui
- Department of Molecular Biology, Institute of Biology and Molecular Medicine, IBMM, Université Libre de Bruxelles, Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium; (J.S.); (F.N.N.)
| | - Stephen Ghogomu
- Molecular and Cell Biology Laboratory, Biotechnology Unit, University of Buea, Buea P.O Box 63, Cameroon;
| | - Ferdinand Ngale Njume
- Department of Molecular Biology, Institute of Biology and Molecular Medicine, IBMM, Université Libre de Bruxelles, Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium; (J.S.); (F.N.N.)
- Molecular and Cell Biology Laboratory, Biotechnology Unit, University of Buea, Buea P.O Box 63, Cameroon;
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Stefanson A, Bakovic M. Dietary polyacetylene falcarinol upregulated intestinal heme oxygenase-1 and modified plasma cytokine profile in late phase lipopolysaccharide-induced acute inflammation in CB57BL/6 mice. Nutr Res 2020; 80:89-105. [PMID: 32738564 DOI: 10.1016/j.nutres.2020.06.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/17/2020] [Indexed: 12/19/2022]
Abstract
Unlike polyphenols, which are widely available in the diet, polyacetylenes are available only from the Apiaceae family vegetables, including carrot, parsnip, fennel, celery, and many herbs (parsley, lovage, etc). The aim of this study was to investigate the hypothesis that polyacetylene falcarinol (FA) reduces intestinal inflammation and examine its similarity of effect to isothiocyanate R-sulforaphane during the late phase of acute inflammation. To this end, 3-month-old male CB57BL/6 mice were fed twice daily for 1 week with 5 mg/kg of FA, sulforaphane, or vehicle before receiving an intraperitoneal injection of 5 mg/kg endotoxin (lipopolysaccharide [LPS]) to induce modest acute inflammation. The expression of intestinal and hepatic heme oxygenase-1 at the mRNA and protein levels, circulating cytokines, as well as intestinal and mesenteric n-6 and n-3 fatty acid lipid mediators was compared 24 hours after LPS administration to examine its effects on the late phase of inflammation. Intestinal nuclear factor (erythroid-derived 2)-like 2 target enzyme heme oxygenase-1 was upregulated 8.42-fold at the mRNA level and 10.7-fold at the protein level by FA-supplemented diet. However, the FA-supplemented diet produced a unique type-2 plasma cytokine skew after LPS treatment. Plasma cytokines interleukin (IL)-4, IL-13, IL-9, and IL-10 were upregulated, reflecting the cytokine profile of reduced type 1 inflammation. A detailed lipidomic analysis of n-6 and n-3 fatty acid pro- and anti-inflammatory pathways in the mesentery and intestinal mucosa showed that FA diet was more similar to the control groups than to other LPS treated groups. In this study, we demonstrated that FA-supplemented diet produced a unique immunomodulatory effect not observed with sulforaphane in late phases of inflammation. These results support the hypothesis that FA may have role as a dietary immunosuppressant in patients with inflammatory gastrointestinal as well as other inflammatory disorders that may be alleviated by increasing consumption of carrot or other FA-containing food sources.
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Affiliation(s)
- Amanda Stefanson
- Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Rd E, Guelph, Ontario, Canada N1G 2W1.
| | - Marica Bakovic
- Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Rd E, Guelph, Ontario, Canada N1G 2W1.
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Accelerated onset of CNS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase. Sci Rep 2020; 10:4554. [PMID: 32165661 PMCID: PMC7067812 DOI: 10.1038/s41598-020-61483-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 02/27/2020] [Indexed: 01/12/2023] Open
Abstract
Prion infections in the central nervous system (CNS) can cause extensive neurodegeneration. Systemic inflammation can affect the progression of some neurodegenerative disorders. Therefore, we used the gastrointestinal helminth pathogen Trichuris muris to test the hypothesis that a chronic systemic inflammatory response to a gastrointestinal infection would similarly affect CNS prion disease pathogenesis. Mice were injected with prions directly into the CNS and subsequently orally co-infected with T. muris before the onset of clinical signs. We show that co-infection with a low dose of T. muris that leads to the development of a chronic T helper cell type 1-polarized systemic immune response accelerated the onset of clinical prion disease. In contrast, co-infection with a high dose of T. muris that induces a T helper cell type 2-polarized immune response did not affect prion disease pathogenesis. The reduced survival times in mice co-infected with a low dose of T. muris on d 105 after CNS prion infection coincided with enhanced astrocyte activation in the brain during the preclinical phase. These data aid our understanding of how systemic inflammation may augment the progression of neurodegeneration in the CNS.
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Rakebrandt N, Joller N. Infection History Determines Susceptibility to Unrelated Diseases. Bioessays 2020; 41:e1800191. [PMID: 31132173 DOI: 10.1002/bies.201800191] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 04/04/2019] [Indexed: 12/11/2022]
Abstract
Epidemiological data suggest that previous infections can alter an individual's susceptibility to unrelated diseases. Nevertheless, the underlying mechanisms are not completely understood. Substantial research efforts have expanded the classical concept of immune memory to also include long-lasting changes in innate immunity and antigen-independent reactivation of adaptive immunity. Collectively, these processes provide possible explanations on how acute infections might induce long-term changes that also affect immunity to unrelated diseases. Here, we review lasting changes the immune compartment undergoes upon infection and how infection experience alters the responsiveness of immune cells towards universal signals. This heightened state of alert enhances the ability of the immune system to combat even unrelated infections but may also increase susceptibility to autoimmunity. At the same time, infection-induced changes in the regulatory compartment may dampen subsequent immune responses and promote pathogen persistence. The concepts presented here outline how infection-induced changes in the immune system may affect human health.
