Front. Immunol., 31 May 2013 | doi: 10.3389/fimmu.2013.00129

Regulation of adaptive immunity; the role of interleukin-10

T. H. Sky Ng, Graham J. Britton, Elaine V. Hill, Johan Verhagen, Bronwen R. Burton and David C. Wraith*

• School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK

Since the discovery of interleukin-10 (IL-10) in the 1980s, a large body of work has led to its recognition as a pleiotropic immunomodulatory cytokine that affects both the innate and adaptive immune systems. IL-10 is produced by a wide range of cell types, but for the purposes of this review we shall focus on IL-10 secreted by CD4⁺ T cells. Here we describe the importance of IL-10 as a mediator of suppression used by both FoxP3⁺and FoxP3⁻ T regulatory cells. Moreover, we discuss the molecular events leading to the induction of IL-10 secretion in T helper cell subsets, where it acts as a pivotal negative feedback mechanism. Finally we discuss how a greater understanding of this principle has allowed for the design of more efficient, antigen-specific immunotherapy strategies to exploit this natural phenomenon clinically.

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Keywords: allergy, autoimmunity, cytokines, immune regulation, immunotherapy, interleukin-10, regulatory T cells, T helper cells

Citation: Ng THS, Britton GJ, Hill EV, Verhagen J, Burton BR and Wraith DC (2013) Regulation of adaptive immunity; the role of interleukin-10. Front. Immunol. 4:129. doi: 10.3389/fimmu.2013.00129

Received: 01 May 2013; Paper pending published: 13 May 2013;
Accepted: 15 May 2013; Published online: 31 May 2013.

Edited by:

Eyad Elkord, United Arab Emirates University, UAE; University of Salford and University of Manchester, UK

Reviewed by:

Giovanna Lombardi, Kings College London, UK
Bin Li, Chinese Academy of Sciences, China

Copyright: © 2013 Ng, Britton, Hill, Verhagen, Burton and Wraith. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: David C. Wraith, School of Cellular and Molecular Medicine, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK e-mail: d.c.wraith@bristol.ac.uk

Rocuronium anaphylaxis in a 3-year-old girl with no previous exposure to neuromuscular blocking agents

 

Asian Pacific Journal of Allergy and Immunology Vol. 31, No. 2, June 2013 > Choi

Rocuronium anaphylaxis in a 3-year-old girl with no previous exposure to neuromuscular blocking agents

Sun-Hee Choi, Jae-Woo Yi, Yeong-Ho Rha

Abstract

During the perioperative period, anaphylactic reactions rarely occur. Neuromuscular blocking agents (NMBAs) are responsible for 60-70% of perioperative anaphylactic reactions. This case, we report a case of rocuronium-induced anaphylaxis in a 3-year-old girl with no previous exposure to NMBAs. This case cautions and informs practitioners that an IgE-mediated anaphylactic reaction with rocuronium is possible even in young children with no previous exposure to NMBAs

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How to Translate Basic Knowledge into Clinical Application of Biologic Therapy in Spondyloarthritis

Clinical and Developmental Immunology
Volume 2013 (2013), Article ID 369202, 6 pages
http://dx.doi.org/10.1155/2013/369202

Review Article

How to Translate Basic Knowledge into Clinical Application of Biologic Therapy in Spondyloarthritis

Chung-Tei Chou

Division of Allergy-Immunology-Rheumatology, Department of Medicine, Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, Taipei 112, Taiwan

Received 7 November 2012; Accepted 24 May 2013

Academic Editor: Jieruo Gu

Copyright © 2013 Chung-Tei Chou. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Spondyloarthritis (SpA) is a family of many diseases, and these diseases share some clinical, genetic, and radiologic features. The disease process in the spine at the beginning is spinal inflammation, in which TNFα is the principal cytokine involved. Therefore, the dramatic clinical and pathologic response of anti-TNFα therapy in SpA is based upon the presence of increased TNFα in synovial tissues and sacroiliac joints, which perpetuates chronic inflammation. The increased Toll-like receptors (TCR) 2 and 4 in the serum, peripheral blood mononuclear cells, or synovial tissues of ankylosing spondyloarthritis (AS) or SpA patients suggest that SpA is highly associated with innate immunity. Any drug including anti-TNFα blocker which can downregulate the TCR, infiltrated neutrophils, or CD163+ macrophages in the synovial tissue is the rationale for the management of SpA. Like rheumatoid arthritis, the increased TH22 and TH17 cells either in blood, synovial fluid, or synovial tissues were also demonstrated in SpA. Thus, TH17 and TH22 may be reasonable cellular targets for therapeutic intervention. Drugs (anti-IL6R or anti-IL6) which can reduce the binding of IL6 and IL6R to the cell surface may be beneficial in SpA. Many proteins are implicated in the new bone formation (syndesmophyte) or ankylosis in AS or SpA. The enhanced BMP and Wnt pathway will activate osteoblasts which promote the new bone formation. However, no drug including anti-TNFα can stop or prevent the syndesmophyte in AS. In summary, looking for new targeting therapies for either anti-inflammation (beyond anti-TNF) or anti-bone formation (including anti-TGFβ or PDGF) is warranted in the future.

