B-Lymphocyte Deficiency Increases Atherosclerosis in LDL Receptor–Null Mice

Abstract

Objective-Atherosclerosis is an inflammatory disease characterized by innate and adaptive immune responses. We investigated the role of B cells and antibodies in the development of atherosclerosis in low density lipoprotein (LDL) receptor-deficient (LDLR Ϫ/Ϫ ) mice. Methods and Results-Using wild-type and B cell-deficient mice as bone marrow donors, we were able to generate LDLR Ϫ/Ϫ mice that possessed Ͻ1.0% of their normal B cell population. B cell-deficient LDLR Ϫ/Ϫ mice on a Western diet showed marked decreases in total serum antibody and anti-oxidized LDL antibody. B cell deficiency was associated with a 30% to 40% increase in the lesion area in the proximal and distal aortas. Real-time reverse transcription-polymerase chain reaction and enzyme-linked immunospot analyses showed a decrease in proatherogenic (interferon-␥) and antiatherogenic (interleukin-10 and transforming growth factor-␤) cytokine mRNA and a decrease in interleukin-4 -and interferon-␥-producing cells. Additionally, we observed a decrease in splenocyte proliferation to oxidized LDL in the B cell-deficient LDLR Ϫ/Ϫ mice, suggesting that B lymphocytes may play a role in the presentation of lipid antigen. Conclusions

IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis

“…As recently demonstrated, without the natural immunoprotection afforded by B cells, atherogenesis can be dramatically accelerated (55). In particular, B-1 cells are primitive tiers of innate immunity and arise spontaneously in mice early in ontogeny (56).…”

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…141 Similarly, B cell deficiency increases atherosclerosis in Ldlr -/-mice. 142 One later study has suggested that B1a cells and their secretion of IgM mediate the protective effects of B cells. 143 Although these data indicate an atheroprotective function of B cells in atherosclerosis, B cell depletion with anti-CD20 was shown to protect against atherosclerosis in Apoe -/-and Ldlr -/-mice, 144 suggesting the contrary.…”

Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE −/− Mice

“…Data from Major et al indicate that B-cell deficiency in LDL-receptor Ϫ/Ϫ mice increases atherosclerosis. 48 B-cells from LDL-receptor Ϫ/Ϫ and apoE Ϫ/Ϫ mice produce antibodies that recognize oxidized LDL and immunization of atherosclerotic mice with modified forms of LDL has been shown to reduce lesion development. 49,50 As noted, OPG Ϫ/Ϫ mice have immature B-cell development and impaired antibody production and administration of recombinant OPG stimulates production of specific antibodies.…”