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Affiliation(s)
- Nikolas Rakebrandt
- Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
| | - Nicole Joller
- Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
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Wolde M, Laan LC, Medhin G, Gadissa E, Berhe N, Tsegaye A. Human Monocytes/Macrophage Inflammatory Cytokine Changes Following in vivo and in vitro Schistomam manoni Infection. J Inflamm Res 2020; 13:35-43. [PMID: 32021377 PMCID: PMC6970607 DOI: 10.2147/jir.s233381] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 12/06/2019] [Indexed: 11/23/2022] Open
Abstract
Introduction Epidemiological and animal studies indicate that helminth infections have positive effects due to their potential to protect against autoimmune diseases. Here, we aim to assess the effect of S. mansoni infection on immune modulation of human monocytes and their potential protection against autoimmune disease development both in vivo and in vitro. Materials and Methods Monocytes were isolated from helminth-infected Ethiopians (MHIE), and from Dutch healthy volunteers (MHV). The MHV were stimulated in vitro with S. mansoni soluble egg antigens (SEA) or soluble worm antigens (SWA). In addition, phenotypical changes were studied directly, as well as after culturing for 6 days in the presence of human serum to obtain macrophages. Q-PCR, flow cytometry, multiplex bead immunoassay, and live-cell imaging were employed during analysis. Results MHIE showed elevated transcripts of SOCS-1 and TNF-α compared to MHV. Similarly, MHV that were stimulated with SEA demonstrated enhanced levels of SOCS-1, IL-10, and IL-12 mRNA, compared to control MHV. Remarkably, the SEA-treated monocytes showed a much higher motility than control monocytes, a hallmark of a patrolling phenotype. Furthermore, in vitro cultured macrophages that were stimulated by SEA exhibited enhanced mRNA levels of SOCS-1, IL-10, TNF-α, IL-12 and TGF-β, compared to control macrophages. Conclusion Macrophages from MHIE as well as SEA-treated MHV show an intermediate activation phenotype with both pro-inflammatory and anti-inflammatory characteristics in vitro. The observed pro-inflammatory properties might reflect a recent response of the cells due to contact with a pathogen, whereas the anti-inflammatory properties might contribute to helminth-induced protection against inflammatory diseases. Large-scale study is recommended to consolidate the findings of the present study. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/SYOVExqwTRU
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Affiliation(s)
- Mistire Wolde
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia.,Department of Medical Laboratory Sciences, College of Health Science, Addis Ababa University, Addis Ababa, Ethiopia
| | - Lisa C Laan
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, the Netherlands
| | - Girmay Medhin
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
| | | | - Nega Berhe
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia.,Oslo University Hospital-Ulleval, Centre for Imported and Tropical Diseases, Oslo, Norway
| | - Aster Tsegaye
- Department of Medical Laboratory Sciences, College of Health Science, Addis Ababa University, Addis Ababa, Ethiopia
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Verma P, Kureel AK, Saini S, Prakash S, Kumari S, Kottarath SK, Srivastava SK, Bhat M, Dinda AK, Thakur CP, Sharma S, Rai AK. Leishmania donovani reduces the levels of retinoic acid-synthesizing enzymes in infected macrophages and favoring its own survival. Parasitol Res 2018; 118:63-71. [PMID: 30338372 DOI: 10.1007/s00436-018-6115-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 10/07/2018] [Indexed: 11/29/2022]
Abstract
People suffering from malnutrition become susceptible to the infection like Leishmania sp., as it results in a compromised immune response. Retinoic acid (RA), an important constituent of nutrition, shows an immune-modulatory activity. However, its role in the containment of infection is not yet ascertained, particularly in case of visceral leishmaniasis (VL). VL patients (n = 10) and healthy endemic controls (n = 9) were recruited to measure the serum levels of RA. An in vitro model of Leishmania infection using the murine mφ cell line J774.1 was used to investigate the RA-synthesizing enzymes (RALDH-1 and RALDH-2). Parasite loads among infected mφ were measured by quantitative expression of kDNA in the presence of an inhibitor of the RALDH-2 enzyme. We found a significant decrease in the serum levels of RA in VL cases. Importantly, we observed decreased levels of RALDH-1 and RALDH-2 among L. donovani-infected mφ along with simultaneous decrease as well as increase in the Th-1 and Th-2-associated factors, respectively. Furthermore, the pretreatment of mφ with an RALDH-2 inhibitor improved parasite in vitro infection. Our findings show impaired RA pathway among infected mφ and indicate that an intact RA pathway is critical for anti-Leishmania immune response. Graphical abstract ᅟ.
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Affiliation(s)
- Pankaj Verma
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, 211004, India
| | - Amit Kumar Kureel
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, 211004, India
| | - Sheetal Saini
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, 211004, India
| | - Satya Prakash
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, 211004, India
| | - Smita Kumari
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, 211004, India
| | - Sarath Kumar Kottarath
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | | | - Madhusudan Bhat
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Amit Kumar Dinda
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | | | - Shivesh Sharma
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, 211004, India
| | - Ambak Kumar Rai
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, 211004, India.
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13
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Zakeri A, Hansen EP, Andersen SD, Williams AR, Nejsum P. Immunomodulation by Helminths: Intracellular Pathways and Extracellular Vesicles. Front Immunol 2018; 9:2349. [PMID: 30369927 PMCID: PMC6194161 DOI: 10.3389/fimmu.2018.02349] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 09/21/2018] [Indexed: 12/13/2022] Open
Abstract
Helminth parasites are masters at manipulating host immune responses, using an array of sophisticated mechanisms. One of the major mechanisms enabling helminths to establish chronic infections is the targeting of pattern recognition receptors (PRRs) including toll-like receptors, C-type lectin receptors, and the inflammasome. Given the critical role of these receptors and their intracellular pathways in regulating innate inflammatory responses, and also directing adaptive immunity toward Th1 and Th2 responses, recognition of the pathways triggered and/or modulated by helminths and their products will provide detailed insights about how helminths are able to establish an immunoregulatory environment. However, helminths also target PRRs-independent mechanisms (and most likely other yet unknown mechanisms and pathways) underpinning the battery of different molecules helminths produce. Herein, the current knowledge on intracellular pathways in antigen presenting cells activated by helminth-derived biomolecules is reviewed. Furthermore, we discuss the importance of helminth-derived vesicles as a less-appreciated components released during infection, their role in activating these host intracellular pathways, and their implication in the development of new therapeutic approaches for inflammatory diseases and the possibility of designing a new generation of vaccines.
