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Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites.

Platzer B, Baker K, Vera MP, Singer K, Panduro M, Lexmond WS, Turner D, Vargas SO, Kinet JP, Maurer D, Baron RM, Blumberg RS, Fiebiger E - Mucosal Immunol (2014)

Bottom Line: Furthermore, conferring expression of FcɛRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcɛRI signals.Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcɛRI cross-linking on papain or lipopolysaccharide-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines.Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
Antigen-mediated cross-linking of Immunoglobulin E (IgE) bound to mast cells/basophils via FcɛRI, the high affinity IgE Fc-receptor, is a well-known trigger of allergy. In humans, but not mice, dendritic cells (DCs) also express FcɛRI that is constitutively occupied with IgE. In contrast to mast cells/basophils, the consequences of IgE/FcɛRI signals for DC function remain poorly understood. We show that humanized mice that express FcɛRI on DCs carry IgE like non-allergic humans and do not develop spontaneous allergies. Antigen-specific IgE/FcɛRI cross-linking fails to induce maturation or production of inflammatory mediators in human DCs and FcɛRI-humanized DCs. Furthermore, conferring expression of FcɛRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcɛRI signals. Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcɛRI cross-linking on papain or lipopolysaccharide-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines. Migration assays confirm that the IgE-dependent decrease in cytokine production results in diminished recruitment of mast cell progenitors; providing a mechanistic explanation for the reduced mast cell-dependent allergic phenotype observed in FcɛRI-humanized mice. Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.

No MeSH data available.


Related in: MedlinePlus

Food allergic responses are significantly reduced in IgER-TG animals. (a) Decreased mast cell-specific transcripts (i.e. mast cell proteases MCPT1, MCPT2, and carboxypeptidase A3 (CPA3)) and lower IL-4, IL-13, CCL-2, and IL-6 expression were detected in IgER-TGs. Sensitized mice are indicated by (+), non-sensitized mice by (−). Normalized mRNA counts or fold change in mRNA levels +/− SEM of small intestinal tissue of 4 independent experiments (per experiment tissue of ≥2 mice was pooled) are shown. (b) and (c) Small intestinal tissue sections were stained, and infiltrating mast cells were counted. (d) Assessment of mast cell protease MCPT1 in serum as a systemic readout for IgE-mediated mast cell activation. Serum was collected 1h after oral challenge. Symbols are representative of individual mice (n=2).
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Figure 4: Food allergic responses are significantly reduced in IgER-TG animals. (a) Decreased mast cell-specific transcripts (i.e. mast cell proteases MCPT1, MCPT2, and carboxypeptidase A3 (CPA3)) and lower IL-4, IL-13, CCL-2, and IL-6 expression were detected in IgER-TGs. Sensitized mice are indicated by (+), non-sensitized mice by (−). Normalized mRNA counts or fold change in mRNA levels +/− SEM of small intestinal tissue of 4 independent experiments (per experiment tissue of ≥2 mice was pooled) are shown. (b) and (c) Small intestinal tissue sections were stained, and infiltrating mast cells were counted. (d) Assessment of mast cell protease MCPT1 in serum as a systemic readout for IgE-mediated mast cell activation. Serum was collected 1h after oral challenge. Symbols are representative of individual mice (n=2).

Mentions: IgE-mediated food allergy presents with extensive Th2-type tissue inflammation in the small intestine, and intestinal mucosal mast cell numbers are an established quantitative measure of disease severity in mice and humans.39 Comparative quantitative mRNA profiling was performed to assess the extent of tissue inflammation in the small intestine of food-allergic animals. We found that the lamina propria of IgER-TG animals was overall substantially less inflamed (Figure 4a and Supplementary Table S2). mRNA transcripts of mast cell-specific proteases (MCPT-1 and MCPT-2, and carboxypeptidase A3), Th2-type cytokines (IL-4 and IL-13), and DC-derived inflammatory mediators such as CCL-2 and IL-6 were significantly less abundant in the tissue of IgER-TGs than in WT controls (Figure 4a). Expression of IFN-γ was low and did not change upon challenge (Supplementary Figure S5a). Additionally, significantly lower transcript levels of the Th2-specific cytokines IL-33 and IL-13 were found in the MLNs of IgER-TGs. In contrast, transcript levels of IL-2 and IL-12p40 and were comparable in both strains demonstrating a specific inhibition of cytokines associated with mucosal Th2 immune responses (Supplementary Figure S5b). We did not detect significant changes between challenged WT and IgER-TG animals in regard to percentages of Foxp3+CD25+ T cells in the MLNs (Supplementary Figure S5c). Furthermore, IL-10 production was similar (Supplementary Figure S5d), suggesting that the regulatory T cell compartment was not responsible for the restrained tissue inflammation in the IgER-TG mice.


Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites.

Platzer B, Baker K, Vera MP, Singer K, Panduro M, Lexmond WS, Turner D, Vargas SO, Kinet JP, Maurer D, Baron RM, Blumberg RS, Fiebiger E - Mucosal Immunol (2014)

Food allergic responses are significantly reduced in IgER-TG animals. (a) Decreased mast cell-specific transcripts (i.e. mast cell proteases MCPT1, MCPT2, and carboxypeptidase A3 (CPA3)) and lower IL-4, IL-13, CCL-2, and IL-6 expression were detected in IgER-TGs. Sensitized mice are indicated by (+), non-sensitized mice by (−). Normalized mRNA counts or fold change in mRNA levels +/− SEM of small intestinal tissue of 4 independent experiments (per experiment tissue of ≥2 mice was pooled) are shown. (b) and (c) Small intestinal tissue sections were stained, and infiltrating mast cells were counted. (d) Assessment of mast cell protease MCPT1 in serum as a systemic readout for IgE-mediated mast cell activation. Serum was collected 1h after oral challenge. Symbols are representative of individual mice (n=2).
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Figure 4: Food allergic responses are significantly reduced in IgER-TG animals. (a) Decreased mast cell-specific transcripts (i.e. mast cell proteases MCPT1, MCPT2, and carboxypeptidase A3 (CPA3)) and lower IL-4, IL-13, CCL-2, and IL-6 expression were detected in IgER-TGs. Sensitized mice are indicated by (+), non-sensitized mice by (−). Normalized mRNA counts or fold change in mRNA levels +/− SEM of small intestinal tissue of 4 independent experiments (per experiment tissue of ≥2 mice was pooled) are shown. (b) and (c) Small intestinal tissue sections were stained, and infiltrating mast cells were counted. (d) Assessment of mast cell protease MCPT1 in serum as a systemic readout for IgE-mediated mast cell activation. Serum was collected 1h after oral challenge. Symbols are representative of individual mice (n=2).
Mentions: IgE-mediated food allergy presents with extensive Th2-type tissue inflammation in the small intestine, and intestinal mucosal mast cell numbers are an established quantitative measure of disease severity in mice and humans.39 Comparative quantitative mRNA profiling was performed to assess the extent of tissue inflammation in the small intestine of food-allergic animals. We found that the lamina propria of IgER-TG animals was overall substantially less inflamed (Figure 4a and Supplementary Table S2). mRNA transcripts of mast cell-specific proteases (MCPT-1 and MCPT-2, and carboxypeptidase A3), Th2-type cytokines (IL-4 and IL-13), and DC-derived inflammatory mediators such as CCL-2 and IL-6 were significantly less abundant in the tissue of IgER-TGs than in WT controls (Figure 4a). Expression of IFN-γ was low and did not change upon challenge (Supplementary Figure S5a). Additionally, significantly lower transcript levels of the Th2-specific cytokines IL-33 and IL-13 were found in the MLNs of IgER-TGs. In contrast, transcript levels of IL-2 and IL-12p40 and were comparable in both strains demonstrating a specific inhibition of cytokines associated with mucosal Th2 immune responses (Supplementary Figure S5b). We did not detect significant changes between challenged WT and IgER-TG animals in regard to percentages of Foxp3+CD25+ T cells in the MLNs (Supplementary Figure S5c). Furthermore, IL-10 production was similar (Supplementary Figure S5d), suggesting that the regulatory T cell compartment was not responsible for the restrained tissue inflammation in the IgER-TG mice.

Bottom Line: Furthermore, conferring expression of FcɛRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcɛRI signals.Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcɛRI cross-linking on papain or lipopolysaccharide-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines.Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
Antigen-mediated cross-linking of Immunoglobulin E (IgE) bound to mast cells/basophils via FcɛRI, the high affinity IgE Fc-receptor, is a well-known trigger of allergy. In humans, but not mice, dendritic cells (DCs) also express FcɛRI that is constitutively occupied with IgE. In contrast to mast cells/basophils, the consequences of IgE/FcɛRI signals for DC function remain poorly understood. We show that humanized mice that express FcɛRI on DCs carry IgE like non-allergic humans and do not develop spontaneous allergies. Antigen-specific IgE/FcɛRI cross-linking fails to induce maturation or production of inflammatory mediators in human DCs and FcɛRI-humanized DCs. Furthermore, conferring expression of FcɛRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcɛRI signals. Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcɛRI cross-linking on papain or lipopolysaccharide-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines. Migration assays confirm that the IgE-dependent decrease in cytokine production results in diminished recruitment of mast cell progenitors; providing a mechanistic explanation for the reduced mast cell-dependent allergic phenotype observed in FcɛRI-humanized mice. Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.

No MeSH data available.


Related in: MedlinePlus