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Front. Immunol., 12 August 2013 | doi: 10.3389/fimmu.2013.00227

Antigen and transforming growth factor beta receptors contribute to long term functional and phenotypic heterogeneity of memory CD8 T cells

Yinghong Hu and Linda Cauley*

• University of Connecticut Health Center, Farmington, CT, USA

Pathogen-specific CD8 T cells provide a mechanism for selectively eliminating host cells that are harboring intracellular pathogens. The pathogens are killed when lytic molecules are injected into the cytoplasm of the infected cells and begin an apoptotic cascade. Activated CD8 T cells also release large quantities of pro-inflammatory cytokines that stimulate other immune cells in the local vicinity. As the alveoli are extraordinarily sensitive to cytokine induced damage, multiple layers of immune regulation limit the activities of immune cells that enter the lungs. These mechanisms include receptor-mediated signaling pathways in CD8 T cells that respond to peptide antigens and transforming growth factor β. Both pathways influence the functional and phenotypic properties of long-lived CD8 T cells populations in peripheral and lymphoid tissues.

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Keywords: transforming growth factor beta, CD8 T cells, homing receptors, prolonged antigen presentation, tissue-resident memory cells, migration

Citation: Hu Y and Cauley L (2013) Antigen and transforming growth factor beta receptors contribute to long term functional and phenotypic heterogeneity of memory CD8 T cells.Front. Immunol. 4:227. doi: 10.3389/fimmu.2013.00227

Received: 07 April 2013; Accepted: 18 July 2013;
Published online: 12 August 2013.

Edited by:

Susan Swain, University of Massachusetts Medical School, USA

Reviewed by:

David Hildeman, Cincinnati Children’s Hospital, USA
Shahram Salek-Ardakani, University of Florida, USA

Copyright: © 2013 Hu and Cauley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Linda Cauley, University of Connecticut Health Center, 263 Farmington Avenue, MC1319 Farmington, CT 06032, USA e-mail: lcauley@uchc.edu

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Research

Myofibroblast expression in airways and alveoli is affected by smoking and COPD

Henna M Karvonen, Siri T Lehtonen, Terttu Harju, Raija T Sormunen, Elisa Lappi-Blanco,Johanna M Mäkinen, Kirsi Laitakari, Shirley Johnson and Riitta L Kaarteenaho

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Respiratory Research 2013, 14:84 doi:10.1186/1465-9921-14-84

Published: 11 August 2013

Abstract (provisional)

Background

Chronic obstructive pulmonary disease (COPD) is characterized by structural changes in alveoli and airways. Our aim was to analyse the numbers of alpha-smooth muscle actin (alpha-SMA) positive cells, as a marker of myofibroblasts, in different lung compartments in non-smokers and smokers with normal lung function or COPD.

Methods

alpha-SMA, tenascin-C (Tn-C) and EDA-fibronectin in alveolar level and airways were assayed by immunohistochemistry and quantified by image analysis. Immunohistochemical findings were correlated with clinical data. alpha-SMA protein was also analysed by Western blotting from fibroblastic cells cultured from peripheral lung of non-smokers, smokers without COPD and smokers with COPD.

Results

In many cases, the endings of the detached alveolar walls were widened, the structures of which were named as widened alveolar tips. Widened alveolar tips contained alpha-SMA positive cells, which were obviously myofibroblasts. There were less alveolar tips containing positive cells for alpha-SMA in alveoli and alpha-SMA positive cells in bronchioles in smokers and in COPD compared to non-smokers. The quantity of alpha-SMA positive cells was increased in bronchi in COPD. Tn-C was elevated in bronchi in COPD and smokers' lung. The alpha-SMA protein level was 1.43-fold higher in stromal cells cultured from non-smokers than in those of smokers.

Conclusions

Myofibroblasts are localized variably in normal and diseased lung. This indicates that they have roles in both regeneration of lung and pathogenesis of COPD. The widened alveolar tips, these newly characterized histological structures, seemed to be the source of myofibroblasts at the alveolar level.