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Affiliation(s)
- Amin Zakeri
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Eline P. Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Sidsel D. Andersen
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Andrew R. Williams
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Peter Nejsum
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
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14
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Rook G, Bäckhed F, Levin BR, McFall-Ngai MJ, McLean AR. Evolution, human-microbe interactions, and life history plasticity. Lancet 2017; 390:521-530. [PMID: 28792414 DOI: 10.1016/s0140-6736(17)30566-4] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Revised: 09/02/2016] [Accepted: 12/20/2016] [Indexed: 02/07/2023]
Abstract
A bacterium was once a component of the ancestor of all eukaryotic cells, and much of the human genome originated in microorganisms. Today, all vertebrates harbour large communities of microorganisms (microbiota), particularly in the gut, and at least 20% of the small molecules in human blood are products of the microbiota. Changing human lifestyles and medical practices are disturbing the content and diversity of the microbiota, while simultaneously reducing our exposures to the so-called old infections and to organisms from the natural environment with which human beings co-evolved. Meanwhile, population growth is increasing the exposure of human beings to novel pathogens, particularly the crowd infections that were not part of our evolutionary history. Thus some microbes have co-evolved with human beings and play crucial roles in our physiology and metabolism, whereas others are entirely intrusive. Human metabolism is therefore a tug-of-war between managing beneficial microbes, excluding detrimental ones, and channelling as much energy as is available into other essential functions (eg, growth, maintenance, reproduction). This tug-of-war shapes the passage of each individual through life history decision nodes (eg, how fast to grow, when to mature, and how long to live).
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Affiliation(s)
- Graham Rook
- Centre for Clinical Microbiology, Department of Infection, UCL (University College London), London, UK.
| | - Fredrik Bäckhed
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Bruce R Levin
- Department of Biology, Emory University, Atlanta, GA, USA
| | | | - Angela R McLean
- Department of Zoology, University of Oxford, South Parks Road, Oxford, UK
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15
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Wuhao L, Ran C, Xujin H, Zhongdao W, Dekumyoy P, Zhiyue L. Parasites and asthma. Parasitol Res 2017; 116:2373-2383. [PMID: 28689246 DOI: 10.1007/s00436-017-5548-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 06/26/2017] [Indexed: 11/30/2022]
Abstract
Nowadays, many studies have found low morbidity of asthma in epidemic areas of parasitic diseases, as shown by the hygiene hypothesis. It is obvious that some parasite infections can prevent asthma and studies have been carried out to clarify the mechanism of the preventive effect and search for the future asthmatic therapies. Previous findings have indicated that this mechanism may be related to the immune response switching from Th1 to Th2 and important cells induced by parasites, including the regulatory T cells, regulatory B cells, dendrite cells, and alternatively activated macrophages. Cytokine IL-10 also plays a nonredundant role in protection against allergic airway inflammation in asthma. This review focuses on the relationship between parasites and asthma, and the potential protection mechanism involved.
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Affiliation(s)
- Lin Wuhao
- Zhongshan School of Medicine, Sun Yat-sen University, 74 2nd Zhongshan Road, Guangzhou, 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China
| | - Chen Ran
- Zhongshan School of Medicine, Sun Yat-sen University, 74 2nd Zhongshan Road, Guangzhou, 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China
| | - He Xujin
- The Affiliated High School of South China Normal University, Guangzhou, 510630, China
| | - Wu Zhongdao
- Zhongshan School of Medicine, Sun Yat-sen University, 74 2nd Zhongshan Road, Guangzhou, 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Paron Dekumyoy
- Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand.
| | - Lv Zhiyue
- Zhongshan School of Medicine, Sun Yat-sen University, 74 2nd Zhongshan Road, Guangzhou, 510080, China. .,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China. .,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China.
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16
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Parande Shirvan S, Ebrahimby A, Dousty A, Maleki M, Movassaghi A, Borji H, Haghparast A. Somatic extracts of Marshallagia marshalli downregulate the Th2 associated immune responses in ovalbumin-induced airway inflammation in BALB/c mice. Parasit Vectors 2017; 10:233. [PMID: 28494800 PMCID: PMC5427607 DOI: 10.1186/s13071-017-2159-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 04/25/2017] [Indexed: 12/26/2022] Open
Abstract
Background Recently the role of gastrointestinal nematodes in modulating the immune responses in inflammatory and immune-mediated conditions such as allergy and autoimmune diseases has been introduced. This is mainly due to the suppressive effects of somatic and excretory secretory (ES) products of nematodes on the immune responses. In this study, we evaluated the immunomodulatory potentials of somatic products of Marshallagia marshalli, a gastrointestinal nematodes of sheep, to suppress the immune-mediated responses in a murine model of allergic airway inflammation. BALB/c mice were intraperitoneally (IP) sensitized with ovalbumin (OVA)/Alum and then challenged with 1% OVA. Somatic products of M. marshalli were administered during each sensitization. The effects of somatic products on development of allergic airway inflammation were evaluated by analyzing inflammatory cells recruitment, histopathological changes, cytokines production (IL-4, IL-13, IL-10, TGF-β) and serum antibody titers (IgG1, IgG2a). Results Somatic products of M. marshalli were able to suppress the induction of allergic airway inflammation in mice. Modulation of Th2 type responses (IL-4, IL-13, IgG1) via upregulations of IL-10 and TGF-β production was observed after injection of somatic products of M. marshalli. In addition, inflammatory cells infiltration and pathological disorders were significantly diminished following administration of somatic products. Conclusions Our data raised the possibility that helminths could be a potential therapeutic candidate to alleviate the inflammatory conditions in allergic asthma. According to these results, we concluded that M. marshalli may contain immune-modulatory molecules that attenuate allergic airway inflammation via induction of regulatory cytokines. Further investigations are required to identify molecules that might have potentials for development of novel therapeutic targets.
