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

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 non-modified 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.

• Apolipoprotein
• atherosclerosis
• autoantibodies
• binding-site
• LDL-receptor

Acknowledgements

This study was supported by grants from the Swedish Research Council, the Swedish Heart-Lung foundation, the King Gustaf V 80th Birthday foundation, the Swedish Society of Medicine, the Crafoord foundation, the Bergvall foundation, the Royal Physiographic Society, Malmö University Hospital foundation, the Lundström foundation, the Bergvall foundation and a grant from the Eisner Foundation to PKS.