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 International Journal of General Medicine

Role of leukotrienes in exercise-induced bronchoconstriction before and after a pilot rehabilitation training program

Original Research

(273) Total Article Views

Authors: El-Akkary IM, El-Khouly ZA, El-Seweify ME, El-Batouti GA, Abdel Aziz E, Adam AI

Published Date July 2013 Volume 2013:6 Pages 631 - 636

DOI: http://dx.doi.org/10.2147/IJGM.S46953

Received:	19 April 2013
Accepted:	05 June 2013
Published:	29 July 2013

Ibrahim M El-Akkary,¹ Zeinat Abdel-Fatah El-Khouly,² Mervat El-Sayed El-Seweify,¹ Gihan A El-Batouti,³ Ekhlas Abdel Aziz,² Abdelnasser I Adam^1
1Department of Human Physiology, ²Department of Applied Medical Chemistry, Medical Research Institute, Alexandria University, ³Department of Microbiology and Immunology, Faculty of Pharmacy, Pharos University, Alexandria, Egypt

Background: Whatever the initial stimulus for the exercise-induced bronchoconstriction (EIB) observed in asthmatic patients after exercise, the final effect is release of bronchoactive mediators, especially cysteinyl leukotrienes. Exercise rehabilitation training programs have been reported to protect against EIB. The exact mechanism(s) involved are not well understood. However, this protective effect may be related to adaptation and better coordination during exercise, depletion of cysteinyl leukotrienes, and/or a sluggish cysteinyl leukotriene response to exercise. The aim of the present work was to test the hypothesis that improvement in the incidence and severity of post-exercise bronchoconstriction after a rehabilitation training program is related to a change in leukotriene levels in response to exercise.
Methods: Twenty asthmatic children aged 6–12 years and known to develop EIB were enrolled in an exercise training program for 12 weeks. The severity and incidence of EIB before and after training was assessed. Baseline and post-exercise sputum cysteinyl leukotriene levels were assessed before and after the training program.
Results: The training program offered significant protection against EIB with a concomitant decrease in sputum cysteinyl leukotriene levels in response to exercise.
Conclusion: A training program can result in depletion and/or a sluggish cysteinyl leukotriene response to exercise and may be responsible for the protective effect of training programs on EIB. It is recommended to use an exercise rehabilitation training program as a complementary tool in the management of bronchial asthma, especially EIB.

Keywords: asthma, leukotrienes, exercise-induced bronchoconstriction, sputum, cysteinyl leukotriene, rehabilitation training program




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Association between Interleukin-4 Receptor α Chain (IL4RA) I50V and Q551R Polymorphisms and Asthma Risk

OPEN ACCESS PEER-REVIEWED

RESEARCH ARTICLE

Association between Interleukin-4 Receptor α Chain (IL4RA) I50V and Q551R Polymorphisms and Asthma Risk: An Update Meta-Analysis

Wei Nie equal contributor,

 

Yuansheng Zang equal contributor,

 

Jiquan Chen equal contributor,

 

Qingyu Xiu mail

Abstract

Background

The associations between the interleukin-4 receptor α chain (IL4RA) I50V and Q551R polymorphisms and asthma risk remained controversial.

Methods

We searched the Pubmed, Embase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases for studies published before February 2013. The strengths of the associations were calculated using odds ratios (ORs) with 95% confidence intervals (CIs).

Results

A total of 50 studies were included in this meta-analysis. There was a significant association between the IL4RA I50V polymorphism and asthma risk in a dominant genetic model (OR = 1.13, 95% CI 1.04–1.23, P = 0.005). The IL4RA Q551R polymorphism was associated with a significantly elevated asthma risk in a recessive genetic model (OR = 1.46, 95% CI 1.22–1.75,P-0.0001). Subgroup analyses found that the IL4RA I50V polymorphism was significantly associated with asthma risk in Asians (OR = 1.72, 95% CI 1.31–2.25, P-0.0001), pediatric asthma risk (OR = 1.50, 95% CI 1.13–1.99, P = 0.005), and atopic asthma risk (OR = 1.88, 95% CI 1.27–2.79, P = 0.002).

