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  1. Article ; Online: Diet, metabolites, and "western-lifestyle" inflammatory diseases.

    Thorburn, Alison N / Macia, Laurence / Mackay, Charles R

    Immunity

    2014  Volume 40, Issue 6, Page(s) 833–842

    Abstract: One explanation for the increased incidence of allergies, asthma, and even some autoimmune diseases has been the hygiene hypothesis. However, recent studies also highlight an important role for diet and bacterial metabolites in controlling various immune ...

    Abstract One explanation for the increased incidence of allergies, asthma, and even some autoimmune diseases has been the hygiene hypothesis. However, recent studies also highlight an important role for diet and bacterial metabolites in controlling various immune pathways, including gut and immune homeostasis, regulatory T cell biology, and inflammation. Dietary-related metabolites engage "metabolite-sensing" G-protein-coupled receptors, such as GPR43, GPR41, GPR109A, GPR120, and GPR35. These receptors are expressed on immune cells and some gut epithelial cells and generally mediate a direct anti-inflammatory effect. Insufficient intake of "healthy foodstuffs" adversely affects the production of bacterial metabolites. These metabolites and those derived directly from food drive beneficial downstream effects on immune pathways. We propose that insufficient exposure to dietary and bacterial metabolites might underlie the development of inflammatory disorders in Western countries. This review highlights what is currently known about diet, metabolites, and their associated immune pathways in relation to the development of inflammatory disease.
    MeSH term(s) Autoimmune Diseases/immunology ; Bacterial Proteins/immunology ; Diet ; Gastrointestinal Tract/immunology ; Gastrointestinal Tract/microbiology ; Humans ; Hypersensitivity/immunology ; Inflammation/immunology ; Inflammation/microbiology ; Life Style ; Metabolome/immunology ; Microbiota/immunology ; Receptors, G-Protein-Coupled/immunology
    Chemical Substances Bacterial Proteins ; Receptors, G-Protein-Coupled
    Language English
    Publishing date 2014-06-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2014.05.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Harnessing regulatory T cells to suppress asthma: from potential to therapy.

    Thorburn, Alison N / Hansbro, Philip M

    American journal of respiratory cell and molecular biology

    2010  Volume 43, Issue 5, Page(s) 511–519

    Abstract: Regulatory T cells (Tregs) play an essential role in maintaining the homeostatic balance of immune responses. Asthma is an inflammatory condition of the airways that is driven by dysregulated immune responses toward normally innocuous antigens. ... ...

    Abstract Regulatory T cells (Tregs) play an essential role in maintaining the homeostatic balance of immune responses. Asthma is an inflammatory condition of the airways that is driven by dysregulated immune responses toward normally innocuous antigens. Individuals with asthma have fewer and less functional Tregs, which may lead to uncontrolled effector cell responses and promote proasthmatic responses of T helper type 2, T helper 17, natural killer T, antigen-presenting, and B cells. Tregs have the capacity to either directly or indirectly suppress these responses. Hence, the induced expansion of functional Tregs in predisposed or individuals with asthma is a potential approach for the prevention and treatment of asthma. Infection by a number of micro-organisms has been associated with reduced prevalence of asthma, and many infectious agents have been shown to induce Tregs and reduce allergic airways disease in mouse models. The translation of the regulatory and therapeutic properties of infectious agents for use in asthma requires the identification of key modulatory components and the development and trial of effective immunoregulatory therapies. Further translational and clinical research is required for the induction of Tregs to be harnessed as a therapeutic strategy for asthma.
    MeSH term(s) Animals ; Asthma/immunology ; Asthma/therapy ; Biomarkers ; Humans ; Immune Tolerance/immunology ; T-Lymphocytes, Regulatory/immunology
    Chemical Substances Biomarkers
    Language English
    Publishing date 2010-01-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2009-0342TR
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Integrated multi-omics for rapid rare disease diagnosis on a national scale.

    Lunke, Sebastian / Bouffler, Sophie E / Patel, Chirag V / Sandaradura, Sarah A / Wilson, Meredith / Pinner, Jason / Hunter, Matthew F / Barnett, Christopher P / Wallis, Mathew / Kamien, Benjamin / Tan, Tiong Y / Freckmann, Mary-Louise / Chong, Belinda / Phelan, Dean / Francis, David / Kassahn, Karin S / Ha, Thuong / Gao, Song / Arts, Peer /
    Jackson, Matilda R / Scott, Hamish S / Eggers, Stefanie / Rowley, Simone / Boggs, Kirsten / Rakonjac, Ana / Brett, Gemma R / de Silva, Michelle G / Springer, Amanda / Ward, Michelle / Stallard, Kirsty / Simons, Cas / Conway, Thomas / Halman, Andreas / Van Bergen, Nicole J / Sikora, Tim / Semcesen, Liana N / Stroud, David A / Compton, Alison G / Thorburn, David R / Bell, Katrina M / Sadedin, Simon / North, Kathryn N / Christodoulou, John / Stark, Zornitza

    Nature medicine

    2023  Volume 29, Issue 7, Page(s) 1681–1691

    Abstract: Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ... ...

    Abstract Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.
    MeSH term(s) Infant ; Child ; Humans ; Rare Diseases/diagnosis ; Rare Diseases/genetics ; Rare Diseases/therapy ; Critical Illness ; Multiomics ; Whole Genome Sequencing/methods ; Exome Sequencing
    Language English
    Publishing date 2023-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-023-02401-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Components of Streptococcus pneumoniae suppress allergic airways disease and NKT cells by inducing regulatory T cells.

    Thorburn, Alison N / Foster, Paul S / Gibson, Peter G / Hansbro, Philip M

    Journal of immunology (Baltimore, Md. : 1950)

    2012  Volume 188, Issue 9, Page(s) 4611–4620

    Abstract: Asthma is an allergic airways disease (AAD) caused by dysregulated immune responses and characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). NKT cells have been shown to contribute to AHR in some mouse ... ...

    Abstract Asthma is an allergic airways disease (AAD) caused by dysregulated immune responses and characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). NKT cells have been shown to contribute to AHR in some mouse models. Conversely, regulatory T cells (Tregs) control aberrant immune responses and maintain homeostasis. Recent evidence suggests that Streptococcus pneumoniae induces Tregs that have potential to be harnessed therapeutically for asthma. In this study, mouse models of AAD were used to identify the S. pneumoniae components that have suppressive properties, and the mechanisms underlying suppression were investigated. We tested the suppressive capacity of type-3-polysaccharide (T3P), isolated cell walls, pneumolysoid (Ply) and CpG. When coadministered, T3P + Ply suppressed the development of: eosinophilic inflammation, Th2 cytokine release, mucus hypersecretion, and AHR. Importantly, T3P + Ply also attenuated features of AAD when administered during established disease. We show that NKT cells contributed to the development of AAD and also were suppressed by T3P + Ply treatment. Furthermore, adoptive transfer of NKT cells induced AHR, which also could be reversed by T3P + Ply. T3P + Ply-induced Tregs were essential for the suppression of NKT cells and AAD, which was demonstrated by Treg depletion. Collectively, our results show that the S. pneumoniae components T3P + Ply suppress AAD through the induction of Tregs that blocked the activity of NKT cells. These data suggest that S. pneumoniae components may have potential as a therapeutic strategy for the suppression of allergic asthma through the induction of Tregs and suppression of NKT cells.
    MeSH term(s) Adoptive Transfer ; Animals ; Asthma/drug therapy ; Asthma/immunology ; Asthma/metabolism ; Asthma/pathology ; Bacterial Capsules/chemistry ; Bacterial Capsules/immunology ; Bacterial Capsules/pharmacology ; Bacterial Proteins/chemistry ; Bacterial Proteins/immunology ; Bacterial Proteins/pharmacology ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred BALB C ; Mucus/immunology ; Mucus/secretion ; Natural Killer T-Cells/immunology ; Natural Killer T-Cells/metabolism ; Natural Killer T-Cells/pathology ; Oligodeoxyribonucleotides/pharmacology ; Streptococcus pneumoniae/chemistry ; Streptococcus pneumoniae/immunology ; Streptolysins/chemistry ; Streptolysins/immunology ; Streptolysins/pharmacology ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytes, Regulatory/pathology ; Th2 Cells/immunology ; Th2 Cells/metabolism ; Th2 Cells/pathology
    Chemical Substances Bacterial Proteins ; CPG-oligonucleotide ; Oligodeoxyribonucleotides ; Streptolysins ; plY protein, Streptococcus pneumoniae ; type 3 capsular polysaccharide, Streptococcus pneumoniae
    Language English
    Publishing date 2012-05-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1101299
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The role of short-chain fatty acids in health and disease.

