A conformation-dependent epitope in Addison's disease and other endocrinological autoimmune diseases maps to a carboxyl-terminal functional domain of human steroid 21-hydroxylase
Nikoshkov, Andrej ; Falorni, Alberto ; Lajic, Svetlana ; Laureti, Stefano ; Wedell, Anna ; Lernmark, Åke LU
and Luthman, Holger
LU
(1999)
In Journal of Immunology
162(4).
p.2422-2426
- Abstract
Idiopathic Addison's disease develops as a consequence of autoimmune destruction of steroid-producing cells in the adrenal gland. A major autoantigen is 21-hydroxylase (21OH; P450c21), which is involved in the biosynthesis of cortisol and aldosterone in the adrenal cortex. We selected a number of functionally important 21OH amino acid substitutions, found in patients with congenital adrenal hyperplasia, to study their effects on the binding of 21OH autoantibodies (21OHAb) to 21OH. The ability of 21OHAb to bind in vitro transcribed and translated wild-type 21OH and five different 21OH mutant proteins was quantified by liquid-phase assays. Sera from 21OHAb- positive patients with idiopathic Addison's disease (n = 24), Graves' disease (n =... (More)
Idiopathic Addison's disease develops as a consequence of autoimmune destruction of steroid-producing cells in the adrenal gland. A major autoantigen is 21-hydroxylase (21OH; P450c21), which is involved in the biosynthesis of cortisol and aldosterone in the adrenal cortex. We selected a number of functionally important 21OH amino acid substitutions, found in patients with congenital adrenal hyperplasia, to study their effects on the binding of 21OH autoantibodies (21OHAb) to 21OH. The ability of 21OHAb to bind in vitro transcribed and translated wild-type 21OH and five different 21OH mutant proteins was quantified by liquid-phase assays. Sera from 21OHAb- positive patients with idiopathic Addison's disease (n = 24), Graves' disease (n = 3), and insulin-dependent diabetes mellitus (n = 1) were used. While the P105L, delE196, and G291S mutations had no effect on autoantibody binding, the P453S mutation had a considerable effect, and the R483P mutation almost completely abolished binding. Synthetic peptides corresponding to linear epitopes defined by amino acids 447-461 and 477-491 were unable to compete with wild-type 21OH for binding to autoantibodies. Direct 21OH DNA sequencing could not reveal any specific genetic variation in alleles found in 21OHAb- positive patients. We conclude that the region involving R483 plays a key role in the formation of a three-dimensional epitope in a functionally important C-terminal domain of the enzyme.
(Less)
- author
- Nikoshkov, Andrej
; Falorni, Alberto
; Lajic, Svetlana
; Laureti, Stefano
; Wedell, Anna
; Lernmark, Åke
LU
and Luthman, Holger
LU
- publishing date
- 1999-02-15
- type
- Contribution to journal
- publication status
- published
- in
- Journal of Immunology
- volume
- 162
- issue
- 4
- pages
- 2422 - 2426
- publisher
- American Association of Immunologists
- external identifiers
-
- scopus:0033558097
- pmid:9973524
- ISSN
- 0022-1767
- language
- English
- LU publication?
- no
- id
- e2ffc971-e16e-46f5-8630-8ddbcdf926a3
- alternative location
- https://www.jimmunol.org/content/jimmunol/162/4/2422.full.pdf
- date added to LUP
- 2019-06-25 13:28:09
- date last changed
- 2024-04-02 10:19:39
@article{e2ffc971-e16e-46f5-8630-8ddbcdf926a3,
abstract = {{<p>Idiopathic Addison's disease develops as a consequence of autoimmune destruction of steroid-producing cells in the adrenal gland. A major autoantigen is 21-hydroxylase (21OH; P450c21), which is involved in the biosynthesis of cortisol and aldosterone in the adrenal cortex. We selected a number of functionally important 21OH amino acid substitutions, found in patients with congenital adrenal hyperplasia, to study their effects on the binding of 21OH autoantibodies (21OHAb) to 21OH. The ability of 21OHAb to bind in vitro transcribed and translated wild-type 21OH and five different 21OH mutant proteins was quantified by liquid-phase assays. Sera from 21OHAb- positive patients with idiopathic Addison's disease (n = 24), Graves' disease (n = 3), and insulin-dependent diabetes mellitus (n = 1) were used. While the P105L, delE196, and G291S mutations had no effect on autoantibody binding, the P453S mutation had a considerable effect, and the R483P mutation almost completely abolished binding. Synthetic peptides corresponding to linear epitopes defined by amino acids 447-461 and 477-491 were unable to compete with wild-type 21OH for binding to autoantibodies. Direct 21OH DNA sequencing could not reveal any specific genetic variation in alleles found in 21OHAb- positive patients. We conclude that the region involving R483 plays a key role in the formation of a three-dimensional epitope in a functionally important C-terminal domain of the enzyme.</p>}},
author = {{Nikoshkov, Andrej and Falorni, Alberto and Lajic, Svetlana and Laureti, Stefano and Wedell, Anna and Lernmark, Åke and Luthman, Holger}},
issn = {{0022-1767}},
language = {{eng}},
month = {{02}},
number = {{4}},
pages = {{2422--2426}},
publisher = {{American Association of Immunologists}},
series = {{Journal of Immunology}},
title = {{A conformation-dependent epitope in Addison's disease and other endocrinological autoimmune diseases maps to a carboxyl-terminal functional domain of human steroid 21-hydroxylase}},
url = {{https://www.jimmunol.org/content/jimmunol/162/4/2422.full.pdf}},
volume = {{162}},
year = {{1999}},
}