Conclusions

The results of this meta-analysis suggested that the IL4RA I50V and Q551R polymorphisms may be risk factors for developing asthma.

Citation: Nie W, Zang Y, Chen J, Xiu Q (2013) Association between Interleukin-4 Receptor α Chain (IL4RA) I50V and Q551R Polymorphisms and Asthma Risk: An Update Meta-Analysis. PLoS ONE 8(7): e69120. doi:10.1371/journal.pone.0069120

Editor: Andreas Zirlik, University Heart Center Freiburg, Germany

Received: April 5, 2013; Accepted: June 12, 2013; Published: July 26, 2013

Copyright: © 2013 Nie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by grants No. 81170025 from National Natural Science Foundation of China and projects of “Major New Drugs Innovation and Development” from the National Ministry of Science and Technology (No. 2011ZX09302-003-001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

• Abstract
• Introduction
• Methods
• Results
• Discussion
• Supporting Information
• Acknowledgments
• Author Contributions
• References
• Reader Comments (0)
• Figures

Association between the polymorphisms of interleukin-4, the interleukin-4 receptor gene and asthma

Chinese Medical Journal 2013;126(15):2943-2951

Association between the polymorphisms of interleukin-4, the interleukin-4 receptor gene and asthma

ZHU Ning, GONG Yi, CHEN Xiao-dong, ZHANG Jing, LONG Feng, HE Jian, XIA Jing-wen and DONG Liang

Keywords

interleukin-4; interleukin-4 receptor; asthma; gene polymorphism; case-controlled study; meta-analysis

Abstract

Background Interleukin-4 (IL4) is one of the most important cytokines involved in a variety of 

allergic disorders, particularly, asthma. A number of genetic epidemiological studies have identified 

an association between the gene polymorphisms of IL4 and interleukin-4 receptor (IL4R) and asthma 

in different populations. However, these studies have been inconsistent and inconclusive. The aim of this 

study was to investigate the association between the single nucleotide polymorphism (SNP) of IL-4, 

IL-4R and asthma risk in case-controlled studies using meta-analysis.

Method A genetic model-free approach was used to perform the meta-analysis. Asthma (atopy status 

nondefined), nonatopic and atopic asthma subgroups were separately analyzed. Next, the ethnic 

subgroup was analyzed. Heterogeneity and publication bias were also explored.

Results Only two polymorphisms of IL4 (rs2243250 and rs2070874) and four polymorphisms of 

IL4R (rs1801275, rs1805011, rs1805010, and rs1805015) were included in the meta-analysis. 

Polymorphisms rs2243250 and rs2070874 of IL-4 and rs1801275 and rs1805011 of IL4R were associated 

with asthma. The overall odds ratio (OR) of rs2243250 in the CC versus TT+TC genotypes was 0.84 

(95% CI: 0.75–0.94), and the Z-test for the overall effect was 3.0 (P=0.003). We obtained significant 

results from this polymorphism in the Caucasian ethnicity and adult groups. However, the overall OR of 

rs1801275 for the GG+AG versus AA genotype was 1.16 (95% CI: 1.00–1.35), and the Z-test for the 

overall effect was 1.87 (P=0.06). Moreover, significant results were only obtained from the sub-group 

analysis in Asians (P=0.02). In the rs1805011 polymorphism of IL4R, the overall OR for the CC +AC versus 

AA genotypes was 0.39 (95% CI: 0.16–0.95), and the Z-test for the overall effect was 2.08 (P=0.04).

Conclusions

Both the IL4 and IL4R polymorphisms were associated with asthma. The rs2243250 polymorphism of IL4 

was more important in the white and adult groups. Individuals who carried the C allele for rs2070874 of the 

IL4 gene demonstrated increased asthma risk compared to TT homozygotes. An individual with an AA 

genotype in rs1805011 of the IL4R gene was less likely to suffer from asthma compared to the other two 

genotypes.

