Induction of Tolerance to Innocuous Inhaled Antigen Relies on a CCR7-Dependent Dendritic Cell-Mediated Antigen Transport to the Bronchial Lymph Node

Hintzen, Gabriele; Ohl, Lars; Rio, María-Luisa del; Rodríguez-Barbosa, José-Ignacio; Pabst, Oliver; Kocks, Jessica R.; Krege, Janet; Hardtke, Svenja; Förster, Reinhold

doi:10.4049/jimmunol.177.10.7346

Cited by 194 publications

(191 citation statements)

References 39 publications

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“…Yen et al 26 reported that DCs matured within inflammatory sites require both chemokine receptor type 7 and prostaglandin E2-induced MMP9 for directional migration to draining lymph nodes. Hintzen et al 27 reported that continuous DC-mediated transport of inhaled antigen to the bronchial lymph node is critical for the induction of tolerance to innocuous antigens. The roles of MMP9 are not restricted to DC migration.…”

Section: Discussionmentioning

confidence: 99%

Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis

et al. 2012

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Matrix metalloproteinase 9 (MMP9) gene has been shown to be involved in the pathogenesis of allergic rhinitis (AR) and asthma. Previous studies suggested that single-nucleotide polymorphisms (SNPs) of the MMP9 gene conferred a risk for childhood asthma. However, whether the SNPs confer a risk for AR has not been previously investigated. The objective of this study was to investigate whether SNPs of the MMP9 gene are associated with risk of seasonal AR (pollinosis), perennial AR and allergen sensitization. A total of 670 school children were recruited in Japan and genotyped for functional polymorphism in the promoter (-1590C/T: rs3918242) and three amino-acid substitutions (R297Q: rs17576; P574R: rs2250889; R668Q: rs17577). Serum levels of total and specific IgE were determined. Disease status and other clinical characteristics of the subjects were investigated using a questionnaire. Associations between the MMP9 SNPs and both AR and serum IgE levels were evaluated. -1590C/T showed significant association with cedar pollinosis (corrected P (Pcor)¼0.039). R668Q was in strong linkage disequilibrium (LD) with -1590C/T and showed significant association with cedar pollinosis (Pcor¼0.023) and serum cedar pollen-specific IgE level (Pcor¼0.022). A haplotype associated with -1590T and 668Q showed a significant association with cedar pollinosis, orchard grass pollinosis and cedar pollen-specific IgE (Pcor¼0.0012, Pcor¼0.0059 and Pcor¼0.0041, respectively). R297Q and P574R were in weak LD with the rest of the SNPs and did not show significant association with disease. Compared with wild-type MMP9 protein (279R-574P-668R), a variant enzyme (279R-574P-668Q) that showed association with pollinosis had lower activity. However, lower enzyme activity was not associated with disease risk because another variant (279Q-574R-668R) showed lower enzyme activity but was not associated with pollinosis. The -1590T allele and its corresponding haplotype was associated with higher promoter activity and with pollen-specific IgE levels and pollinosis, suggesting that -1590C/T may have more impact on sensitization and disease development than R668Q. Our results suggest that the MMP9 gene confers susceptibility to cedar pollinosis in Japanese children. The MMP9 gene may be associated with pollinosis through sensitization processes. Journal of Human Genetics (2012) 57, 176-183; doi:10.1038/jhg.2011.148; published online 12 January 2012 Keywords: allergic rhinitis; association; cedar pollinosis; haplotype; matrix metalloproteinase; MMP9 gene; serum IgE; SNP INTRODUCTIONThe main symptoms of allergic rhinitis (AR) are nasal congestion caused by mucosal edema; runny nose caused by hypersecretion; and repetitive sneezing. Pollinosis is a seasonal type of AR caused by an allergic reaction to pollen. Japanese cedar pollen is the most common causative allergen for pollinosis in Japan. According to a recent study, the prevalence rates of AR and cedar pollinosis in 2006 were 27.2 and 8.0%, respectively; both of which were higher than the rates in 1996. 1...

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Section: Discussionmentioning

confidence: 99%

Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis

et al. 2012

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“…Some investigators could show that tolerance induction and formation of Treg depends on an intact pDC system [9,36,37]. Others found that tolerance also required cDC that migrated to the MLN in a CCR7-dependent manner [38,39]. In some models of inhalation tolerance, CD103 1 CD11b À cDC were better at cross-tolerizing the CD8 1 lymphocytes, whereas CD11b hi cDC tolerized CD4 1 T cells.…”

Section: Antigen Presentation and T-cell Polarizationmentioning

confidence: 99%

Origin and functional specializations of DC subsets in the lung

2010

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Lung DC bridge innate and adaptive immunity, and depending on the context, induce Th1, Th2 or Th17 response, to optimally clear infections. Conversely, lung DC can also prevent overt and harmful immune responses to harmless inhaled antigens via induction of Treg cells or via induction of neutralizing mucosal IgA antibodies. Here, we propose that these functions are not the result of a single population of DC, and instead, subsets of DC perform specialized functions.

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“…For continuous BrdU incorporation, mice were injected initially with 3 mg of BrdU in 200 l of PBS and subsequently received BrdU via the drinking water (80 mg of BrdU in 100 ml of water). Induction of allergic Ag-specific reactions in the lung and intestine by sensitization/challenge with OVA has been described previously (14,15). Ag challenge was performed either as dried OVA aerosol (1% OVA in water for 20 min/day) for 7 consecutive days or orally every second day (50 mg of OVA in PBS by gavage) for five to six times.…”

Section: Micementioning

confidence: 99%

Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine

Carlens

Wahl

Ballmaier

et al. 2009

The Journal of Immunology

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101

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Eosinophils are potent effector cells that are recruited to sites of inflammation. However, in some tissues, in particular in the gastrointestinal tract, eosinophils constitute an abundant leukocyte population also under homeostatic conditions. The lack of suitable isolation protocols restricted the analysis of these cells to histological assessment of cell numbers while important aspects of their phenotype, turnover, and functions remain unresolved. In this study, we report a protocol that allows the quantitative isolation of intestinal eosinophils. We characterized small intestinal eosinophils by flow cytometry as SSChighCD11b+CD11c+CCR3+Siglec-F+ cells. Intestinal eosinophils resembled eosinophils isolated from thymus and uterus but differed from eosinophils isolated from lung or blood. Eosinophils in intestine, thymus, and uterus showed in vivo a markedly higher life time compared with eosinophils present in lung and blood measured by incorporation of BrdU. This indicates that under steady-state conditions homeostasis of eosinophils is controlled by regulation of cell survival. Intestinal eosinophils are severely reduced in the intestines of Rag-2/common γ-chain double-deficient mice but not Rag-2-deficient mice, correlating with differential expression of GM-CSF and CCL11 in both mouse strains. Moreover, under steady-state conditions, intestinal eosinophils constitutively express high levels of the common γ-chain transcripts compared with lung eosinophils as well as eosinophils present under inflammatory conditions. These observations reveal a hitherto unrecognized diversity in phenotypic and functional properties of eosinophils and suggest that tissue-specific common γ-chain-dependent signals might profoundly affect eosinophil function and homeostasis.

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Induction of Tolerance to Innocuous Inhaled Antigen Relies on a CCR7-Dependent Dendritic Cell-Mediated Antigen Transport to the Bronchial Lymph Node

Cited by 194 publications

References 39 publications

Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis

Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis

Origin and functional specializations of DC subsets in the lung

Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine

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