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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

Expression of FcεRI on DCs results in a DC-specific IgE pool as seen in non-allergic humans. (a) Human peripheral blood DCs of a non-allergic individual carry surface IgE. DCs (in blue) were identified by gating on CD1c+ CD19− cells to distinguish them from CD1c+CD19+ B cells (in green) and analyzed for cell surface-bound IgE. DCs carry significant amounts of IgE but less than CD203+ basophils and mast cells (in purple). (b) CD11c+ DCs of IgER-TG mice carry IgE at steady state. Representative FACS plots of WT- and IgER-TG DCs isolated from spleens and quantification of the DC-bound IgE pool using mean fluorescence intensities (MFI) determined by flow cytometric analysis. (c) Baseline serum IgE levels are lower in non-sensitized IgER-TG animals. Symbols in are representative of individual mice of ≥ 2 independent experiments (*p < 0.05; ***p< 0.001).
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Figure 1: Expression of FcεRI on DCs results in a DC-specific IgE pool as seen in non-allergic humans. (a) Human peripheral blood DCs of a non-allergic individual carry surface IgE. DCs (in blue) were identified by gating on CD1c+ CD19− cells to distinguish them from CD1c+CD19+ B cells (in green) and analyzed for cell surface-bound IgE. DCs carry significant amounts of IgE but less than CD203+ basophils and mast cells (in purple). (b) CD11c+ DCs of IgER-TG mice carry IgE at steady state. Representative FACS plots of WT- and IgER-TG DCs isolated from spleens and quantification of the DC-bound IgE pool using mean fluorescence intensities (MFI) determined by flow cytometric analysis. (c) Baseline serum IgE levels are lower in non-sensitized IgER-TG animals. Symbols in are representative of individual mice of ≥ 2 independent experiments (*p < 0.05; ***p< 0.001).

Mentions: The surface of humans DCs is coated with IgE bound to FcεRI.11-13 To study the consequences of IgE/FcεRI-mediated DC activation for the regulation of IgE-mediated allergic responses in vivo, we capitalized on the availability of a mouse strain that is humanized for FcεRI expression on DCs (referred to as IgER-TG;31). IgE is a constituent of the baseline polyclonal humoral response and is found in non-sensitized animals that are reared under specific pathogen-free (SPF) conditions. We first analyzed whether FcεRI expression on murine DCs (Supplementary Figure S1) alters the distribution of the baseline IgE pool in SPF-housed mice. Similar to healthy non-allergic humans (Figure 1a and 11, 12, 32), a fraction of DCs from non-sensitized IgER-TG mice bears IgE at the cell surface (Figure 1b and 1c). Importantly, the FcεRI-humanized mice do not display a gross-morphological allergic phenotype despite the presence of the DC-specific IgE pool. These cells are further comparable to human DCs (Figure 1a) in that the cells with the highest FcεRI expression and IgE binding capacity in the IgER-TG animals are CD8− DCs (Platzer et al manuscript under review and 31), which have been recently identified to be the homologous DC subset to human CD1c+ DCs.33, 34 This expression profile demonstrates that IgER-TG mice phenocopy the FcεRI- and IgE-binding pattern of human DCs. In contrast to IgER-TG DCs, DCs from wild type (WT) mice do not carry any surface IgE (Figure 1b). In BALB/c IgER-TG mice, a strain with higher baseline IgE levels than C57BL/6, the DC-bound IgE fraction was readily detectable at ≤8 weeks, and no age-dependent increase was found (Supplementary Figure S2a). IgER-TG mice on the C57BL/6 background showed a significant increase in the DC-bound IgE pool with age (Supplemental Supplementary Figure S2b). The age-dependent induction of IgG1 was comparable in IgER-TG and WT animals (Supplementary Figure S2c). In the absence of inflammation, serum IgE levels of IgER-TG mice were actually reduced when compared to WT controls (Figure 1c), likely due to a shift from the serum to the cell-bound IgE fraction. We further confirmed that comparable levels of CD23, the low affinity IgE receptor, are found on B cells in WT and IgER-TG animals but that CD23 is not expressed on DCs (Supplementary Figure S3). Thus, CD23 cannot contribute to the DC-bound IgE pool at steady state in 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)