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Affiliation(s)
- Sima Parande Shirvan
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, P. O. Box: 91775-1793, Mashhad, Iran
| | - Azadeh Ebrahimby
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, P. O. Box: 91775-1793, Mashhad, Iran
| | - Arezoo Dousty
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, P. O. Box: 91775-1793, Mashhad, Iran
| | - Mohsen Maleki
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, P. O. Box: 91775-1793, Mashhad, Iran
| | - Ahmadreza Movassaghi
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, P. O. Box: 91775-1793, Mashhad, Iran
| | - Hassan Borji
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, P. O. Box: 91775-1793, Mashhad, Iran.
| | - Alireza Haghparast
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, P. O. Box: 91775-1793, Mashhad, Iran. .,Division of Biotechnology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, P. O. Box: 91775-1793, Mashhad, Iran.
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17
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Hang L, Blum AM, Kumar S, Urban JF, Mitreva M, Geary TG, Jardim A, Stevenson MM, Lowell CA, Weinstock JV. Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis. THE JOURNAL OF IMMUNOLOGY 2016; 197:2948-57. [PMID: 27559049 DOI: 10.4049/jimmunol.1600063] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 07/14/2016] [Indexed: 12/21/2022]
Abstract
Helminthic infections modulate host immunity and may protect people in less-developed countries from developing immunological diseases. In a murine colitis model, the helminth Heligmosomoides polygyrus bakeri prevents colitis via induction of regulatory dendritic cells (DCs). The mechanism driving the development of these regulatory DCs is unexplored. There is decreased expression of the intracellular signaling pathway spleen tyrosine kinase (Syk) in intestinal DCs from H. polygyrus bakeri-infected mice. To explore the importance of this observation, it was shown that intestinal DCs from DC-specific Syk(-/-) mice were powerful inhibitors of murine colitis, suggesting that loss of Syk was sufficient to convert these cells into their regulatory phenotype. DCs sense gut flora and damaged epithelium via expression of C-type lectin receptors, many of which signal through the Syk signaling pathway. It was observed that gut DCs express mRNA encoding for C-type lectin (CLEC) 7A, CLEC9A, CLEC12A, and CLEC4N. H. polygyrus bakeri infection downmodulated CLEC mRNA expression in these cells. Focusing on CLEC7A, which encodes for the dectin-1 receptor, flow analysis showed that H. polygyrus bakeri decreases dectin-1 expression on the intestinal DC subsets that drive Th1/Th17 development. DCs become unresponsive to the dectin-1 agonist curdlan and fail to phosphorylate Syk after agonist stimulation. Soluble worm products can block CLEC7A and Syk mRNA expression in gut DCs from uninfected mice after a brief in vitro exposure. Thus, downmodulation of Syk expression and phosphorylation in intestinal DCs could be important mechanisms through which helminths induce regulatory DCs that limit colitis.
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Affiliation(s)
- Long Hang
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111
| | - Arthur M Blum
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111
| | - Sangeeta Kumar
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111
| | - Joseph F Urban
- Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705
| | - Makedonka Mitreva
- Genome Institute, Washington University School of Medicine, St. Louis, MO 63108
| | - Timothy G Geary
- Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, Quebec H9X 3V9, Canada
| | - Armando Jardim
- Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, Quebec H9X 3V9, Canada
| | - Mary M Stevenson
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada; Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada; and
| | - Clifford A Lowell
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143
| | - Joel V Weinstock
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111;
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18
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Anstadt EJ, Fujiwara M, Wasko N, Nichols F, Clark RB. TLR Tolerance as a Treatment for Central Nervous System Autoimmunity. THE JOURNAL OF IMMUNOLOGY 2016; 197:2110-8. [PMID: 27503211 DOI: 10.4049/jimmunol.1600876] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 07/10/2016] [Indexed: 12/16/2022]
Abstract
The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low-level Pam2CSK4 or L654 to mice receiving encephalitogenic cells and in doing so induced both TLR2 tolerance and attenuation of EAE. Disease attenuation was accompanied in the CNS by a decrease in macrophage activation, a decrease in a specific proinflammatory macrophage population, and a decrease in Th17 cells. In addition, disease attenuation was associated with an increase in splenic type 1 regulatory T cells. Kinetic tolerance induction studies revealed a critical period for TLR2 involvement in adoptive transfer EAE. Overall, these results suggest that inducing TLR tolerance may offer a new approach to treating CNS autoimmune diseases such as MS.
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Affiliation(s)
- Emily J Anstadt
- Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06032; and
| | - Mai Fujiwara
- Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06032; and
| | - Nicholas Wasko
- Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06032; and
| | - Frank Nichols
- School of Dental Medicine, University of Connecticut School of Medicine, Farmington, CT 06032
| | - Robert B Clark
- Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06032; and
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19
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Donaldson DS, Mabbott NA. The influence of the commensal and pathogenic gut microbiota on prion disease pathogenesis. J Gen Virol 2016; 97:1725-1738. [PMID: 27193137 DOI: 10.1099/jgv.0.000507] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Prion diseases are a unique group of transmissible, chronic, neurodegenerative disorders. Following peripheral exposure (e.g. oral), prions often accumulate first within the secondary lymphoid tissues before they infect the central nervous system (CNS). Prion replication within secondary lymphoid tissues is crucial for the efficient spread of disease to the CNS. Once within the CNS, the responses of innate immune cells within it can have a significant influence on neurodegeneration and disease progression. Recently, there have been substantial advances in our understanding of how cross-talk between the host and the vast community of commensal microorganisms present at barrier surfaces such as the gut influences the development and regulation of the host's immune system. These effects are evident not only in the mucosal immune system in the gut, but also in the CNS. The actions of this microbial community (the microbiota) have many important beneficial effects on host health, from metabolism of nutrients and regulation of host development to protection from pathogen infection. However, the microbiota can also have detrimental effects in some circumstances. In this review we discuss the many and varied interactions between prions, the host and the gut microbiota. Particular emphasis is given to the ways by which changes to the composition of the commensal gut microbiota or congruent pathogen infection may influence prion disease pathogenesis and/or disease susceptibility. Understanding how these factors influence prion pathogenesis and disease susceptibility is important for assessing the risk to infection and the design of novel opportunities for therapeutic intervention.