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Factors associated with cord blood IgE levels

Asian Pacific Journal of Allergy and Immunology Vol. 31, No. 2, June 2013 > Nabavi

Factors associated with cord blood IgE levels

Mohammad Nabavi, Raheb Ghorbani, Amir Massod Asadi, Mohammad Faranoush

Abstract

Background:  The cord blood IgE level is thought to be a predictor of allergic disorders in childhood. It is not well understood how this marker is influenced by the fetal environment, such as maternal, paternal, placenta, and fetal characteristics. 

Objective: We aimed to investigate the association between cord blood IgE levels and various genetic and environmental factors.

Methods: This was a cross-sectional study including a total of 181 neonates and their mothers. A questionnaire asking about demographic data, delivery characteristics, maternal past medical history and information on exposure to known environmental allergens was distributed to pregnant women. Blood samples from them and neonatal cord blood samples were taken at the same time for IgE assay.

Conclusion: Among the evaluated factors, the presence of any kind of allergic disorder in the mother or her family and elevated maternal blood IgE level are associated with the  cord blood IgE of the child. Maternal age and smoking, neonatal gender, type of delivery, season of birth and parity are probable predictors. 

Results:  By univariate analysis we found an association between cord blood IgE levels and higher number of previous pregnancies, delivery season, type of delivery, history of allergy during pregnancy, but not the type of allergic disease and history of allergic disease before pregnancy, were associated with elevated cord blood IgE
levels. The maternal blood level of IgE was correlated with its level in cord blood. By multivariate analysis, the number of previous pregnancies, the type and season of delivery and a history of allergy during pregnancy and maternal age and blood IgE levels were variables which had a significant association with cord blood IgE levels. 

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Research

Ingestion of milk containing the Dp2 peptide, a dust mite allergen, protects mice from allergic airway inflammation and hyper-responsiveness

Hsu-Chung Liu, Shun-Yuan Pai, Winston TK Cheng, Hsiao-Ling Chen, Tung-Chou Tsai, Shang-Hsun Yang and Chuan-Mu Chen

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Allergy, Asthma & Clinical Immunology 2013, 9:21 doi:10.1186/1710-1492-9-21

Published: 13 June 2013

Abstract (provisional)

Background

Allergen-specific immunotherapy has been demonstrated to have potential for the treatment of allergic diseases. Transgenic animals are currently the best available bioreactors to produce recombinant proteins, which can be secreted in milk. It has not been clearly demonstrated whether milk from transgenic animals expressing recombinant allergens has immunomodulatory effects on allergic asthma.

Methods

We aimed to determine whether the oral administration of milk containing a mite allergen can down-regulate allergen-specific airway inflammation. Transgenic CD-1 mice that express a recombinant group 2 allergen from Dermatophagoides pteronyssinus (Dp2) in their milk were generated using an embryonic gene-microinjection technique. Mouse pups were fed transgenic Dp2-containing milk or wild-type milk. Subsequently, these mice were sensitized and challenged with Dp2 to induce allergic airway inflammation.

Results

Upon sensitization and challenge, mice fed transgenic Dp2 milk had decreased T-helper 2 (Th2) and increased T-helper 1 (Th1) responses in the airway compared with mice fed wild-type milk. Moreover, pre-treatment with transgenic Dp2 milk attenuated airway inflammation and decreased airway hyper-responsiveness.

Conclusions

This study provides new evidence that oral administration of transgenic milk containing the Dp2 allergen down-regulated and moderately protected against allergic airway inflammation. Milk from transgenic animals expressing allergens may have potential use in the prevention of allergic asthma.

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Epigenetic regulation of inducible gene expression in the immune system.

Immunology

Volume 139, Issue 3, pages 285–293, July 2013

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Epigenetic regulation of inducible gene expression in the immune system

1. Pek Siew Lim¹, 
2. Jasmine Li^1,2, 
3. Adele F Holloway^3,*, 
4. Sudha Rao^1,*

Article first published online: 13 JUN 2013

DOI: 10.1111/imm.12100

© 2013 John Wiley & Sons Ltd

Summary

T cells are exquisitely poised to respond rapidly to pathogens and have proved an instructive model for exploring the regulation of inducible genes. Individual genes respond to antigenic stimulation in different ways, and it has become clear that the interplay between transcription factors and the chromatin platform of individual genes governs these responses. Our understanding of the complexity of the chromatin platform and the epigenetic mechanisms that contribute to transcriptional control has expanded dramatically in recent years. These mechanisms include the presence/absence of histone modification marks, which form an epigenetic signature to mark active or inactive genes. These signatures are dynamically added or removed by epigenetic enzymes, comprising an array of histone-modifying enzymes, including the more recently recognized chromatin-associated signalling kinases. In addition, chromatin-remodelling complexes physically alter the chromatin structure to regulate chromatin accessibility to transcriptional regulatory factors. The advent of genome-wide technologies has enabled characterization of the chromatin landscape of T cells in terms of histone occupancy, histone modification patterns and transcription factor association with specific genomic regulatory regions, generating a picture of the T-cell epigenome. Here, we discuss the multi-layered regulation of inducible gene expression in the immune system, focusing on the interplay between transcription factors, and the T-cell epigenome, including the role played by chromatin remodellers and epigenetic enzymes. We will also use IL2, a key inducible cytokine gene in T cells, as an example of how the different layers of epigenetic mechanisms regulate immune responsive genes during T-cell activation.

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Letter to the editor

Antibiotic skin testing accompanied by provocative challenges in children is a useful clinical tool

Fotini D Kavadas, Anna Kasprzak and Adelle R Atkinson

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Allergy, Asthma & Clinical Immunology 2013, 9:22 doi:10.1186/1710-1492-9-22

Published: 14 June 2013

Abstract (provisional)

Background

Diagnostic testing to antibiotics other than to penicillin has not been widely available, making the diagnosis of antibiotic allergy difficult and often erroneous. There is often reluctance in performing challenges to antibiotics when standardized testing is lacking. However, while the immunogenic determinants are not known for most antibiotics, a skin reaction at a non-irritating concentration (NIC) may mean that antibodies to the native form are present in the circulation. While the NIC's for many non penicillin antibiotics have been determined in adults, the use of these concentrations for skin testing pediatric subjects prior to provocative challenge has not been done. Our objective was to determine if we could successfully uncover the true nature of antibiotic allergy in children using these concentrations for testing.

Methods

Children were included between 2003--2009 upon being referred to the Drug and Adverse Reaction/Toxicology (DART) clinic of the Hospital for Sick Children in Toronto, Ontario Canada. The referral needed to demonstrate that clinical care was being compromised by the limitation in antibiotic options or there was a significant medical condition for which the label of antibiotic allergy may prove detrimental. Patients were not seen if there was a suggestion of serum like sickness, Stevens Johnson Syndrome or Toxic Epidermal Necrolysis. Patients were excluded from testing if there was objective evidence of anaphylaxis. All other patients were consented to receive testing and/or challenges. A retrospective chart review was then performed of the results.

Results

We were able to exclude an antibiotic allergy in the majority of our patients who had a negative intradermal test result and were then challenged (>90%). Only one patient was challenged with a positive intradermal test to Cotrimoxazole because of a questionable history and this patient failed the provocative challenge. While we did not challenge more patients with positive testing, we did note that 10/11 (91%) patients with positive intradermal testing had some aspect of a Type 1 reaction in their history.

Conclusions

Through testing with NIC's of various antibiotics in children and providing provocative challenges based on negative skin testing results, we were able to advance the medical care of the majority of our patients by increasing their antibiotic options in order to successfully treat future infections. While challenging patients with positive testing was not deemed ethically appropriate at this stage of our study, it would be a useful future step to reaching statistical validity of testing to these antibiotics.

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ANALYSIS

Restoring invisible and abandoned trials: a call for people to publish the findings

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f2865 (Published 13 June 2013)

Cite this as: BMJ 2013;346:f2865

1. Peter Doshi, postdoctoral fellow1, 
2. Kay Dickersin, professor, director234, 
3. David Healy, professor of psychiatry5, 
4. S Swaroop Vedula, postdoctoral fellow6, 
5. Tom Jefferson, researcher7

Author Affiliations

1. Correspondence to: P Doshi, Reed Hall West, Room 201-C, 1620 McElderry Street, Baltimore, MD 21205, USA pdoshi@post.harvard.edu

• Accepted 5 April 2013

Unpublished and misreported studies make it difficult to determine the true value of a treatment. Peter Doshi and colleagues call for sponsors and investigators of abandoned studies to publish (or republish) and propose a system for independent publishing if sponsors fail to respond

Well designed and well performed randomised controlled trials are considered to provide the most reliable evidence on the effects of health related interventions. However, the credibility of findings from individual trials and from summaries of trials examining a similar research question (that is, systematic reviews and meta-analyses) has been undermined by numerous reporting biases in the published medical literature.1 2 3 4 5 6 7 8 9 10 11 12 13 14 Reporting biases are often difficult to detect, but have the potential to discredit earnest efforts towards evidence based decision making.

Two basic problems of representation are driving growing concerns about relying on published research to reflect the truth.10 15 The first is no representation (invisibility), which occurs when a trial remains unpublished years after completion. The second is distorted representation (distortion), which occurs when publications in medical journals present a biased or misleading description of the design, conduct, or results of a trial.1 6 10 14 Both go against the fundamental scientific and ethical responsibility that all research on humans be used to advance knowledge and are symptomatic of a general culture of data secrecy. The end result is that the healthcare, biomedical research, and policy communities may, despite best intentions and best practices, end up drawing scientifically invalid conclusions based on only those parts of the evidence base they can see.

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