    Tan, Jian / McKenzie, Craig / Potamitis, Maria / Thorburn, Alison N / Mackay, Charles R / Macia, Laurence

    Advances in immunology

    2014  Volume 121, Page(s) 91–119

    Abstract: There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the ... ...

    Abstract There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFA-mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter.
    MeSH term(s) Animals ; Cytokines/antagonists & inhibitors ; Cytokines/biosynthesis ; Cytokines/physiology ; Fatty Acids, Volatile/biosynthesis ; Fatty Acids, Volatile/physiology ; Histone Deacetylase Inhibitors/metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/prevention & control ; Microbiota/immunology ; Microbiota/physiology ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Nicotinic/metabolism ; Signal Transduction/immunology ; Substrate Specificity/immunology
    Chemical Substances Cytokines ; FFAR3 protein, human ; Fatty Acids, Volatile ; HCAR2 protein, human ; Histone Deacetylase Inhibitors ; Receptors, G-Protein-Coupled ; Receptors, Nicotinic
    Language English
    Publishing date 2014
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 80226-8
    ISSN 1557-8445 ; 0065-2776
    ISSN (online) 1557-8445
    ISSN 0065-2776
    DOI 10.1016/B978-0-12-800100-4.00003-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: TLR2, TLR4 AND MyD88 Mediate Allergic Airway Disease (AAD) and Streptococcus pneumoniae-Induced Suppression of AAD.

    Thorburn, Alison N / Tseng, Hsin-Yi / Donovan, Chantal / Hansbro, Nicole G / Jarnicki, Andrew G / Foster, Paul S / Gibson, Peter G / Hansbro, Philip M

    PloS one

    2016  Volume 11, Issue 6, Page(s) e0156402

    Abstract: Background: Exposure to non-pathogenic Streptococcus pneumoniae and vaccination are inversely associated with asthma. Studies in animal models demonstrate that airway administration of S. pneumoniae (live or killed), or its vaccines or components, ... ...

    Abstract Background: Exposure to non-pathogenic Streptococcus pneumoniae and vaccination are inversely associated with asthma. Studies in animal models demonstrate that airway administration of S. pneumoniae (live or killed), or its vaccines or components, suppresses the characteristic features of asthma in mouse models of allergic airway disease (AAD). These components could be developed into immunoregulatory therapies. S. pneumoniae components are recognized by Toll-like receptors (TLR) 2 and TLR4, and both induce inflammatory cell responses through the adaptor protein myeloid differentiation primary response gene 88 (MyD88). The involvement of TLR2, TLR4 and MyD88 in the pathogenesis of AAD and asthma is incompletely understood, and has not been studied in S. pneumoniae-mediated suppression of AAD. We investigated the role of TLR2, TLR4 and MyD88 in the development of AAD and S. pneumoniae-mediated suppression of AAD.
    Methods and findings: OVA-induced AAD and killed S. pneumoniae-mediated suppression of AAD were assessed in wild-type, TLR2-/-, TLR4-/-, TLR2/4-/- and MyD88-/- BALB/c mice. During OVA-induced AAD, TLR2, TLR4 and MyD88 were variously involved in promoting eosinophil accumulation in bronchoalveolar lavage fluid and blood, and T-helper type (Th)2 cytokine release from mediastinal lymph node T cells and splenocytes. However, all were required for the induction of airways hyperresponsiveness (AHR). In S. pneumoniae-mediated suppression of AAD, TLR2, TLR4 and MyD88 were variously involved in the suppression of eosinophilic and splenocyte Th2 responses but all were required for the reduction in AHR.
    Conclusions: These results highlight important but complex roles for TLR2, TLR4 and MyD88 in promoting the development of OVA-induced AAD, but conversely in the S. pneumoniae-mediated suppression of AAD, with consistent and major contributions in both the induction and suppression of AHR. Thus, TLR signaling is likely required for both the development of asthma and the suppression of asthma by S. pneumoniae, and potentially other immunoregulatory therapies.
    MeSH term(s) Animals ; Bronchoalveolar Lavage Fluid/immunology ; Bronchoalveolar Lavage Fluid/microbiology ; Eosinophils/immunology ; Eosinophils/pathology ; Female ; Gene Expression Regulation ; Hot Temperature ; Immunotherapy/methods ; Lymph Nodes/immunology ; Lymph Nodes/pathology ; Mice ; Mice, Inbred BALB C ; Myeloid Differentiation Factor 88/genetics ; Myeloid Differentiation Factor 88/immunology ; Ovalbumin ; Protective Factors ; Respiratory Hypersensitivity/chemically induced ; Respiratory Hypersensitivity/immunology ; Respiratory Hypersensitivity/pathology ; Respiratory Hypersensitivity/prevention & control ; Signal Transduction ; Spleen/immunology ; Spleen/pathology ; Streptococcus pneumoniae/chemistry ; Streptococcus pneumoniae/immunology ; Th2 Cells/immunology ; Th2 Cells/pathology ; Toll-Like Receptor 2/genetics ; Toll-Like Receptor 2/immunology ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 4/immunology
    Chemical Substances Myd88 protein, mouse ; Myeloid Differentiation Factor 88 ; Tlr2 protein, mouse ; Tlr4 protein, mouse ; Toll-Like Receptor 2 ; Toll-Like Receptor 4 ; Ovalbumin (9006-59-1)
    Language English
    Publishing date 2016-06-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0156402
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  7. Article ; Online: Pneumococcal vaccines for allergic airways diseases.

    Thorburn, Alison N / Hansbro, Philip M / Gibson, Peter G

    Expert opinion on biological therapy

    2008  Volume 9, Issue 5, Page(s) 621–629

    Abstract: Background: Asthma is a common global health problem. Environmental exposures such as bacteria may protect against asthma development.: Objective: This review aims to examine the possible protective role of pneumococcal infection and vaccination in ... ...

    Abstract Background: Asthma is a common global health problem. Environmental exposures such as bacteria may protect against asthma development.
    Objective: This review aims to examine the possible protective role of pneumococcal infection and vaccination in asthma.
    Methods: A review of known experimental biology and human epidemiology relating to asthma and pneumococcal infection was performed.
    Results: Pneumococcal infection can modulate components of allergic airways disease such as airways hyperresponsiveness and airway eosinophilia. Exposure to killed pneumococcus can reproduce these effects and the mechanism may involve control by T regulatory cells.
    Conclusions: Pneumococcal immunoregulatory therapy is a potentially important approach to asthma management that requires further evaluation in well-designed research studies.
    MeSH term(s) Animals ; Asthma/immunology ; Asthma/microbiology ; Asthma/prevention & control ; Humans ; Hypersensitivity/immunology ; Hypersensitivity/microbiology ; Hypersensitivity/prevention & control ; Pneumococcal Infections/immunology ; Pneumococcal Infections/prevention & control ; Pneumococcal Vaccines/therapeutic use ; Pneumonia, Pneumococcal/immunology ; Pneumonia, Pneumococcal/prevention & control
    Chemical Substances Pneumococcal Vaccines
    Language English
    Publishing date 2008-11-24
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2052501-1
    ISSN 1744-7682 ; 1471-2598
    ISSN (online) 1744-7682
    ISSN 1471-2598
    DOI 10.1517/14712590902916999
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6094: Show issues Location:
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  8. Article ; Online: Inflammation and lymphopenia trigger autoimmunity by suppression of IL-2-controlled regulatory T cell and increase of IL-21-mediated effector T cell expansion.

    Chevalier, Nina / Thorburn, Alison N / Macia, Laurence / Tan, Jian / Juglair, Laurent / Yagita, Hideo / Yu, Di / Hansbro, Philip M / Mackay, Charles R

    Journal of immunology (Baltimore, Md. : 1950)

    2014  Volume 193, Issue 10, Page(s) 4845–4858

    Abstract: The dynamic interplay between regulatory T cells (T(regs)) and effector T cells (T(effs)) governs the balance between tolerance and effector immune responses. Perturbations of T(reg) frequency and function or imbalances in T(reg)/T(eff) levels are ... ...

    Abstract The dynamic interplay between regulatory T cells (T(regs)) and effector T cells (T(effs)) governs the balance between tolerance and effector immune responses. Perturbations of T(reg) frequency and function or imbalances in T(reg)/T(eff) levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. T(regs) displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to T(effs) (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient T(reg) control of T(effs) and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic T(reg) production and recruitment to inflamed tissues was too slow for disease prevention. Increased T(eff) over T(reg) expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that T(reg) expansion mainly depended on this cytokine. IL-21R(-/-) cells were used to demonstrate that IL-21 promoted the maintenance of T(effs). Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers T(reg) proliferation, whereas exaggerated IL-21 levels overwhelm T(reg) control by supporting T(eff) expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.
    MeSH term(s) Animals ; Arthritis/complications ; Arthritis/genetics ; Arthritis/immunology ; Arthritis/pathology ; Autoimmunity ; Cell Proliferation ; Gene Expression Regulation ; Immune Tolerance ; Inflammation/complications ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/pathology ; Interleukin-2/genetics ; Interleukin-2/immunology ; Interleukins/genetics ; Interleukins/immunology ; Lymphopenia/complications ; Lymphopenia/genetics ; Lymphopenia/immunology ; Lymphopenia/pathology ; Mice ; Mice, Transgenic ; Receptors, Interleukin-21/genetics ; Receptors, Interleukin-21/immunology ; Signal Transduction ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/pathology ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/pathology
    Chemical Substances Interleukin-2 ; Interleukins ; Receptors, Interleukin-21 ; interleukin-21
    Language English
    Publishing date 2014-11-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1302966
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Avenues to autoimmune arthritis triggered by diverse remote inflammatory challenges.

    Chevalier, Nina / Tan, Jian K / Mason, Linda J / Robert, Remy / McKenzie, Craig I / Lim, Florence / Wong, Connie H / Macia, Laurence / Thorburn, Alison N / Russ, Brendan E / Masters, Seth L / Mackay, Charles R

    Journal of autoimmunity

    2016  Volume 73, Page(s) 120–129

    Abstract: Environmental factors contribute to development of autoimmune diseases. For instance, human autoimmune arthritis can associate with intestinal inflammation, cigarette smoking, periodontal disease, and various infections. The cellular and, molecular ... ...

    Abstract Environmental factors contribute to development of autoimmune diseases. For instance, human autoimmune arthritis can associate with intestinal inflammation, cigarette smoking, periodontal disease, and various infections. The cellular and, molecular pathways whereby such remote challenges might precipitate arthritis or flares remain unclear. Here, we used a transfer model of self-reactive arthritis-inducing CD4(+) cells from KRNtg mice that, upon transfer, induce a very mild form of autoinflammatory arthritis in recipient animals. This model enabled us to identify external factors that greatly aggravated disease. We show that several distinct challenges precipitated full-blown arthritis, including intestinal inflammation through DSS-induced colitis, and bronchial stress through Influenza infection. Both triggers induced strong IL-17 expression primarily in self-reactive CD4(+) cells in lymph nodes draining the site of inflammation. Moreover, treatment of mice with IL-1β greatly exacerbated arthritis, while transfer of KRNtg CD4(+) cells lacking IL-1R significantly reduced disease and IL-17 expression. Thus, IL-1β enhances the autoaggressive potential of self-reactive CD4(+) cells, through increased Th17 differentiation, and this influences inflammatory events in the joints. We propose that diverse challenges that cause remote inflammation (lung infection or colitis, etc.) result in IL-1β-driven Th17 differentiation, and this precipitates arthritis in genetically susceptible individuals. Thus the etiology of autoimmune inflammatory arthritis likely relates to diverse triggers that converge to a common pathway involving IL-1β production and Th17 cell distribution.
    MeSH term(s) Adoptive Transfer ; Animals ; Arthritis, Experimental/immunology ; Arthritis, Rheumatoid/genetics ; Arthritis, Rheumatoid/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cell Differentiation/immunology ; Colitis/chemically induced ; Colitis/immunology ; Dextran Sulfate/toxicity ; Genetic Predisposition to Disease ; Influenza A virus/immunology ; Interleukin-17/metabolism ; Interleukin-1beta/metabolism ; Joints/immunology ; Klebsiella pneumoniae/immunology ; Lung Diseases/immunology ; Lung Diseases/virology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Transgenic ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/virology ; Pneumonia, Bacterial/immunology ; Pneumonia, Bacterial/microbiology ; Receptors, Interleukin-1/genetics ; Receptors, Interleukin-1/metabolism ; Spondylarthritis/immunology ; Th17 Cells/immunology ; Th17 Cells/metabolism
    Chemical Substances IL1B protein, mouse ; Interleukin-17 ; Interleukin-1beta ; Receptors, Interleukin-1 ; Dextran Sulfate (9042-14-2)
    Language English
    Publishing date 2016
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639452-8
    ISSN 1095-9157 ; 0896-8411
    ISSN (online) 1095-9157
    ISSN 0896-8411
    DOI 10.1016/j.jaut.2016.06.018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Pneumococcal components induce regulatory T cells that attenuate the development of allergic airways disease by deviating and suppressing the immune response to allergen.