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Affiliation(s)
- David S Donaldson
- The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Edinburgh, UK
| | - Neil A Mabbott
- The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Edinburgh, UK
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20
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Obuku AE, Asiki G, Abaasa A, Ssonko I, Harari A, van Dam GJ, Corstjens PL, Joloba M, Ding S, Mpendo J, Nielsen L, Kamali A, Elliott AM, Pantaleo G, Kaleebu P, Pala P. Effect of Schistosoma mansoni Infection on Innate and HIV-1-Specific T-Cell Immune Responses in HIV-1-Infected Ugandan Fisher Folk. AIDS Res Hum Retroviruses 2016; 32:668-75. [PMID: 26864743 PMCID: PMC4931742 DOI: 10.1089/aid.2015.0274] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
In Uganda, fisher folk have HIV prevalence rates, about four times higher than the national average, and are often coinfected with Schistosoma mansoni. We hypothesized that innate immune responses and HIV-specific Th1 immune responses might be downmodulated in HIV/S. mansoni-coinfected individuals compared with HIV+/S. mansoni-negative individuals. We stimulated whole blood with innate receptor agonists and analyzed supernatant cytokines by Luminex. We evaluated HIV-specific responses by intracellular cytokine staining for IFN-γ, IL-2, and TNF-α. We found that the plasma viral load and CD4 count were similar between the HIV+SM+ and HIV+SM− individuals. In addition, the TNF-α response to the imidazoquinoline compound CL097 and β-1, 3-glucan (curdlan), was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. The frequency of HIV-specific IFN-γ+IL-2–TNF-α− CD8 T cells and IFN-γ+IL-2–TNF-α+ CD4 T cells was significantly higher in HIV/S. mansoni-coinfected individuals compared with HIV only-infected individuals. These findings do not support the hypothesis that S. mansoni downmodulates innate or HIV-specific Th1 responses in HIV/S. mansoni-coinfected individuals.
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Affiliation(s)
- Andrew Ekii Obuku
- Basic Science Programme, Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - Gershim Asiki
- HIV Prevention and Epidemiology Programme, Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - Andrew Abaasa
- HIV Prevention and Epidemiology Programme, Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - Isaac Ssonko
- HIV Prevention and Epidemiology Programme, Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - Alexandre Harari
- Division of Immunology and Allergy, Department of Medicine, Lausanne University Teaching Hospital, Lausanne, Switzerland
| | | | | | - Moses Joloba
- Department of Medical Microbiology, Makerere University College of Health Sciences, Kampala, Uganda
| | - Song Ding
- EuroVacc Foundation, Amsterdam, the Netherlands
| | - Juliet Mpendo
- Uganda Virus Research Institute/International AIDS Vaccine Initiative, Entebbe, Uganda
| | - Leslie Nielsen
- Uganda Virus Research Institute/International AIDS Vaccine Initiative, Entebbe, Uganda
| | - Anatoli Kamali
- HIV Prevention and Epidemiology Programme, Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - Alison M. Elliott
- Co-Infections Programme, Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
- Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Giuseppe Pantaleo
- Division of Immunology and Allergy, Department of Medicine, Lausanne University Teaching Hospital, Lausanne, Switzerland
| | - Pontiano Kaleebu
- Basic Science Programme, Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
- Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Pietro Pala
- Basic Science Programme, Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
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21
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Zakeri A, Borji H, Haghparast A. Interaction Between Helminths and Toll-Like Receptors: Possibilities and Potentials for Asthma Therapy. Int Rev Immunol 2016; 35:219-48. [PMID: 27120222 DOI: 10.3109/08830185.2015.1096936] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Toll-like receptors (TLRs) are essential components of the innate immune system. They play an important role in the pathogenesis of allergic diseases, especially asthma. Since TLRs significantly orchestrate innate and adaptive immune response, their manipulation has widely been considered as a potential approach to control asthma symptoms. It is well established that helminths have immunoregulatory effects on host immune responses, especially innate immunity. They release bioactive molecules such as excretory-secretory (ES) products manipulating TLRs expression and signaling. Thus, given the promising results derived from preclinical studies, harnessing helminth-derived molecules affecting TLRs can be considered as a potential biological therapy for allergic diseases. Prospectively, the data that are available at present suggest that, in the near future, it is possible that helminth antigens will offer new therapeutic strategies and druggable targets for fighting allergic diseases. This review describes the interactions between helminths and TLRs and discusses the potential possibilities for asthma therapy. In this opinion paper, the authors aimed to review the updated literatures on the interplay between helminths, TLRs, and asthma with a view to proposing helminth-based asthma therapy.
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Affiliation(s)
- Amin Zakeri
- a Parasitology Section, Department of Pathobiology , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran.,b Immunology Sections, Department of Pathobiology, Faculty of Veterinary Medicine , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran
| | - Hassan Borji
- a Parasitology Section, Department of Pathobiology , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran
| | - Alireza Haghparast
- b Immunology Sections, Department of Pathobiology, Faculty of Veterinary Medicine , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran.,c Biotechnology Section, Department of Pathobiology , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran
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22
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Steinfelder S, O’Regan NL, Hartmann S. Diplomatic Assistance: Can Helminth-Modulated Macrophages Act as Treatment for Inflammatory Disease? PLoS Pathog 2016; 12:e1005480. [PMID: 27101372 PMCID: PMC4839649 DOI: 10.1371/journal.ppat.1005480] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Helminths have evolved numerous pathways to prevent their expulsion or elimination from the host to ensure long-term survival. During infection, they target numerous host cells, including macrophages, to induce an alternatively activated phenotype, which aids elimination of infection, tissue repair, and wound healing. Multiple animal-based studies have demonstrated a significant reduction or complete reversal of disease by helminth infection, treatment with helminth products, or helminth-modulated macrophages in models of allergy, autoimmunity, and sepsis. Experimental studies of macrophage and helminth therapies are being translated into clinical benefits for patients undergoing transplantation and those with multiple sclerosis. Thus, helminths or helminth-modulated macrophages present great possibilities as therapeutic applications for inflammatory diseases in humans. Macrophage-based helminth therapies and the underlying mechanisms of their therapeutic or curative effects represent an under-researched area with the potential to open new avenues of treatment. This review explores the application of helminth-modulated macrophages as a new therapy for inflammatory diseases.