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General practice variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease

Research article

General practice variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease in Denmark: a population-based observational study

Mette M Koefoed, Jens Søndergaard, René dePont Christensen and Dorte E Jarbøl

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BMC Family Practice 2013, 14:113 doi:10.1186/1471-2296-14-113

Published: 7 August 2013

Abstract (provisional)

Background

Spirometry testing is essential to confirm an obstructive lung disease, but studies have reported that a large proportion of patients diagnosed with COPD or asthma have no history of spirometry testing. Also, it has been shown that many patients are prescribed medication for obstructive lung disease without a relevant diagnosis or spirometry test registered. General practice characteristics have been reported to influence diagnosis and management of several chronic diseases. However, these findings are inconsistent, and it is uncertain whether practice characteristics influence spirometry testing among patients receiving medication for obstructive lung disease. The aim of this study was therefore to examine if practice characteristics are associated with spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease.

Methods

A national register-based cohort study was performed. All patients over 18 years receiving first-time prescriptions for medication targeting obstructive lung disease in 2008 were identified and detailed patient-specific data on sociodemographic status and spirometry tests were extracted. Information on practice characteristics like number of doctors, number of patients per doctor, training practice status, as well as age and gender of the general practitioners was linked to each medication user.

Results

Partnership practices had a higher odds ratio (OR) of performing spirometry compared with single-handed practices (OR 1.24, CI 1.09-1.40). We found a significant association between increasing general practitioner age and decreasing spirometry testing. This tendency was most pronounced among partnership practices, where doctors over 65 years had the lowest odds of spirometry testing (OR 0.25, CI 0.10-0.61). Training practice status was significantly associated with spirometry testing among single-handed practices (OR 1.40, CI 1.10-1.79).

Conclusion

Some of the variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease was associated with practice characteristics. This variation in performance may indicate a potential for quality improvement.

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Research

GST-omega genes interact with environmental tobacco smoke on adult level of lung function

Kim de Jong, H Marike Boezen, Nick HT Hacken, Dirkje S Postma and Judith M Vonk

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Respiratory Research 2013, 14:83 doi:10.1186/1465-9921-14-83

Published: 9 August 2013

Abstract (provisional)

Background

Lung growth in utero and lung function loss during adulthood can be affected by exposure to environmental tobacco smoke (ETS). The underlying mechanisms have not been fully elucidated. Both ETS exposure and single nucleotide polymorphisms (SNPs) in Glutathione S-Transferase (GST) Omega genes have been associated with the level of lung function. This study aimed to assess if GSTO SNPs interact with ETS exposure in utero and during adulthood on the level of lung function during adulthood.

Methods

We used cross-sectional data of 8,128 genotyped participants from the LifeLines cohort study. Linear regression models (adjusted for age, sex, height, weight, current smoking, ex-smoking and packyears smoked) were used to analyze the associations between in utero, daily and workplace ETS exposure, GSTO SNPs, the interaction between ETS and GSTOs, and level of lung function (FEV1, FEV1/FVC). Since the interactions between ETS and GSTOs may be modified by active tobacco smoking we additionally assessed associations in never and ever smokers separately. A second sample of 5,308 genotyped LifeLines participants was used to verify our initial findings.

Results

Daily and workplace ETS exposure was associated with significantly lower FEV1 levels. GSTO SNPs (recessive model) interacted with in utero ETS and were associated with higher levels of FEV1, whereas the interactions with daily and workplace ETS exposure were associated with lower levels of FEV1, effects being more pronounced in never smokers. The interaction of GSTO2 SNP rs156697 with in utero ETS associated with a higher level of FEV1 was significantly replicated in the second sample. Overall, the directions of the interactions of in utero and workplace ETS exposure with the SNPs found in the second (verification) sample were in line with the first sample.

Conclusions

GSTO genotypes interact with in utero and adulthood ETS exposure on adult lung function level, but in opposite directions.

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