Limits...
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

Intestinal DCs express FcεRI and allergic sensitization increases the DC-bound IgE pool of IgER-TG animals. (a) FcεRI expression (in red) in the small intestine of IgER-TG mice is found on CD11c+ DCs (in blue). CD11c+ DCs from IgER-TG are GFP positive because the transgenic construct contains an IRES-GPF reporter element. (b) FcεRI expression on CD11c+ DCs in the human small intestine. Human FcεRIα (green, first panel), CD11c (red, second panel). Mast cells as depicted by c-kit are not found in non-inflamed human tissue using immunofluorescence (row two, red). DAPI-stain for nuclei (blue). (c) and (d) Analysis of OVA-specific IgE and IgG1 levels in serum of sensitized mice before antigen challenge. (e) and (f) Sensitization and antigen challenge increases the amount of surface-bound IgE on DCs of IgER-TG mice but not WT animals. DCs were isolated from the spleens and mesenteric lymph nodes (MLNs) of OVA-challenged WT and IgER-TG mice, respectively. Sensitized mice are indicated by (+), non-sensitized mice by (−). Symbols are representative of individual mice (n=2).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4363306&req=5

Figure 3: Intestinal DCs express FcεRI and allergic sensitization increases the DC-bound IgE pool of IgER-TG animals. (a) FcεRI expression (in red) in the small intestine of IgER-TG mice is found on CD11c+ DCs (in blue). CD11c+ DCs from IgER-TG are GFP positive because the transgenic construct contains an IRES-GPF reporter element. (b) FcεRI expression on CD11c+ DCs in the human small intestine. Human FcεRIα (green, first panel), CD11c (red, second panel). Mast cells as depicted by c-kit are not found in non-inflamed human tissue using immunofluorescence (row two, red). DAPI-stain for nuclei (blue). (c) and (d) Analysis of OVA-specific IgE and IgG1 levels in serum of sensitized mice before antigen challenge. (e) and (f) Sensitization and antigen challenge increases the amount of surface-bound IgE on DCs of IgER-TG mice but not WT animals. DCs were isolated from the spleens and mesenteric lymph nodes (MLNs) of OVA-challenged WT and IgER-TG mice, respectively. Sensitized mice are indicated by (+), non-sensitized mice by (−). Symbols are representative of individual mice (n=2).

Mentions: To address how IgE/FcεRI-activation of DCs affects the severity of allergic responses in vivo, we turned to a well-characterized model of experimental food allergy that uses Th2-type sensitization with OVA/alum injections followed by repeated gavages of the model antigen to mimic physiological allergen exposure.39 First, we confirmed that in FcεRI-humanized mice DCs of the small intestine express FcεRI, an expression pattern likewise found in humans (Figure 3a and 3b, respectively). Comparable levels of sensitization were observed in WT and IgER-TG animals as determined by serum levels of antigen-specific IgE and IgG1 (Figure 3c and 3d) arguing against a pronounced role for DC-mediated FcεRI-facilitating serum IgE clearance30 during the sensitization phase in our model. As described for allergic humans,29 sensitization and challenge significantly increased the DC-bound IgE pool systemically in the spleen as well as locally in the mesenteric lymph nodes (Figure 3e and 3f, respectively). Even though OVA-specific IgE was readily detected in serum of WT mice (Figure 3e), no IgE was found on the DC surface in these animals (Figure 3e and 3f), indicating that the inducible murine form of FcεRI on DCs, which was described after house dust mite (HDM) exposure and in models of viral infection,22, 40 was not present in this model.


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)

Intestinal DCs express FcεRI and allergic sensitization increases the DC-bound IgE pool of IgER-TG animals. (a) FcεRI expression (in red) in the small intestine of IgER-TG mice is found on CD11c+ DCs (in blue). CD11c+ DCs from IgER-TG are GFP positive because the transgenic construct contains an IRES-GPF reporter element. (b) FcεRI expression on CD11c+ DCs in the human small intestine. Human FcεRIα (green, first panel), CD11c (red, second panel). Mast cells as depicted by c-kit are not found in non-inflamed human tissue using immunofluorescence (row two, red). DAPI-stain for nuclei (blue). (c) and (d) Analysis of OVA-specific IgE and IgG1 levels in serum of sensitized mice before antigen challenge. (e) and (f) Sensitization and antigen challenge increases the amount of surface-bound IgE on DCs of IgER-TG mice but not WT animals. DCs were isolated from the spleens and mesenteric lymph nodes (MLNs) of OVA-challenged WT and IgER-TG mice, respectively. Sensitized mice are indicated by (+), non-sensitized mice by (−). Symbols are representative of individual mice (n=2).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Intestinal DCs express FcεRI and allergic sensitization increases the DC-bound IgE pool of IgER-TG animals. (a) FcεRI expression (in red) in the small intestine of IgER-TG mice is found on CD11c+ DCs (in blue). CD11c+ DCs from IgER-TG are GFP positive because the transgenic construct contains an IRES-GPF reporter element. (b) FcεRI expression on CD11c+ DCs in the human small intestine. Human FcεRIα (green, first panel), CD11c (red, second panel). Mast cells as depicted by c-kit are not found in non-inflamed human tissue using immunofluorescence (row two, red). DAPI-stain for nuclei (blue). (c) and (d) Analysis of OVA-specific IgE and IgG1 levels in serum of sensitized mice before antigen challenge. (e) and (f) Sensitization and antigen challenge increases the amount of surface-bound IgE on DCs of IgER-TG mice but not WT animals. DCs were isolated from the spleens and mesenteric lymph nodes (MLNs) of OVA-challenged WT and IgER-TG mice, respectively. Sensitized mice are indicated by (+), non-sensitized mice by (−). Symbols are representative of individual mice (n=2).
Mentions: To address how IgE/FcεRI-activation of DCs affects the severity of allergic responses in vivo, we turned to a well-characterized model of experimental food allergy that uses Th2-type sensitization with OVA/alum injections followed by repeated gavages of the model antigen to mimic physiological allergen exposure.39 First, we confirmed that in FcεRI-humanized mice DCs of the small intestine express FcεRI, an expression pattern likewise found in humans (Figure 3a and 3b, respectively). Comparable levels of sensitization were observed in WT and IgER-TG animals as determined by serum levels of antigen-specific IgE and IgG1 (Figure 3c and 3d) arguing against a pronounced role for DC-mediated FcεRI-facilitating serum IgE clearance30 during the sensitization phase in our model. As described for allergic humans,29 sensitization and challenge significantly increased the DC-bound IgE pool systemically in the spleen as well as locally in the mesenteric lymph nodes (Figure 3e and 3f, respectively). Even though OVA-specific IgE was readily detected in serum of WT mice (Figure 3e), no IgE was found on the DC surface in these animals (Figure 3e and 3f), indicating that the inducible murine form of FcεRI on DCs, which was described after house dust mite (HDM) exposure and in models of viral infection,22, 40 was not present in this model.

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