    Thorburn, Alison N / Brown, Alexandra C / Nair, Prema M / Chevalier, Nina / Foster, Paul S / Gibson, Peter G / Hansbro, Philip M

    Journal of immunology (Baltimore, Md. : 1950)

    2013  Volume 191, Issue 8, Page(s) 4112–4120

    Abstract: The induction of regulatory T cells (Tregs) to suppress aberrant inflammation and immunity has potential as a therapeutic strategy for asthma. Recently, we identified key immunoregulatory components of Streptococcus pneumoniae, type 3 polysaccharide and ... ...

    Abstract The induction of regulatory T cells (Tregs) to suppress aberrant inflammation and immunity has potential as a therapeutic strategy for asthma. Recently, we identified key immunoregulatory components of Streptococcus pneumoniae, type 3 polysaccharide and pneumolysoid (T+P), which suppress allergic airways disease (AAD) in mouse models of asthma. To elucidate the mechanisms of suppression, we have now performed a thorough examination of the role of Tregs. BALB/c mice were sensitized to OVA (day 0) i.p. and challenged intranasal (12-15 d later) to induce AAD. T+P was administered intratracheally at the time of sensitization in three doses (0, 12, and 24 h). T+P treatment induced an early (36 h-4 d) expansion of Tregs in the mediastinal lymph nodes, and later (12-16 d) increases in these cells in the lungs, compared with untreated allergic controls. Anti-CD25 treatment showed that Treg-priming events involving CD25, CCR7, IL-2, and TGF-β were required for the suppression of AAD. During AAD, T+P-induced Tregs in the lungs displayed a highly suppressive phenotype and had an increased functional capacity. T+P also blocked the induction of IL-6 to prevent the Th17 response, attenuated the expression of the costimulatory molecule CD86 on myeloid dendritic cells (DCs), and reduced the number of DCs carrying OVA in the lung and mediastinal lymph nodes. Therefore, bacterial components (T+P) drive the differentiation of highly suppressive Tregs, which suppress the Th2 response, prevent the Th17 response and disable the DC response resulting in the effective suppression of AAD.
    MeSH term(s) Animals ; Asthma/immunology ; B7-2 Antigen/biosynthesis ; Cells, Cultured ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Female ; Inflammation/immunology ; Interleukin-2/metabolism ; Interleukin-2 Receptor alpha Subunit/metabolism ; Interleukin-6/biosynthesis ; Lung/immunology ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred BALB C ; Ovalbumin/immunology ; Polysaccharides, Bacterial/administration & dosage ; Polysaccharides, Bacterial/immunology ; Receptors, CCR7/metabolism ; Streptococcus pneumoniae/immunology ; T-Lymphocytes, Regulatory/immunology ; Th17 Cells/immunology ; Th2 Cells/immunology ; Transforming Growth Factor beta/metabolism
    Chemical Substances B7-2 Antigen ; Ccr7 protein, mouse ; Interleukin-2 ; Interleukin-2 Receptor alpha Subunit ; Interleukin-6 ; Polysaccharides, Bacterial ; Receptors, CCR7 ; Transforming Growth Factor beta ; pneumococcal polysaccharide, type III ; Ovalbumin (9006-59-1)
    Language English
    Publishing date 2013-10-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1201232
    Database MEDical Literature Analysis and Retrieval System OnLINE

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