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Affiliation(s)
- Svenja Steinfelder
- Department of Veterinary Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany
| | - Noëlle Louise O’Regan
- Department of Veterinary Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany
| | - Susanne Hartmann
- Department of Veterinary Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany
- * E-mail:
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23
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Chan PY, Carrera Silva EA, De Kouchkovsky D, Joannas LD, Hao L, Hu D, Huntsman S, Eng C, Licona-Limón P, Weinstein JS, Herbert DR, Craft JE, Flavell RA, Repetto S, Correale J, Burchard EG, Torgerson DG, Ghosh S, Rothlin CV. The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 2016; 352:99-103. [PMID: 27034374 PMCID: PMC4935984 DOI: 10.1126/science.aaf1358] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 02/24/2016] [Indexed: 12/25/2022]
Abstract
Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4. T cell-specificPros1knockouts phenocopied the loss ofTyro3 Thus, a PROS1-mediated feedback from adaptive immunity engages a rheostat, TYRO3, on innate immune cells to limit the intensity of type 2 responses.
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Affiliation(s)
- Pamela Y Chan
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Eugenio A Carrera Silva
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Laboratorio de Trombosis Experimental, Instituto de Medicina Experimental, Academia Nacional de Medicina-CONICET, Buenos Aires, 1425, Argentina
| | - Dimitri De Kouchkovsky
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Leonel D Joannas
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Liming Hao
- Department of Pathology, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Donglei Hu
- Department of Medicine, University of California San Francisco, CA 94158, USA
| | - Scott Huntsman
- Department of Medicine, University of California San Francisco, CA 94158, USA
| | - Celeste Eng
- Department of Medicine, University of California San Francisco, CA 94158, USA
| | - Paula Licona-Limón
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Jason S Weinstein
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - De'Broski R Herbert
- Department of Experimental Medicine, University of California San Francisco, CA 94158, USA
| | - Joseph E Craft
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Department of Internal Medicine (Rheumatology), School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Richard A Flavell
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Silvia Repetto
- Instituto de Investigaciones en Microbiología y Parasitología Médica, University of Buenos Aires-CONICET, Buenos Aires, 1121, Argentina. Hospital de Clinicas Jose de San Martin, University of Buenos Aires, 1120, Argentina
| | - Jorge Correale
- Center for Research on Neuroimmunological Diseases, Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires 1428, Argentina
| | - Esteban G Burchard
- Department of Medicine, University of California San Francisco, CA 94158, USA. Department of Bioengineering, School of Pharmacy, University of California San Francisco, CA 94158, USA
| | - Dara G Torgerson
- Department of Medicine, University of California San Francisco, CA 94158, USA
| | - Sourav Ghosh
- Department of Neurology, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Carla V Rothlin
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA.
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24
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Goswami R, Kaplan MH. Essential vitamins for an effective T cell response. World J Immunol 2016; 6:39-59. [DOI: 10.5411/wji.v6.i1.39] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 10/07/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023] Open
Abstract
Effective adaptive immune responses rely upon appropriate activation of T cells by antigenic peptide-major histocompatibility complex on the surface of antigen presenting cells (APCs). Activation relies on additional signals including co-stimulatory molecules on the surface of the APCs that promote T cell expansion. The immune response is further sculpted by the cytokine environment. However, T cells also respond to other environmental signals including hormones, neurotransmitters, and vitamins. In this review, we summarize the mechanisms through which vitamins A and D impact immune responses, particularly in the context of T cell responses.
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25
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Correale J, Gaitán MI. Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein-Barr virus infection. Acta Neurol Scand 2016; 132:46-55. [PMID: 26046559 DOI: 10.1111/ane.12431] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2015] [Indexed: 01/08/2023]
Abstract
Pathogenic mechanisms underlying multiple sclerosis development have yet to be clearly identified, but considerable evidence indicates that autoimmunity plays an important role in the etiology of the disease. It is generally accepted that autoimmune diseases like MS arise from complex interactions between genetic susceptibility and environmental factors. Although environmental factors unequivocally influencing MS development have yet to be established, accumulating evidence singles out several candidates, including sunlight-UV exposure or vitamin D deficiency, viral infections, hygiene, and cigarette smoking. Vitamin D deficiency has been associated with different autoimmune diseases. Several investigations indicate 125 (OH)2 vitamin D plays a critical role in shaping T-cell response and inducing T cells with immunosuppressive properties. Likewise, helminth infections represent another potential environmental factor exerting immunomodulatory properties. Both epidemiological and experimental data provide evidence to support autoimmune down-regulation secondary to parasite infections in patients with MS, through regulatory T- and B-cell action, with effects extending beyond simple response to an infectious agent. Finally, different epidemiological studies have demonstrated that Epstein-Barr virus infection confers added risk of developing MS. Proposed mechanisms responsible for this association include activation and expansion of self-reactive T and B cells, lower threshold for self-tolerance breakdown, and enhanced autoreactive B-cell survival, all to be discussed in this review. Understanding environmental factors influencing propensity to MS will lead to new and more effective approaches to prevent and treat the disease.
