Harboring of Particulate Allergens within Secretory Compartments by Mast Cells following IgE/FcεRI-Lipid Raft-Mediated Phagocytosis

Shin, Jeoung-Sook; Shelburne, Christopher P.; Jin, Cong; LeFurgey, E. Ann; Abraham, Soman N.

doi:10.4049/jimmunol.177.9.5791

Cited by 17 publications

(18 citation statements)

References 40 publications

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“…These findings, in concert with recent observations that IgE-sensitized MCs retain naturally particulate allergens without degradation for extended periods of time (26), suggest a scenario in which pulmonary MCs mediate sustained signaling for extended periods of time after exposure to pAgs. This model may be supported by observations in asthmatic patients, in which MCs exhibit a chronically activated phenotype, even after exposure of the patient to the offending allergen has been eliminated (15).…”

Section: Discussionsupporting

confidence: 62%

“…Our previous study revealed that the FcεRI-mediated phagocytosis of pollen into MCs is lipid raft dependent (26). Lipid rafts are specialized membrane domains that are dynamic assemblies of proteins, lipids and signaling substrates (27)(28)(29).…”

Section: Figurementioning

confidence: 99%

“…Lipid rafts are specialized membrane domains that are dynamic assemblies of proteins, lipids and signaling substrates (27)(28)(29). Recent studies showed that lipid rafts promote many critical signaling activities of MCs, including recruitment of signaling molecules that mediate FcεRI signaling (30-33) as well as endocytosis of IgE/FcεRI complexes (26,34,35). To investigate the spatial localization of lipid raft microdomains and compartments housing allergens, we examined resting BMMCs for lipid rafts.…”

Section: Figurementioning

confidence: 99%

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Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation

Jin¹,

Shelburne²,

Li³

et al. 2011

J. Clin. Invest.

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Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and a cellular infiltrate dominated by eosinophils. Numerous epidemiological studies have related the exacerbation of allergic asthma with an increase in ambient inhalable particulate matter from air pollutants. This is because inhalable particles efficiently deliver airborne allergens deep into the airways, where they can aggravate allergic asthma symptoms. However, the cellular mechanisms by which inhalable particulate allergens (pAgs) potentiate asthmatic symptoms remain unknown, in part because most in vivo and in vitro studies exploring the pathogenesis of allergic asthma use soluble allergens (sAgs). Using a mouse model of allergic asthma, we found that, compared with their sAg counterparts, pAgs triggered markedly heightened airway hyperresponsiveness and pulmonary eosinophilia in allergen-sensitized mice. Mast cells (MCs) were implicated in this divergent response, as the differences in airway inflammatory responses provoked by the physical nature of the allergens were attenuated in MC-deficient mice. The pAgs were found to mediate MC-dependent responses by enhancing retention of pAg/IgE/FcεRI complexes within lipid raft-enriched, CD63 + endocytic compartments, which prolonged IgE/ FcεRI-initiated signaling and resulted in heightened cytokine responses. These results reveal how the physical attributes of allergens can co-opt MC endocytic circuitry and signaling responses to aggravate pathological responses of allergic asthma in mice.

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Section: Discussionsupporting

confidence: 62%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation

Jin¹,

Shelburne²,

Li³

et al. 2011

J. Clin. Invest.

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“…The colorimetric hexosaminidase release assay was employed as described previously (33). Briefly, BMMCs equilibrated with Tyroid buffer were mixed with human IgE or anti-hFcεRI antibody:anti-mouse IgG antibody complexes in a 96 well plate.…”

Section: Methodsmentioning

confidence: 99%

“…It is noteworthy that the injected human IgE had been pre-tested and confirmed for the absence of aggregates that can potentially activate hFcεRI-expressing cells by crosslinking hFcεRI. Briefly, we added the human IgE preparation to mast cells cultured from FCER1A-Tg mouse bone marrow and measured degranulation of these cells by a hexosaminidase release assay (33). The addition of up to 10 μg/ml of IgE to the cells did not cause any release of hexosaminidase above the level of spontaneous release (Supplemental Figure 8).…”

Section: Fcεri Is Specifically Localized In Endolysosomes Of Dcs and mentioning

confidence: 99%

Serum IgE clearance is facilitated by human FcεRI internalization

Greer¹,

Wu²,

Putnam³

et al. 2014

J. Clin. Invest.

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The high-affinity IgE receptor FcεRI is constitutively expressed in mast cells and basophils and is required for transmitting stimulatory signals upon engagement of IgE-bound allergens. FcεRI is also constitutively expressed in dendritic cells (DCs) and monocytes in humans; however, the specific functions of the FcεRI expressed by these cells are not completely understood. Here, we found that FcεRI expressed by human blood DC antigen 1-positive (BDCA1 + ) DCs and monocytes, but not basophils, traffics to endolysosomal compartments under steady-state conditions. Furthermore, IgE bound to FcεRI on BDCA1 + DCs was rapidly endocytosed, transported to the lysosomes, and degraded in vitro. IgE injected into mice expressing human FcεRIα (FCER1A-Tg mice) was endocytosed by conventional DCs and monocytes, and endocytosis was associated with rapid clearance of circulating IgE from these mice. Importantly, this rapid IgE clearance was dependent on monocytes or DCs but not basophils. These findings strongly suggest that constitutive internalization of human FcεRI by DCs and monocytes distinctively contributes to serum IgE clearance.

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Arginines in the CDR of anti‐dsDNA autoantibodies facilitate cell internalization via electrostatic interactions

Song¹,

Sun²,

Lee³

et al. 2008

Eur J Immunol

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Internalization of autoantibodies against double-stranded DNA (anti-dsDNA) is crucial to the pathogenesis of systemic lupus erythematosus. Anti-dsDNA may bind to cell-surface targets in order to facilitate the subsequent cell penetration of the anti-dsDNA. In this study, we observed that the 9D7 monoclonal anti-dsDNA autoantibody (9D7 mAb) penetrates into Jurkat cells via a novel alternative pathway. Endocytosis inhibitors or a lipid-raft inhibitor did not significantly change the penetration of 9D7 mAb into the Jurkat cells. However, heparin sulfate, chondroitin sulfate B, decaarginine and chondroitinase ABC significantly suppressed the internalization and the 9D7 mAb inhibited the internalization of Tat-GFP. Moreover, the penetration of the 9D7 mAb was significantly reduced in proteoglycan-deficient cells (pgs A-745). Positively charged amino acids including arginine are commonly found in the CDR of the 9D7 mAb. Point mutations to the arginine residues in the CDR of the H chain of the recombinant 9D7 mAb significantly attenuated its DNAbinding and cell-penetration abilities. These findings indicate that cell penetration of antidsDNA is due to the electrostatic interactions of arginine residues in the CDR with the negatively charged sulfated polysaccharides on the cell surface.

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Harboring of Particulate Allergens within Secretory Compartments by Mast Cells following IgE/FcεRI-Lipid Raft-Mediated Phagocytosis

Cited by 17 publications

References 40 publications

Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation

Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation

Serum IgE clearance is facilitated by human FcεRI internalization

Arginines in the CDR of anti‐dsDNA autoantibodies facilitate cell internalization via electrostatic interactions

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