title: Combined B, T and NK Cell Deficiency Accelerates Atherosclerosis in BALB/c Mice.
abstract: This study focused on the unique properties of both the Ldlr knockout defect (closely mimicking the human situation) and the BALB/c (C) inbred mouse strain (Th-2 slanted immune response). We generated two immunodeficient strains with severe combined B- and T-cell immunodeficiency with or without a complete lack of natural killer cells to revisit the role of adaptive immune responses on atherogenesis. C-Ldlr-/- Rag1-/- mice, which show severe combined B- and T-cell immunodeficiency and C-Ldlr-/- Rag1-/- Il2rg-/- mice, which combine the T- and B-cell defect with a complete lack of natural killer cells and inactivation of multiple cytokine signalling pathways were fed an atherogenic Western type diet (WTD). Both B6-Ldlr-/- and C-Ldlr-/- immunocompetent mice were used as controls. Body weights and serum cholesterol levels of both immunodeficient strains were significantly increased compared to C-Ldlr-/- controls, except for cholesterol levels of C-Ldlr-/- Rag1-/- double mutants after 12 weeks on the WTD. Quantification of the aortic sinus plaque area revealed that both strains of immunodeficient mice developed significantly more atherosclerosis compared to C-Ldlr-/- controls after 24 weeks on the WTD. Increased atherosclerotic lesion development in C-Ldlr-/- Rag1-/- Il2rg-/- triple mutants was associated with significantly increased numbers of macrophages and significantly decreased numbers of smooth muscle cells compared to both C-Ldlr-/- wild type and C-Ldlr-/- Rag1-/- double mutants pointing to a plaque destabilizing effect of NK cell loss. Collectively, the present study reveals a previously unappreciated complexity with regard to the impact of lymphocytes on lipoprotein metabolism and the role of lymphocyte subsets in plaque composition.
authors: Dr. Margarete Fischer-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany.
authors: Fei
authors: F
authors: Cheng
authors: Department of Laboratory Medicine, Robert-Bosch-Hospital, Stuttgart, Germany.
authors: Laura
authors: L
authors: Twardowski
authors: Center for Preclinical Research, German Cancer Research Center, Heidelberg, Germany.
authors: Kurt
authors: K
authors: Reifenberg
authors: Dr. Margarete Fischer-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany.
authors: Kerstin
authors: K
authors: Winter
authors: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
authors: Antje
authors: A
authors: Canisius
authors: Dr. Margarete Fischer-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany.
authors: Eva
authors: E
authors: Pross
authors: Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors: Jianglin
authors: J
authors: Fan
authors: Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
authors: Edgar
authors: E
authors: Schmitt
authors: The Jackson Laboratory, Bar Harbor, Maine, United State of America.
authors: Leonard D
authors: LD
authors: Shultz
authors: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
authors: Karl J
authors: KJ
authors: Lackner
authors: Department of Laboratory Medicine, Robert-Bosch-Hospital, Stuttgart, Germany.
authors: Michael
authors: M
authors: Torzewski
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology*; D001402:B-Lymphocytes / Q000166:cytology*; D002784:Cholesterol / Q000097:blood; D005260:Female; D007107:Immune System; D007153:Immunologic Deficiency Syndromes / Q000473:pathology*; D007694:Killer Cells, Natural / Q000166:cytology*; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology*; D014280:Triglycerides / Q000097:blood
chemical_list: D008074:Lipoproteins; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol