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Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lung.

Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, Lencer WI - J. Exp. Med. (2002)

Bottom Line: Exactly how IgG crosses epithelial barriers to function in mucosal immunity remains unknown.Thus, IgG, like dimeric IgA, can cross epithelial barriers by receptor-mediated transcytosis in adult animals.These data show that mucosal surfaces that express FcRn reabsorb IgG and explain a mechanism by which IgG may act in immune surveillance to retrieve lumenal antigens for processing in the lamina propria or systemically.

View Article: PubMed Central - PubMed

Affiliation: The Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital, Boston, MA 02115, USA.

ABSTRACT
Mucosal secretions of the human gastrointestinal, respiratory, and genital tracts contain the immunoglobulins (Ig)G and secretory IgA (sIgA) that function together in host defense. Exactly how IgG crosses epithelial barriers to function in mucosal immunity remains unknown. Here, we test the idea that the MHC class I-related Fc-receptor, FcRn, transports IgG across the mucosal surface of the human and mouse lung from lumen to serosa. We find that bronchial epithelial cells of the human, nonhuman primate, and mouse, express FcRn in adult-life, and demonstrate FcRn-dependent absorption of a bioactive Fc-fusion protein across the respiratory epithelium of the mouse in vivo. Thus, IgG, like dimeric IgA, can cross epithelial barriers by receptor-mediated transcytosis in adult animals. These data show that mucosal surfaces that express FcRn reabsorb IgG and explain a mechanism by which IgG may act in immune surveillance to retrieve lumenal antigens for processing in the lamina propria or systemically.

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FcRn-specific absorption of Epo–Fc across the epithelial cell barrier of the adult mouse lung in vivo. (A) Dose dependent increase in reticulocyte count for Epo–Fc administered intranasally. Mean ± SEM, six mice per group. *P < 0.05 versus baseline. Maximal response in adult mice ∼17%, see Fig. 2 D. (B) Reticulocyte fractions induced by intranasal administration of fusion proteins containing functional FcRn-binding sites, WT Epo–Fc (column 2) and Epo–Fc/LLG (column 4), by Epo–Fc/IHH that lacks an FcRn-binding site (column 3), and by PBS alone (column 1). All fusion proteins were administered at 10 μg/mouse. Mean ± SEM. n = 5 for all groups except n = 2 for PBS control. *P < 0.05 versus baseline. (C) Absorption of Epo–Fc and Epo–Fc/IHH as assessed directly by ELISA of serum obtained 8 h after nasal administration of fusion proteins at the indicated doses. (D) Reticulocyte fractions induced by intranasal WT Epo–Fc (2 μg, 1 μg, or 0.5 μg/mouse) administered together with 650-, 1,300-, or 2,600-fold excess mouse IgG (g/g, 1.3 mg total dose, light gray bar) 1,300-fold excess chicken IgY (1.3 mg total dose, dark gray bar) or nonspecific protein albumin (1.3 mg total dose, black bars) as competing ligands, and by PBS alone (white bar). Mean ± SEM from two independent experiments *P < 0.05 relative to Epo–Fc plus albumin control. n = 12 mice per group for doses of Epo–Fc 1 μg/mouse and PBS control. n = 6 mice/group for all other doses of Epo–Fc. In the absence of IgG block, absorption of 0.09–0.24 μg of Epo–Fc, or ∼10–18% of the administered dose was detected as assessed by calibration against Epo–Fc injected intravenously (see Supplemental Data).
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fig5: FcRn-specific absorption of Epo–Fc across the epithelial cell barrier of the adult mouse lung in vivo. (A) Dose dependent increase in reticulocyte count for Epo–Fc administered intranasally. Mean ± SEM, six mice per group. *P < 0.05 versus baseline. Maximal response in adult mice ∼17%, see Fig. 2 D. (B) Reticulocyte fractions induced by intranasal administration of fusion proteins containing functional FcRn-binding sites, WT Epo–Fc (column 2) and Epo–Fc/LLG (column 4), by Epo–Fc/IHH that lacks an FcRn-binding site (column 3), and by PBS alone (column 1). All fusion proteins were administered at 10 μg/mouse. Mean ± SEM. n = 5 for all groups except n = 2 for PBS control. *P < 0.05 versus baseline. (C) Absorption of Epo–Fc and Epo–Fc/IHH as assessed directly by ELISA of serum obtained 8 h after nasal administration of fusion proteins at the indicated doses. (D) Reticulocyte fractions induced by intranasal WT Epo–Fc (2 μg, 1 μg, or 0.5 μg/mouse) administered together with 650-, 1,300-, or 2,600-fold excess mouse IgG (g/g, 1.3 mg total dose, light gray bar) 1,300-fold excess chicken IgY (1.3 mg total dose, dark gray bar) or nonspecific protein albumin (1.3 mg total dose, black bars) as competing ligands, and by PBS alone (white bar). Mean ± SEM from two independent experiments *P < 0.05 relative to Epo–Fc plus albumin control. n = 12 mice per group for doses of Epo–Fc 1 μg/mouse and PBS control. n = 6 mice/group for all other doses of Epo–Fc. In the absence of IgG block, absorption of 0.09–0.24 μg of Epo–Fc, or ∼10–18% of the administered dose was detected as assessed by calibration against Epo–Fc injected intravenously (see Supplemental Data).

Mentions: To demonstrate FcRn function at this site, we examined the mouse lung. As in the human and nonhuman primate, total tissue lysates obtained from the lungs of adult mice contained a glycosylated 49-kD band consistent with FcRn as assessed by SDS-PAGE and Western blot analysis (Fig. 4 A). Bronchial epithelial cells stained positive for FcRn as assessed by immunohistochemistry. A low level of background staining, presumed to be nonspecific based on our functional studies (see below and Fig. 5) , was also observed in the lamina propria of the mouse using this Ab (Fig. 4 B).


Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lung.

Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, Lencer WI - J. Exp. Med. (2002)

FcRn-specific absorption of Epo–Fc across the epithelial cell barrier of the adult mouse lung in vivo. (A) Dose dependent increase in reticulocyte count for Epo–Fc administered intranasally. Mean ± SEM, six mice per group. *P < 0.05 versus baseline. Maximal response in adult mice ∼17%, see Fig. 2 D. (B) Reticulocyte fractions induced by intranasal administration of fusion proteins containing functional FcRn-binding sites, WT Epo–Fc (column 2) and Epo–Fc/LLG (column 4), by Epo–Fc/IHH that lacks an FcRn-binding site (column 3), and by PBS alone (column 1). All fusion proteins were administered at 10 μg/mouse. Mean ± SEM. n = 5 for all groups except n = 2 for PBS control. *P < 0.05 versus baseline. (C) Absorption of Epo–Fc and Epo–Fc/IHH as assessed directly by ELISA of serum obtained 8 h after nasal administration of fusion proteins at the indicated doses. (D) Reticulocyte fractions induced by intranasal WT Epo–Fc (2 μg, 1 μg, or 0.5 μg/mouse) administered together with 650-, 1,300-, or 2,600-fold excess mouse IgG (g/g, 1.3 mg total dose, light gray bar) 1,300-fold excess chicken IgY (1.3 mg total dose, dark gray bar) or nonspecific protein albumin (1.3 mg total dose, black bars) as competing ligands, and by PBS alone (white bar). Mean ± SEM from two independent experiments *P < 0.05 relative to Epo–Fc plus albumin control. n = 12 mice per group for doses of Epo–Fc 1 μg/mouse and PBS control. n = 6 mice/group for all other doses of Epo–Fc. In the absence of IgG block, absorption of 0.09–0.24 μg of Epo–Fc, or ∼10–18% of the administered dose was detected as assessed by calibration against Epo–Fc injected intravenously (see Supplemental Data).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2193935&req=5

