The Role of IgA in Atherosclerosis
Abstract
Introduction: Atherosclerosis is the leading cause of death worldwide. The immune system plays an important role in atherogenesis. B cell response is a subset-specific with B1 and MZ B cells playing a protective role and FO B cells being atherogenic. One of the major B cell functions is to produce antibodies (Abs). IgA is primarily produced by B1 cells and supports the maintenance of balanced mucosal immunity. While IgM Abs are protective, IgG2a Abs play a pathological role in atherosclerosis. To date, the role of IgA in atherogenesis is unknown.
Methods: IgA-deficient low density lipoprotein-deficient (IgA-/-Ldlr-/-) and control Ldlr-/- male mice were fed a high fat diet for ~14-16 weeks and blood samples were obtained for total cholesterol. Aorta and brachiocephalic artery (BCA) were analyzed for plaque burden. Whole blood, spleen, omentum, and peritoneal lavage were collected and total cell distribution was compared between experimental groups. Significance was tested using a unpaired, two-way Student's T Test with a significance at p<0.05.
Results: The IgA deficiency resulted in reduced lesions in IgA-/-Ldlr-/- compared with Ldlr-/- controls. Unexpectedly, we found no significant differences in plaque burden in BCA. IgA-deficiency attenuated total cholesterol levels and this reduction correlated with a moderately reduced body weight in IgA-/- Ldlr-/- vs Ldlr-/- mice. Chronic activation is associated with increased leukocyte numbers within the local and secondary lymphoid tissues. While splenic cell counts were not different between the groups, the peritoneal leukocytes were elevated in IgA-/-Ldlr-/- vs Ldlr-/- mice. The omentum and carotid cell counts were lower in the IgA-/-Ldlr-/- vd Ldlr-/-mice. FACS showed a difference in circulating blood leukocytes, especially in neutrophils.
Conclusion: Overall, our results suggest that IgA plays a site-specific role in atherosclerosis, particularly contributing to atherogenesis in large blood vessels such as the aorta. IgA deficiency also alters leukocyte numbers in different tissues, highlighting the role of IgA in the regulation of local immunity. Our next goals would be to analyze the immune response in gut, PP, and omentum as the main sites of IgA production and dissect mechanisms by which IgA modulated lesions formation at different vascular beds.