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Autoimmune responses against the apo B-100 LDL receptor-binding site protect against arterial accumulation of lipids in LDL receptor deficient mice.

Nordin Fredrikson, Gunilla LU ; Lindholm, Marie LU ; Ljungcrantz, Irena LU ; Söderberg, Ingrid LU ; Shah, Prediman K and Nilsson, Jan LU (2007) In Autoimmunity 40(2). p.122-130
Abstract
Background: Oxidation of LDL is associated with generation of autoantibodies against a large number of different aldehyde-modified peptide sequences in apo B-100. Autoantibodies recognizing peptide sequences in the LDL receptor-binding region of apo B-100 could potentially affect both cholesterol metabolism and atherosclerosis. The aim of the present study was to determine physiological effects of induction of immune responses against the apo B-100 LDL receptor-binding site in mice deficient for the LDL receptor. Methods and results: Mice received three immunizations, beginning at 6 weeks of age, with aldehyde-modified or nonmodified peptides corresponding to the amino acid sequence of the LDL receptor-binding site. Analysis of antibody... (More)
Background: Oxidation of LDL is associated with generation of autoantibodies against a large number of different aldehyde-modified peptide sequences in apo B-100. Autoantibodies recognizing peptide sequences in the LDL receptor-binding region of apo B-100 could potentially affect both cholesterol metabolism and atherosclerosis. The aim of the present study was to determine physiological effects of induction of immune responses against the apo B-100 LDL receptor-binding site in mice deficient for the LDL receptor. Methods and results: Mice received three immunizations, beginning at 6 weeks of age, with aldehyde-modified or nonmodified peptides corresponding to the amino acid sequence of the LDL receptor-binding site. Analysis of antibody response by ELISA unexpectedly revealed high titers of pre-existing IgG against both native and aldehyde-modified binding site sequences in non-immunized mice. Immunization with aldehyde-modified binding site sequences resulted in an almost complete down-regulation of this autoimmune response. It was also associated with a rapid increase in lipid-rich plaques in the aorta and a substantial depletion of the lipid content of the liver, whereas plasma lipid and apo B values were similar in all groups. Conclusions: These observations demonstrate existence of an endogenous T cell-dependent autoimmune response against the LDL receptor-binding site in LDL receptor(-/-) mice and suggest that this may help to prevent accumulation of lipoprotein lipids in the artery wall, whereas immunization with the corresponding aldehyde modified sequence down-regulates this response and induces substantial atherosclerotic development. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
apolipoprotein, autoantibodies, LDL-receptor, binding-site, atherosclerosis
in
Autoimmunity
volume
40
issue
2
pages
122 - 130
publisher
Taylor & Francis
external identifiers
  • wos:000246108100006
  • scopus:34250319739
ISSN
0891-6934
DOI
10.1080/08916930601165107
language
English
LU publication?
yes
id
07b5bf6d-5292-47cb-af52-6308869b9ad4 (old id 167409)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17453711&dopt=Abstract
date added to LUP
2007-07-27 11:12:34
date last changed
2017-01-22 04:00:52
@article{07b5bf6d-5292-47cb-af52-6308869b9ad4,
  abstract     = {Background: Oxidation of LDL is associated with generation of autoantibodies against a large number of different aldehyde-modified peptide sequences in apo B-100. Autoantibodies recognizing peptide sequences in the LDL receptor-binding region of apo B-100 could potentially affect both cholesterol metabolism and atherosclerosis. The aim of the present study was to determine physiological effects of induction of immune responses against the apo B-100 LDL receptor-binding site in mice deficient for the LDL receptor. Methods and results: Mice received three immunizations, beginning at 6 weeks of age, with aldehyde-modified or nonmodified peptides corresponding to the amino acid sequence of the LDL receptor-binding site. Analysis of antibody response by ELISA unexpectedly revealed high titers of pre-existing IgG against both native and aldehyde-modified binding site sequences in non-immunized mice. Immunization with aldehyde-modified binding site sequences resulted in an almost complete down-regulation of this autoimmune response. It was also associated with a rapid increase in lipid-rich plaques in the aorta and a substantial depletion of the lipid content of the liver, whereas plasma lipid and apo B values were similar in all groups. Conclusions: These observations demonstrate existence of an endogenous T cell-dependent autoimmune response against the LDL receptor-binding site in LDL receptor(-/-) mice and suggest that this may help to prevent accumulation of lipoprotein lipids in the artery wall, whereas immunization with the corresponding aldehyde modified sequence down-regulates this response and induces substantial atherosclerotic development.},
  author       = {Nordin Fredrikson, Gunilla and Lindholm, Marie and Ljungcrantz, Irena and Söderberg, Ingrid and Shah, Prediman K and Nilsson, Jan},
  issn         = {0891-6934},
  keyword      = {apolipoprotein,autoantibodies,LDL-receptor,binding-site,atherosclerosis},
  language     = {eng},
  number       = {2},
  pages        = {122--130},
  publisher    = {Taylor & Francis},
  series       = {Autoimmunity},
  title        = {Autoimmune responses against the apo B-100 LDL receptor-binding site protect against arterial accumulation of lipids in LDL receptor deficient mice.},
  url          = {http://dx.doi.org/10.1080/08916930601165107},
  volume       = {40},
  year         = {2007},
}