Association of Asthma Severity and Bronchial Hyperresponsiveness With a Polymorphism in the Cytotoxic T-Lymphocyte Antigen-4 Gene

Lee, Sang Yeub; Lee, Young Ho; Shin, Chol; Shim, Jae Jeong; Kang, Kyung Ho; Yoo, Se Hwa; In, Kwang Ho

doi:10.1378/chest.122.1.171

Cited by 65 publications

(58 citation statements)

References 23 publications

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“…Similarly, Hellings and colleagues (13) demonstrated an aggravation of Th2-mediated allergic airway disease during anti-CTLA-4 treatment. Furthermore, in humans, CTLA-4 promoter polymorphism has been linked to total serum IgE levels (18) and bronchial hyperresponsivity (19) in asthmatic patients, meaning CTLA-4 is implicated in regulating the intensity of allergic disease. Several nonmutually exclusive mechanisms can be proposed that may underlie regulation of an allergic response by CTLA-4 signaling.…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

Wijk¹,

Hoeks²,

Nierkens³

et al. 2005

The Journal of Immunology

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Although food allergy has emerged as a major health problem, the mechanisms that are decisive in the development of sensitization to dietary Ag remain largely unknown. CTLA-4 signaling negatively regulates immune activation, and may play a crucial role in preventing induction and/or progression of sensitization to food Ag. To elucidate the role of CTLA-4 signaling in responses to food allergens, a murine model of peanut allergy was used. During oral exposure to peanut protein extract (PPE) together with the mucosal adjuvant cholera toxin (CT), which induces peanut allergy, CTLA-4 ligation was prevented using a CTLA-4 mAb. Additionally, the effect of inhibition of the CTLA-4 pathway on oral exposure to PPE in the absence of CT, which leads to unresponsiveness to peanut Ag, was explored. During sensitization, anti-CTLA-4 treatment considerably enhanced IgE responses to PPE and the peanut allergens, Ara h 1, Ara h 3, and Ara h 6, resulting in elevated mast cell degranulation upon an oral challenge. Remarkably, antagonizing CTLA-4 during exposure to PPE in the absence of CT resulted in significant induction of Th2 cytokines and an elevation in total serum IgE levels, but failed to induce allergen-specific IgE responses and mast cell degranulation upon a PPE challenge. These results indicate that CTLA-4 signaling is not the crucial factor in preventing sensitization to food allergens, but plays a pivotal role in regulating the intensity of a food allergic sensitization response. Furthermore, these data indicate that a profoundly Th2-biased cytokine environment is insufficient to induce allergic responses against dietary Ag.

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Section: Discussionmentioning

confidence: 99%

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

Wijk¹,

Hoeks²,

Nierkens³

et al. 2005

The Journal of Immunology

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“…The same SNPs, however, were linked to elevated total serum IgE levels in both Dutch and Japanese asthmatics 20,21 and with either asthma severity or airway hyper-responsiveness in Korean patients. 22 The observations that PD-1 is likely to be involved in maintaining peripheral tolerance, and that its gene is adjacent to the 2q33 region, made PDCD1 a strong candidate susceptibility gene for asthma and its related phenotypes. We have undertaken a systematic search for SNPs in this gene and tested these for association to measures of atopy in two panels of families.…”

Section: Introductionmentioning

confidence: 99%

PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders

et al. 2005

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Variation in genes encoding costimulatory molecules expressed on lymphocytes has been expected to contribute to the genetic component of inflammatory disease, but only the gene encoding the inhibitory protein, CTLA-4, seems consistently to confer disease susceptibility. Studies in murine models implicate the inhibitory product of the pd1 gene, programmed death-1, in the maintenance of peripheral tolerance to self-antigens. We identify 22 single-nucleotide polymorphisms (SNPs) in the equivalent human gene, PDCD1, a number of which show significant associations with the specific immunoglobulin E response to grass allergens in atopic individuals. Stepwise analyses indicate that four of the disease-associated SNPs have independent effects. The two most common haplotypes show positive and negative associations but rarer haplotypes are also likely to be of influence. In a case-control study, multiple regression analysis of genotypic data implies that PDCD1 also confers susceptibility to rheumatoid arthritis. Along with work linking PDCD1 with susceptibility to another autoimmune condition, systemic lupus erythematosus, our data identify PDCD1 as a second immunomodulatory gene with pleiotropic effects in human disease. Genes encoding negative regulators may generally confer a significant fraction of the genetic risk associated with inherited inflammatory disorders.

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“…In human bronchial asthma, an association between certain single nucleotide polymorphisms (SNPs) within the CTLA-4 gene and increased total serum IgE levels (+49A/G [91]), bronchial hyperresponsiveness (BHR) (-1147C/T and +49A/G [92]) and asthma severity (-318C/T [92]) was demonstrated. In two other cohorts, no association of the +49A/G and -318C/T polymorphisms and the development of the asthma phenotype was found [93,94].…”

Section: Co-stimulatory Signals Regulate Allergic Airway Inflammationmentioning

confidence: 99%

T-cell co-stimulatory molecules: their role in allergic immune reactions

Kallinich¹,

Beier²,

Wahn³

et al. 2007

European Respiratory Journal

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The development of allergic diseases, such as allergic asthma, depends upon the initiation and maintenance of T-helper cell type-2-skewed allergen-specific immune reactions. Although it is clear that susceptibility to this process is under genetic and environmental control, the fine-tuning and regulation of the type-2 T-helper cell immune response is not yet fully understood. In this second article in the present series, current understanding regarding the involvement of T-cells and antigen-presenting cells is summarised, with emphasis on the interaction between these two types of immune regulatory cells by means of co-stimulatory molecules.

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Association of Asthma Severity and Bronchial Hyperresponsiveness With a Polymorphism in the Cytotoxic T-Lymphocyte Antigen-4 Gene

Cited by 65 publications

References 23 publications

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders

T-cell co-stimulatory molecules: their role in allergic immune reactions

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