Expression of FcεRI on DCs results in a DC-specific IgE pool as seen in non-allergic humans. (a) Human peripheral blood DCs of a non-allergic individual carry surface IgE. DCs (in blue) were identified by gating on CD1c+ CD19− cells to distinguish them from CD1c+CD19+ B cells (in green) and analyzed for cell surface-bound IgE. DCs carry significant amounts of IgE but less than CD203+ basophils and mast cells (in purple). (b) CD11c+ DCs of IgER-TG mice carry IgE at steady state. Representative FACS plots of WT- and IgER-TG DCs isolated from spleens and quantification of the DC-bound IgE pool using mean fluorescence intensities (MFI) determined by flow cytometric analysis. (c) Baseline serum IgE levels are lower in non-sensitized IgER-TG animals. Symbols in are representative of individual mice of ≥ 2 independent experiments (*p < 0.05; ***p< 0.001).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4363306&req=5

Figure 1: Expression of FcεRI on DCs results in a DC-specific IgE pool as seen in non-allergic humans. (a) Human peripheral blood DCs of a non-allergic individual carry surface IgE. DCs (in blue) were identified by gating on CD1c+ CD19− cells to distinguish them from CD1c+CD19+ B cells (in green) and analyzed for cell surface-bound IgE. DCs carry significant amounts of IgE but less than CD203+ basophils and mast cells (in purple). (b) CD11c+ DCs of IgER-TG mice carry IgE at steady state. Representative FACS plots of WT- and IgER-TG DCs isolated from spleens and quantification of the DC-bound IgE pool using mean fluorescence intensities (MFI) determined by flow cytometric analysis. (c) Baseline serum IgE levels are lower in non-sensitized IgER-TG animals. Symbols in are representative of individual mice of ≥ 2 independent experiments (*p < 0.05; ***p< 0.001).
Mentions: The surface of humans DCs is coated with IgE bound to FcεRI.11-13 To study the consequences of IgE/FcεRI-mediated DC activation for the regulation of IgE-mediated allergic responses in vivo, we capitalized on the availability of a mouse strain that is humanized for FcεRI expression on DCs (referred to as IgER-TG;31). IgE is a constituent of the baseline polyclonal humoral response and is found in non-sensitized animals that are reared under specific pathogen-free (SPF) conditions. We first analyzed whether FcεRI expression on murine DCs (Supplementary Figure S1) alters the distribution of the baseline IgE pool in SPF-housed mice. Similar to healthy non-allergic humans (Figure 1a and 11, 12, 32), a fraction of DCs from non-sensitized IgER-TG mice bears IgE at the cell surface (Figure 1b and 1c). Importantly, the FcεRI-humanized mice do not display a gross-morphological allergic phenotype despite the presence of the DC-specific IgE pool. These cells are further comparable to human DCs (Figure 1a) in that the cells with the highest FcεRI expression and IgE binding capacity in the IgER-TG animals are CD8− DCs (Platzer et al manuscript under review and 31), which have been recently identified to be the homologous DC subset to human CD1c+ DCs.33, 34 This expression profile demonstrates that IgER-TG mice phenocopy the FcεRI- and IgE-binding pattern of human DCs. In contrast to IgER-TG DCs, DCs from wild type (WT) mice do not carry any surface IgE (Figure 1b). In BALB/c IgER-TG mice, a strain with higher baseline IgE levels than C57BL/6, the DC-bound IgE fraction was readily detectable at ≤8 weeks, and no age-dependent increase was found (Supplementary Figure S2a). IgER-TG mice on the C57BL/6 background showed a significant increase in the DC-bound IgE pool with age (Supplemental Supplementary Figure S2b). The age-dependent induction of IgG1 was comparable in IgER-TG and WT animals (Supplementary Figure S2c). In the absence of inflammation, serum IgE levels of IgER-TG mice were actually reduced when compared to WT controls (Figure 1c), likely due to a shift from the serum to the cell-bound IgE fraction. We further confirmed that comparable levels of CD23, the low affinity IgE receptor, are found on B cells in WT and IgER-TG animals but that CD23 is not expressed on DCs (Supplementary Figure S3). Thus, CD23 cannot contribute to the DC-bound IgE pool at steady state in 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