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Immune responses against aldehyde-modified laminin accelerate atherosclerosis in Apoe(-/-) mice.

Dunér, Pontus LU ; To, Fong LU ; Berg, Katarina LU ; Alm, Ragnar LU ; Björkbacka, Harry LU ; Engelbertsen, Daniel LU ; Nordin Fredrikson, Gunilla LU ; Nilsson, Jan LU and Bengtsson, Eva LU (2010) In Atherosclerosis 212(2). p.457-465
Abstract
BACKGROUND: LDL oxidation in the vascular wall is associated with aldehyde modification of surrounding extracellular matrix proteins that may target autoimmune responses against vascular tissues. Here we investigated the possible influence of immunity against a malondialdehyde (MDA)-modified form of the basement membrane protein laminin on atherosclerosis. METHODS AND RESULTS: IgM and IgG autoantibodies were present in human plasma and a prospective clinical study demonstrated that individuals who later suffered from acute cardiovascular events had lower levels of MDA-laminin antibodies compared to those in the control group. Immunohistochemical analysis of atherosclerotic plaques from Apoe(-/-) mice demonstrated co-localization between... (More)
BACKGROUND: LDL oxidation in the vascular wall is associated with aldehyde modification of surrounding extracellular matrix proteins that may target autoimmune responses against vascular tissues. Here we investigated the possible influence of immunity against a malondialdehyde (MDA)-modified form of the basement membrane protein laminin on atherosclerosis. METHODS AND RESULTS: IgM and IgG autoantibodies were present in human plasma and a prospective clinical study demonstrated that individuals who later suffered from acute cardiovascular events had lower levels of MDA-laminin antibodies compared to those in the control group. Immunohistochemical analysis of atherosclerotic plaques from Apoe(-/-) mice demonstrated co-localization between laminin and MDA epitopes, however MDA-laminin IgG was absent in mouse plasma. To determine the effect of MDA-laminin immunity, Apoe(-/-) mice were immunized with MDA-laminin. Analysis of circulating leukocytes at 12 weeks demonstrated increased T-cell activation, expansion of Th17 cells and a lower fraction of regulatory T cells (Tregs) in mice immunized with MDA-laminin. At 25 weeks, aortic atherosclerosis was increased by more than 60% in mice immunized with MDA-laminin, together with increased levels of MDA-laminin IgG1 and MDA-laminin-specific T-cells expressing IL-2, IL-4 and IL-6 in the spleen. CONCLUSION: The clinical observations suggest that immune responses against MDA-laminin may be involved in the development of cardiovascular disease in humans. Furthermore, observations in mice provide evidence for the presence of aldehyde-modified laminin in atherosclerotic lesions and demonstrate that induction of an immune response against these structures is associated with activation of Th17 cells, reduced fraction of Tregs and a more aggressive development of atherosclerosis. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Atherosclerosis
volume
212
issue
2
pages
457 - 465
publisher
Elsevier
external identifiers
  • wos:000282678500017
  • pmid:20810111
  • scopus:77957696516
ISSN
1879-1484
DOI
10.1016/j.atherosclerosis.2010.07.014
language
English
LU publication?
yes
id
eff31a2c-1e6a-4860-90b3-21d58a806d6b (old id 1688624)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20810111?dopt=Abstract
date added to LUP
2010-10-03 19:32:50
date last changed
2018-05-29 11:40:34
@article{eff31a2c-1e6a-4860-90b3-21d58a806d6b,
  abstract     = {BACKGROUND: LDL oxidation in the vascular wall is associated with aldehyde modification of surrounding extracellular matrix proteins that may target autoimmune responses against vascular tissues. Here we investigated the possible influence of immunity against a malondialdehyde (MDA)-modified form of the basement membrane protein laminin on atherosclerosis. METHODS AND RESULTS: IgM and IgG autoantibodies were present in human plasma and a prospective clinical study demonstrated that individuals who later suffered from acute cardiovascular events had lower levels of MDA-laminin antibodies compared to those in the control group. Immunohistochemical analysis of atherosclerotic plaques from Apoe(-/-) mice demonstrated co-localization between laminin and MDA epitopes, however MDA-laminin IgG was absent in mouse plasma. To determine the effect of MDA-laminin immunity, Apoe(-/-) mice were immunized with MDA-laminin. Analysis of circulating leukocytes at 12 weeks demonstrated increased T-cell activation, expansion of Th17 cells and a lower fraction of regulatory T cells (Tregs) in mice immunized with MDA-laminin. At 25 weeks, aortic atherosclerosis was increased by more than 60% in mice immunized with MDA-laminin, together with increased levels of MDA-laminin IgG1 and MDA-laminin-specific T-cells expressing IL-2, IL-4 and IL-6 in the spleen. CONCLUSION: The clinical observations suggest that immune responses against MDA-laminin may be involved in the development of cardiovascular disease in humans. Furthermore, observations in mice provide evidence for the presence of aldehyde-modified laminin in atherosclerotic lesions and demonstrate that induction of an immune response against these structures is associated with activation of Th17 cells, reduced fraction of Tregs and a more aggressive development of atherosclerosis.},
  author       = {Dunér, Pontus and To, Fong and Berg, Katarina and Alm, Ragnar and Björkbacka, Harry and Engelbertsen, Daniel and Nordin Fredrikson, Gunilla and Nilsson, Jan and Bengtsson, Eva},
  issn         = {1879-1484},
  language     = {eng},
  number       = {2},
  pages        = {457--465},
  publisher    = {Elsevier},
  series       = {Atherosclerosis},
  title        = {Immune responses against aldehyde-modified laminin accelerate atherosclerosis in Apoe(-/-) mice.},
  url          = {http://dx.doi.org/10.1016/j.atherosclerosis.2010.07.014},
  volume       = {212},
  year         = {2010},
}