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Affiliation(s)
- J. Correale
- Department of Neurology; Institute for Neurological Research Dr. Raúl Carrea; FLENI; Buenos Aires Argentina
| | - M. I. Gaitán
- Department of Neurology; Institute for Neurological Research Dr. Raúl Carrea; FLENI; Buenos Aires Argentina
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26
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Hygiene and other early childhood influences on the subsequent function of the immune system. Brain Res 2015; 1617:47-62. [DOI: 10.1016/j.brainres.2014.04.004] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 02/17/2014] [Accepted: 04/05/2014] [Indexed: 02/08/2023]
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27
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Siles-Lucas M, Morchon R, Simon F, Manzano-Roman R. Exosome-transported microRNAs of helminth origin: new tools for allergic and autoimmune diseases therapy? Parasite Immunol 2015; 37:208-14. [PMID: 25712154 DOI: 10.1111/pim.12182] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 02/17/2015] [Indexed: 12/11/2022]
Abstract
Chronic diseases associated with inflammation show fast annual increase in their incidence. This has been associated with excessive hygiene habits that limit contacts between the immune system and helminth parasites. Helminthic infections induce regulation and expansion of regulatory T cells (Treg) leading to atypical Th2 type immune responses, with downregulation of the inflammatory component usually associated with these type of responses. Many cells, including those of the immune system, produce extracellular vesicles called exosomes which mediate either immune stimulation (DCs) or immune modulation (T cells). The transfer of miRNAs contained in T-cell exosomes has been shown to contribute to downregulate the production of inflammatory mediators. It has been recently described the delivery to the host-parasite interface of exosomes containing miRNAs by helminths and its internalization by host cells. In this sense, helminth microRNAs transported in exosomes and internalized by immune host cells exert an important role in the expansion of Treg cells, resulting in the control of inflammation. We here provide relevant information obtained in the field of exosomes, cell-cell communication and miRNAs, showing the high potential of helminth miRNAs delivered in exosomes to host cells as new therapeutic tools against diseases associated with exacerbated inflammatory responses.
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Affiliation(s)
- M Siles-Lucas
- Instituto de Recursos Naturales y Agrobiologia de Salamanca (IRNASA-CSIC), Salamanca, Spain
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28
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Schistosoma mansoni Soluble Egg Antigens Induce Expression of the Negative Regulators SOCS1 and SHP1 in Human Dendritic Cells via Interaction with the Mannose Receptor. PLoS One 2015; 10:e0124089. [PMID: 25897665 PMCID: PMC4405200 DOI: 10.1371/journal.pone.0124089] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 02/25/2015] [Indexed: 12/31/2022] Open
Abstract
Schistosomiasis is a common debilitating human parasitic disease in (sub)tropical areas, however, schistosome infections can also protect against a variety of inflammatory diseases. This has raised broad interest in the mechanisms by which Schistosoma modulate the immune system into an anti-inflammatory and regulatory state. Human dendritic cells (DCs) show many phenotypic changes upon contact with Schistosoma mansoni soluble egg antigens (SEA). We here show that oxidation of SEA glycans, but not heat-denaturation, abrogates the capacity of SEA to suppress both LPS-induced cytokine secretion and DC proliferation, indicating an important role of SEA glycans in these processes. Remarkably, interaction of SEA glycans with DCs results in a strongly increased expression of Suppressor Of Cytokine Signalling1 (SOCS1) and SH2-containing protein tyrosine Phosphatase-1 (SHP1), important negative regulators of TLR4 signalling. In addition, SEA induces the secretion of transforming growth factor β (TGF-β), and the surface expression of the costimulatory molecules Programmed Death Ligand-1 (PD-L1) and OX40 ligand (OX40L), which are known phenotypic markers for the capacity of DCs to polarize naïve T cells into Th2/Treg cell subsets. Inhibition of mannose receptor (MR)-mediated internalization of SEA into DCs by blocking with allyl α-D-mannoside or anti-MR antibodies, significantly reduced SOCS1 and SHP1 expression. In conclusion, we demonstrate that SEA glycans are essential for induction of enhanced SOCS1 and SHP1 levels in DCs via the MR. Our data provide novel mechanistic evidence for the potential of S. mansoni SEA glycans to modulate human DCs, which may contribute to the capacity of SEA to down-regulate inflammatory responses.
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29
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Finlay CM, Walsh KP, Mills KHG. Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases. Immunol Rev 2014; 259:206-30. [PMID: 24712468 DOI: 10.1111/imr.12164] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Helminth parasites are highly successful pathogens, chronically infecting a quarter of the world's population, causing significant morbidity but rarely causing death. Protective immunity and expulsion of helminths is mediated by T-helper 2 (Th2) cells, type 2 (M2) macrophages, type 2 innate lymphoid cells, and eosinophils. Failure to mount these type 2 immune responses can result in immunopathology mediated by Th1 or Th17 cells. Helminths have evolved a wide variety of approaches for immune suppression, especially the generation of regulatory T cells and anti-inflammatory cytokines interleukin-10 and transforming growth factor-β. This is a very effective strategy for subverting protective immune responses to prolong their survival in the host but has the bystander effect of modulating immune responses to unrelated antigens. Epidemiological studies in humans have shown that infection with helminth parasites is associated with a low incidence of allergy/asthma and autoimmunity in developing countries. Experimental studies in mice have demonstrated that regulatory immune responses induced by helminth can suppress Th2 and Th1/Th17 responses that mediate allergy and autoimmunity, respectively. This has provided a rational explanation of the 'hygiene hypothesis' and has also led to the exploitation of helminths or their immunomodulatory products in the development of new immunosuppressive therapies for inflammatory diseases in humans.
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Affiliation(s)
- Conor M Finlay
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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30
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Weinstock JV, Elliott DE. Helminth infections decrease host susceptibility to immune-mediated diseases. THE JOURNAL OF IMMUNOLOGY 2014; 193:3239-47. [PMID: 25240019 DOI: 10.4049/jimmunol.1400927] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Helminthic infection has become rare in highly industrialized nations. Concurrent with the decline in helminthic infection has been an increase in the prevalence of inflammatory disease. Removal of helminths from our environment and their powerful effects on host immunity may have contributed to this increase. Several helminth species can abrogate disease in murine models of inflammatory bowel disease, type 1 diabetes, multiple sclerosis, and other conditions. Helminths evoke immune regulatory pathways often involving dendritic cells, regulatory T cells, and macrophages that help to control disease. Cytokines, such as IL-4, IL-10, and TGF-β, have a role. Notable is the helminthic modulatory effect on innate immunity, which impedes development of aberrant adaptive immunity. Investigators are identifying key helminth-derived immune modulatory molecules that may have therapeutic usefulness in the control of inflammatory disease.
