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The N-glycans determine the differential blood clearance and hepatic uptake of human immunoglobulin (Ig)A1 and IgA2 isotypes.

Rifai A, Fadden K, Morrison SL, Chintalacharuvu KR - J. Exp. Med. (2000)

Bottom Line: The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1.The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2.In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Rhode Island Hospital, Brown University, Providence, Rhode Island 02903, USA.

ABSTRACT
Human immunoglobulin (Ig)A exists in blood as two isotypes, IgA1 and IgA2, with IgA2 present as three allotypes: IgA2m(1), IgA2m(2), and IgA2m(n). We now demonstrate that recombinant, chimeric IgA1 and IgA2 differ in their pharmacokinetic properties. The major pathway for the clearance of all IgA2 allotypes is the liver. Liver-mediated uptake is through the asialoglycoprotein receptor (ASGR), since clearance can be blocked by injection of excess galactose-Ficoll ligand and suppressed in ASGR-deficient mice. In contrast, only a small percentage of IgA1 is cleared through this pathway. The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1. IgA1 and IgA2 that are not rapidly eliminated by the ASGR are both removed through an undefined ASGR-independent pathway with half-lives of 14 and 10 h, respectively. The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2. In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.

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Comparison of kinetics of serum clearance of IgA2m(1) and IgA2m(2) in C57BL/6 (W.T.) and ASGR−/− knockout mice. Radiolabeled IgA2m(1) (A) or IgA2m(2) (B) was injected into the tail vein of C57BL/6 or ASGR−/− knockout mice. At the indicated time points, the IgA remaining in the blood was determined as described in the legend to Fig. 3. The amount of TCA-soluble material present in the blood at the different times is shown in the insert. Each data point represents the mean ± SD of three mice.
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Figure 7: Comparison of kinetics of serum clearance of IgA2m(1) and IgA2m(2) in C57BL/6 (W.T.) and ASGR−/− knockout mice. Radiolabeled IgA2m(1) (A) or IgA2m(2) (B) was injected into the tail vein of C57BL/6 or ASGR−/− knockout mice. At the indicated time points, the IgA remaining in the blood was determined as described in the legend to Fig. 3. The amount of TCA-soluble material present in the blood at the different times is shown in the insert. Each data point represents the mean ± SD of three mice.

Mentions: To further explore the role of the ASGR in the catabolism of IgA2, the 24-h clearance of IgA2m(1) and IgA2m(2) in wild-type and ASGR−/− mice was compared. The 24-h disappearance curves for IgA2m(1), Fig. 7 A, were composed of three exponential components, as determined by graphic peeling in conjunction with linear regression analysis. There is a significant difference (P = 0.0016) in the amount of IgA2m(1) removed from circulation in the first rapid phase, with 43.7 ± 5.1% rapidly removed in wild-type compared with 16.8 ± 2.1% in ASGR−/− mice. In the second intermediate phase, there was no significant difference between the amount of IgA2m(1) in wild-type (39.0 ± 4.0%) and ASGR−/− (37.0 ± 2.5%) mice. The decrease in the amount of IgA2m(1) removal in the first phase in the ASGR−/− mice is accompanied by an increase in the amount slowly metabolized in the terminal phase (from 17.4 ± 1.2% in wild-type to 46.3 ± 2.7% in ASGR−/− mice; P = 0.0004). Interestingly, during this phase a similar rate of clearance was seen in the ASGR−/− and wild-type mice (9.6 ± 0.2 h in wild-type vs. 10.5 ± 0.8 h in ASGR−/−). The rapid increase of TCA-soluble radioactivity during the first 4 h (Fig. 7 A, insert) seen in the wild-type mice but not in ASGR−/− mice during this period is consistent with the elimination pattern.


The N-glycans determine the differential blood clearance and hepatic uptake of human immunoglobulin (Ig)A1 and IgA2 isotypes.

Rifai A, Fadden K, Morrison SL, Chintalacharuvu KR - J. Exp. Med. (2000)

Comparison of kinetics of serum clearance of IgA2m(1) and IgA2m(2) in C57BL/6 (W.T.) and ASGR−/− knockout mice. Radiolabeled IgA2m(1) (A) or IgA2m(2) (B) was injected into the tail vein of C57BL/6 or ASGR−/− knockout mice. At the indicated time points, the IgA remaining in the blood was determined as described in the legend to Fig. 3. The amount of TCA-soluble material present in the blood at the different times is shown in the insert. Each data point represents the mean ± SD of three mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2193211&req=5

Figure 7: Comparison of kinetics of serum clearance of IgA2m(1) and IgA2m(2) in C57BL/6 (W.T.) and ASGR−/− knockout mice. Radiolabeled IgA2m(1) (A) or IgA2m(2) (B) was injected into the tail vein of C57BL/6 or ASGR−/− knockout mice. At the indicated time points, the IgA remaining in the blood was determined as described in the legend to Fig. 3. The amount of TCA-soluble material present in the blood at the different times is shown in the insert. Each data point represents the mean ± SD of three mice.
Mentions: To further explore the role of the ASGR in the catabolism of IgA2, the 24-h clearance of IgA2m(1) and IgA2m(2) in wild-type and ASGR−/− mice was compared. The 24-h disappearance curves for IgA2m(1), Fig. 7 A, were composed of three exponential components, as determined by graphic peeling in conjunction with linear regression analysis. There is a significant difference (P = 0.0016) in the amount of IgA2m(1) removed from circulation in the first rapid phase, with 43.7 ± 5.1% rapidly removed in wild-type compared with 16.8 ± 2.1% in ASGR−/− mice. In the second intermediate phase, there was no significant difference between the amount of IgA2m(1) in wild-type (39.0 ± 4.0%) and ASGR−/− (37.0 ± 2.5%) mice. The decrease in the amount of IgA2m(1) removal in the first phase in the ASGR−/− mice is accompanied by an increase in the amount slowly metabolized in the terminal phase (from 17.4 ± 1.2% in wild-type to 46.3 ± 2.7% in ASGR−/− mice; P = 0.0004). Interestingly, during this phase a similar rate of clearance was seen in the ASGR−/− and wild-type mice (9.6 ± 0.2 h in wild-type vs. 10.5 ± 0.8 h in ASGR−/−). The rapid increase of TCA-soluble radioactivity during the first 4 h (Fig. 7 A, insert) seen in the wild-type mice but not in ASGR−/− mice during this period is consistent with the elimination pattern.

Bottom Line: The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1.The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2.In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Rhode Island Hospital, Brown University, Providence, Rhode Island 02903, USA.

ABSTRACT
Human immunoglobulin (Ig)A exists in blood as two isotypes, IgA1 and IgA2, with IgA2 present as three allotypes: IgA2m(1), IgA2m(2), and IgA2m(n). We now demonstrate that recombinant, chimeric IgA1 and IgA2 differ in their pharmacokinetic properties. The major pathway for the clearance of all IgA2 allotypes is the liver. Liver-mediated uptake is through the asialoglycoprotein receptor (ASGR), since clearance can be blocked by injection of excess galactose-Ficoll ligand and suppressed in ASGR-deficient mice. In contrast, only a small percentage of IgA1 is cleared through this pathway. The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1. IgA1 and IgA2 that are not rapidly eliminated by the ASGR are both removed through an undefined ASGR-independent pathway with half-lives of 14 and 10 h, respectively. The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2. In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.

Show MeSH
Related in: MedlinePlus