fig5: FcRn-specific absorption of Epo–Fc across the epithelial cell barrier of the adult mouse lung in vivo. (A) Dose dependent increase in reticulocyte count for Epo–Fc administered intranasally. Mean ± SEM, six mice per group. *P < 0.05 versus baseline. Maximal response in adult mice ∼17%, see Fig. 2 D. (B) Reticulocyte fractions induced by intranasal administration of fusion proteins containing functional FcRn-binding sites, WT Epo–Fc (column 2) and Epo–Fc/LLG (column 4), by Epo–Fc/IHH that lacks an FcRn-binding site (column 3), and by PBS alone (column 1). All fusion proteins were administered at 10 μg/mouse. Mean ± SEM. n = 5 for all groups except n = 2 for PBS control. *P < 0.05 versus baseline. (C) Absorption of Epo–Fc and Epo–Fc/IHH as assessed directly by ELISA of serum obtained 8 h after nasal administration of fusion proteins at the indicated doses. (D) Reticulocyte fractions induced by intranasal WT Epo–Fc (2 μg, 1 μg, or 0.5 μg/mouse) administered together with 650-, 1,300-, or 2,600-fold excess mouse IgG (g/g, 1.3 mg total dose, light gray bar) 1,300-fold excess chicken IgY (1.3 mg total dose, dark gray bar) or nonspecific protein albumin (1.3 mg total dose, black bars) as competing ligands, and by PBS alone (white bar). Mean ± SEM from two independent experiments *P < 0.05 relative to Epo–Fc plus albumin control. n = 12 mice per group for doses of Epo–Fc 1 μg/mouse and PBS control. n = 6 mice/group for all other doses of Epo–Fc. In the absence of IgG block, absorption of 0.09–0.24 μg of Epo–Fc, or ∼10–18% of the administered dose was detected as assessed by calibration against Epo–Fc injected intravenously (see Supplemental Data).
Mentions: To demonstrate FcRn function at this site, we examined the mouse lung. As in the human and nonhuman primate, total tissue lysates obtained from the lungs of adult mice contained a glycosylated 49-kD band consistent with FcRn as assessed by SDS-PAGE and Western blot analysis (Fig. 4 A). Bronchial epithelial cells stained positive for FcRn as assessed by immunohistochemistry. A low level of background staining, presumed to be nonspecific based on our functional studies (see below and Fig. 5) , was also observed in the lamina propria of the mouse using this Ab (Fig. 4 B).

Bottom Line: Exactly how IgG crosses epithelial barriers to function in mucosal immunity remains unknown.Thus, IgG, like dimeric IgA, can cross epithelial barriers by receptor-mediated transcytosis in adult animals.These data show that mucosal surfaces that express FcRn reabsorb IgG and explain a mechanism by which IgG may act in immune surveillance to retrieve lumenal antigens for processing in the lamina propria or systemically.

View Article: PubMed Central - PubMed

Affiliation: The Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital, Boston, MA 02115, USA.

ABSTRACT
Mucosal secretions of the human gastrointestinal, respiratory, and genital tracts contain the immunoglobulins (Ig)G and secretory IgA (sIgA) that function together in host defense. Exactly how IgG crosses epithelial barriers to function in mucosal immunity remains unknown. Here, we test the idea that the MHC class I-related Fc-receptor, FcRn, transports IgG across the mucosal surface of the human and mouse lung from lumen to serosa. We find that bronchial epithelial cells of the human, nonhuman primate, and mouse, express FcRn in adult-life, and demonstrate FcRn-dependent absorption of a bioactive Fc-fusion protein across the respiratory epithelium of the mouse in vivo. Thus, IgG, like dimeric IgA, can cross epithelial barriers by receptor-mediated transcytosis in adult animals. These data show that mucosal surfaces that express FcRn reabsorb IgG and explain a mechanism by which IgG may act in immune surveillance to retrieve lumenal antigens for processing in the lamina propria or systemically.

Show MeSH
Related in: MedlinePlus