抄録
IgA nephropathy (IgAN), a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (Gd-IgA1; autoantigen) and anti-glycan autoantibodies deposit in the glomeruli and induce renal injury. Serum IgA1 has three to six clustered O-glycans, some of which may be deficient in galactose and thus expose terminal or sialylated N-acetylgalactosamine. Patients with IgAN usually have elevated serum levels of Gd-IgA1. The mechanisms involved in production of Gd-IgA1 are not fully understood. Using IgA1-producing cell lines, we have analyzed the heterogeneity of IgA1 O-glycosylation and the corresponding biosynthetic pathways. IgA1 secreted by cells from IgAN patients vs. healthy controls had more galactose-deficient sites and overall more O-glycans. These changes were associated with differential expression/ activity of key glycosyltransferases in cells from patients with IgAN vs. controls, elevated for an initiating enzyme N-acetylgalactosaminyl (GalNAc)- transferase 14 and for GalNAc-specific sialyltransferase (ST6GalNAc-II) and, conversely, decreased for the galactosyltransferase (C1GalT1) and C1GalT1- associated chaperone Cosmc. Involvement of the key enzymes in the production of Gd-IgA1 was confirmed by siRNA knockdown and biochemical approaches. Moreover, expression of these enzymes is affected by some cytokines that further enhance the enzyme imbalance to increase Gd-IgA1 production. In summary, the production of Gd-IgA1, the key autoantigen in IgAN, by IgA1- secreting cells results from dysregulation of key glycosyltransferases and is augmented by certain cytokines. These findings provide insight into possible approaches for future disease-specific therapy.
| 元の言語 | English |
|---|---|
| ホスト出版物のタイトル | Pathogenesis and Treatment in IgA Nephropathy |
| ホスト出版物のサブタイトル | An International Comparison |
| 出版者 | Springer Japan |
| ページ | 53-68 |
| ページ数 | 16 |
| ISBN（電子版） | 9784431555889 |
| ISBN（印刷物） | 9784431555872 |
| DOI | |
| 出版物ステータス | Published - 10-03-2016 |
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All Science Journal Classification (ASJC) codes
- Medicine(all)
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Heterogeneity of aberrant O-glycosylation of IgA1 in IgA nephropathy. / Novak, Jan; Takahashi, Kazuo; Suzuki, Hitoshi; Reily, Colin; Stewart, Tyler; Ueda, Hiroyuki; Yamada, Koshi; Moldoveanu, Zina; Hastings, M. Colleen; Wyatt, Robert J.; Mestecky, Jiri; Raska, Milan; Julian, Bruce A.; Renfrow, Matthew B.
Pathogenesis and Treatment in IgA Nephropathy: An International Comparison. Springer Japan, 2016. p. 53-68.研究成果: Chapter
TY - CHAP
T1 - Heterogeneity of aberrant O-glycosylation of IgA1 in IgA nephropathy
AU - Novak, Jan
AU - Takahashi, Kazuo
AU - Suzuki, Hitoshi
AU - Reily, Colin
AU - Stewart, Tyler
AU - Ueda, Hiroyuki
AU - Yamada, Koshi
AU - Moldoveanu, Zina
AU - Hastings, M. Colleen
AU - Wyatt, Robert J.
AU - Mestecky, Jiri
AU - Raska, Milan
AU - Julian, Bruce A.
AU - Renfrow, Matthew B.
PY - 2016/3/10
Y1 - 2016/3/10
N2 - IgA nephropathy (IgAN), a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (Gd-IgA1; autoantigen) and anti-glycan autoantibodies deposit in the glomeruli and induce renal injury. Serum IgA1 has three to six clustered O-glycans, some of which may be deficient in galactose and thus expose terminal or sialylated N-acetylgalactosamine. Patients with IgAN usually have elevated serum levels of Gd-IgA1. The mechanisms involved in production of Gd-IgA1 are not fully understood. Using IgA1-producing cell lines, we have analyzed the heterogeneity of IgA1 O-glycosylation and the corresponding biosynthetic pathways. IgA1 secreted by cells from IgAN patients vs. healthy controls had more galactose-deficient sites and overall more O-glycans. These changes were associated with differential expression/ activity of key glycosyltransferases in cells from patients with IgAN vs. controls, elevated for an initiating enzyme N-acetylgalactosaminyl (GalNAc)- transferase 14 and for GalNAc-specific sialyltransferase (ST6GalNAc-II) and, conversely, decreased for the galactosyltransferase (C1GalT1) and C1GalT1- associated chaperone Cosmc. Involvement of the key enzymes in the production of Gd-IgA1 was confirmed by siRNA knockdown and biochemical approaches. Moreover, expression of these enzymes is affected by some cytokines that further enhance the enzyme imbalance to increase Gd-IgA1 production. In summary, the production of Gd-IgA1, the key autoantigen in IgAN, by IgA1- secreting cells results from dysregulation of key glycosyltransferases and is augmented by certain cytokines. These findings provide insight into possible approaches for future disease-specific therapy.
AB - IgA nephropathy (IgAN), a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (Gd-IgA1; autoantigen) and anti-glycan autoantibodies deposit in the glomeruli and induce renal injury. Serum IgA1 has three to six clustered O-glycans, some of which may be deficient in galactose and thus expose terminal or sialylated N-acetylgalactosamine. Patients with IgAN usually have elevated serum levels of Gd-IgA1. The mechanisms involved in production of Gd-IgA1 are not fully understood. Using IgA1-producing cell lines, we have analyzed the heterogeneity of IgA1 O-glycosylation and the corresponding biosynthetic pathways. IgA1 secreted by cells from IgAN patients vs. healthy controls had more galactose-deficient sites and overall more O-glycans. These changes were associated with differential expression/ activity of key glycosyltransferases in cells from patients with IgAN vs. controls, elevated for an initiating enzyme N-acetylgalactosaminyl (GalNAc)- transferase 14 and for GalNAc-specific sialyltransferase (ST6GalNAc-II) and, conversely, decreased for the galactosyltransferase (C1GalT1) and C1GalT1- associated chaperone Cosmc. Involvement of the key enzymes in the production of Gd-IgA1 was confirmed by siRNA knockdown and biochemical approaches. Moreover, expression of these enzymes is affected by some cytokines that further enhance the enzyme imbalance to increase Gd-IgA1 production. In summary, the production of Gd-IgA1, the key autoantigen in IgAN, by IgA1- secreting cells results from dysregulation of key glycosyltransferases and is augmented by certain cytokines. These findings provide insight into possible approaches for future disease-specific therapy.
UR - http://www.scopus.com/inward/record.url?scp=85028529854&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028529854&partnerID=8YFLogxK
U2 - 10.1007/978-4-431-55588-9_4
DO - 10.1007/978-4-431-55588-9_4
M3 - Chapter
AN - SCOPUS:85028529854
SN - 9784431555872
SP - 53
EP - 68
BT - Pathogenesis and Treatment in IgA Nephropathy
PB - Springer Japan
ER -