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Affiliation(s)
- Joel V Weinstock
- Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111; and
| | - David E Elliott
- Division of Gastroenterology, University of Iowa, Iowa City, IA 52242
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31
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Vartoukian SR, Tilakaratne WM, Seoudi N, Bombardieri M, Bergmeier L, Tappuni AR, Fortune F. Dysregulation of the suppressor of cytokine signalling 3-signal transducer and activator of transcription-3 pathway in the aetiopathogenesis of Sjögren's syndrome. Clin Exp Immunol 2014; 177:618-29. [PMID: 24827536 PMCID: PMC4137846 DOI: 10.1111/cei.12377] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/17/2014] [Indexed: 12/20/2022] Open
Abstract
The suppressor of cytokine signalling 3 (SOCS3) negatively regulates the Janus kinase (JAK)/signal transducer and activator of transcription-3 (STAT-3)/interleukin (IL)-17 pathway. The proinflammatory cytokine IL-17 is over-expressed in Sjögren's syndrome (SS) and is a key factor in its pathogenesis. We hypothesized that IL-17 over-expression in SS results from ineffective regulation by SOCS3. The expression of SOCS3 was analysed in peripheral blood mononuclear cells (PBMC) from SS cases, sicca controls (SC) and healthy controls (HC) and tissue samples from SS, SC and healthy salivary glands (HSG). PBMC and salivary gland tissue from SS and controls were dual-immunostained for SOCS3 and IL-17. IL-6-stimulated PBMC from SS and controls were evaluated for time-dependent STAT-3 activation and SOCS3 induction, and for IL-17 expression. Immunoblotting revealed greater levels of SOCS3 in PBMC from SS than SC (P = 0·017) or HC (P < 0·001). Similarly, the proportion of salivary-gland tissue cells staining for SOCS3 was significantly higher in SS than SC (P = 0·029) or HSG (P = 0·021). The cells in PBMC/salivary gland samples from controls predominantly expressed either SOCS3 or IL-17. However, there was a high frequency of SOCS3/IL-17 co-expression within cells of SS samples. IL-6-stimulation of PBMC from SS cases revealed prolonged activation of STAT-3 with reduced negative regulation by SOCS3, and enhanced expression of IL-17. This study showed that SOCS3 expression is up-regulated in SS. However, the absence in SS of the normal inverse relationship between SOCS3 and pSTAT-3/IL-17 indicates a functional disturbance in this signalling cascade. Consequently, a reduction in function, rather than a reduction in expression of SOCS3 accounts for the unregulated expression of IL-17 in SS, and may play a crucial role in aetiopathogenesis.
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Affiliation(s)
- S R Vartoukian
- Centre for Clinical and Diagnostic Oral Sciences, Queen Mary University of London, Barts and The London School of Medicine & Dentistry, London, UK
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32
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Parasites and immunotherapy: with or against? J Parasit Dis 2014; 40:217-26. [PMID: 27413282 DOI: 10.1007/s12639-014-0533-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 08/13/2014] [Indexed: 01/12/2023] Open
Abstract
Immunotherapy is a sort of therapy in which antibody or antigen administrates to the patient in order to treat or reduce the severity of complications of disease. This kind of treatment practiced in a wide variety of diseases including infectious diseases, autoimmune disorders, cancers and allergy. Successful and unsuccessful immunotherapeutic strategies have been practiced in variety of parasitic infections. On the other hand parasites or parasite antigens have also been considered for immunotherapy against other diseases such as cancer, asthma and multiple sclerosis. In this paper immunotherapy against common parasitic infections, and also immunotherapy of cancer, asthma and multiple sclerosis with parasites or parasite antigens have been reviewed.
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33
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Abstract
Vitamin A is an essential nutrient with important roles in immunological responses and in brain development. Its main metabolite is retinoic acid (RA), which is responsible for the neuroimmunological functions related to vitamin A. In the brain, RA is known to have interactions with other nuclear receptor-mediated signalling pathways. RA is involved in plasticity, regeneration, cognition and behaviour. In the peripheral blood, RA plays a major role both in increasing tolerance and in decreasing inflammation, through balancing T-lymphocyte populations. It is likely that RA synthesis may be manipulated by complex cross-talk among cells during infection and inflammation. The role of vitamin A in multiple sclerosis (MS) could be dual: at the same time as it decreases inflammation and increases tolerance of autoimmunity, it may also help in brain protection. The present review discusses the beneficial effects that vitamin A might have for controlling MS, although it must be clearly stated that, at the present time, there is no clear indication for using vitamin A as a treatment for MS. However, the results from the present review should encourage clinical trials with vitamin supplementation as a potential treatment or as an add-on option. Vitamin A acts in synergy with vitamin D, and the immunological homeostasis ensured by these vitamins should not be unbalanced in favour of only one of them.
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Abstract
In the last 50 years, environmental factors such as helminth infections have been proposed to explain why autoimmunity is less prevalent in the developing world; this proposal has been termed the hygiene or old friends hypothesis. The epidemiology of MS shows an inverse correlation with helminth infections. Positive effects of helminths in animal models of MS and observational studies in people with MS naturally infected with helminths suggest that those organisms can act as immune regulators and led to clinical trials of helminth therapy. The goal of helminth therapy is to introduce parasitic organisms into people with MS in a controlled and predictable fashion, and to prevent immune-mediated disease without increasing the risk of pathology with high parasite load. This chapter focuses on intestinal worms as they are the current choice as a therapeutic strategy in a number of autoimmune diseases, including MS. Here we review current data regarding the rationale and the current state of research in the field of helminth therapies in MS.
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