The Role of IgA in Atherosclerosis
Department
Biomedical and Translational Sciences
Graduate Level
Doctoral
Graduate Program/Concentration
Eastern Virginia Medical School - Biomedical and Translational Sciences
Presentation Type
Poster Presentation
Abstract
INTRODUCTION: Atherosclerosis is a disease primarily characterized by the build-up of fatty lesions in large and medium-sized vessels, chronic inflammation, dyslipidemia, and obesity. Immune systems from all lineages, especially B cell subsets, play a complex role in the development of plaque formation during atherosclerosis. Innate response activator and follicular B cells are known to be pro-atherogenic whereas, B1 cells, and marginal zone B cells show protective functions in atherosclerosis. B1 cells produce immunoglobulin A (IgA) Abs that are crucial for mucosal immunity. Gut microbiota plays an important role in shaping the immune system at all stages of life. IgA Abs are involved in maintaining intestinal homeostasis and have the ability to mediate gut protective immunity. Interestingly, studies have shown a close relation between altered gut microbiota and the presence of bacterial populations within atherosclerotic plaques. However, the role of IgA in atherogenesis development is still largely unknown. In this study, we investigate the role of IgA in developing atherosclerosis and associated changes in gut health that accompany plaque progression.
METHODS: IgA-deficient low-density lipoprotein–deficient receptor (IgA-/-Ldlr-/-) and control Ldlr-/- male mice were fed a high-fat diet (HFD) for 17 weeks to induce hyperlipidemia and the development of atherosclerotic lesions. Plasma cholesterol levels and lesion formation in the aorta and the brachiocephalic artery (BCA) were measured. Single-cell suspensions from different tissues were collected and analyzed with Spectral Flow to assess immune cell distribution and activation. The hearts were collected and stained with MOVAT to assess plaque size and stability phenotype. Guts were collected and stained with specific Abs to measure gut health and inflammatory status. Immunoglobulin levels in plasma were detected using ELISA.
RESULTS: The IgA deficiency significantly reduced atherosclerosis in IgA-/-Ldlr-/- by 42.6% (6.5%, lesion size IgA-/-Ldlr-/- and control 11.4% lesion size Ldlr-/-, with SE ; pLdlr-/- mice (Grade 1: 22.22%, Grade 3: 77.77%) compared to IgA-/-Ldlr-/- mice (Grade 1: 22.2%, Grade 2: 44.4%, Grade 3: 33.3%). We detected an increased number of leukocytes in Ldlr-/- mice compared to the IgA-/-Ldlr-/- control mice in the omentum (by 61.4%) and carotids (by 71.7%) (pIgA-/-Ldlr-/- mice were substantially increased by 90.5% and 96.5%, respectively, compared to their Ldlr-/- counterparts. IgG2b plasma levels in HFD and chow fed IgA-/-Ldlr-/- mice were also increased by 18.0% and 39.4%, respectively, compared to their Ldlr-/- counterparts. IgM plasma levels in HFD fed IgA-/-Ldlr-/- mice were decreased by 10.9% compared to the Ldlr-/- mice, whereas increased by 39.8% in the chow fed IgA-/-Ldlr-/- mice. Further analysis of flow cytometry and histology data is underway.
CONCLUSION: Our data so far suggests IgA plays an unexpected pro-atherogenic role, likely by altering the local immune composition and reshaping the ability of B cells to produce other immunoglobulins. Future work will focus on identifying the mechanisms by which IgA-deficient B cells regulate plaque development and plaque stability.
Keywords
Atherosclerosis, Fatty lesions, Chronic inflammation, Dyslipidemia, Obesity, Immune system, B cell subsets, Innate response activator B cells, Follicular B cells, B1 cells, Marginal zone B cells, Immunoglobulin A (IgA), Gut microbiota, Intestinal homeostasis, Gut protective immunity, Atherogenesis, Plaque progression, Hyperlipidemia, Low-density lipoprotein receptor (Ldlr-/-), High-fat diet (HFD), Aorta, Brachiocephalic artery (BCA), Spectral Flow cytometry, MOVAT staining, Leukocytes, IgG1, IgG2b, IgM, Histology, Plaque development, Plaque stability
The Role of IgA in Atherosclerosis
INTRODUCTION: Atherosclerosis is a disease primarily characterized by the build-up of fatty lesions in large and medium-sized vessels, chronic inflammation, dyslipidemia, and obesity. Immune systems from all lineages, especially B cell subsets, play a complex role in the development of plaque formation during atherosclerosis. Innate response activator and follicular B cells are known to be pro-atherogenic whereas, B1 cells, and marginal zone B cells show protective functions in atherosclerosis. B1 cells produce immunoglobulin A (IgA) Abs that are crucial for mucosal immunity. Gut microbiota plays an important role in shaping the immune system at all stages of life. IgA Abs are involved in maintaining intestinal homeostasis and have the ability to mediate gut protective immunity. Interestingly, studies have shown a close relation between altered gut microbiota and the presence of bacterial populations within atherosclerotic plaques. However, the role of IgA in atherogenesis development is still largely unknown. In this study, we investigate the role of IgA in developing atherosclerosis and associated changes in gut health that accompany plaque progression.
METHODS: IgA-deficient low-density lipoprotein–deficient receptor (IgA-/-Ldlr-/-) and control Ldlr-/- male mice were fed a high-fat diet (HFD) for 17 weeks to induce hyperlipidemia and the development of atherosclerotic lesions. Plasma cholesterol levels and lesion formation in the aorta and the brachiocephalic artery (BCA) were measured. Single-cell suspensions from different tissues were collected and analyzed with Spectral Flow to assess immune cell distribution and activation. The hearts were collected and stained with MOVAT to assess plaque size and stability phenotype. Guts were collected and stained with specific Abs to measure gut health and inflammatory status. Immunoglobulin levels in plasma were detected using ELISA.
RESULTS: The IgA deficiency significantly reduced atherosclerosis in IgA-/-Ldlr-/- by 42.6% (6.5%, lesion size IgA-/-Ldlr-/- and control 11.4% lesion size Ldlr-/-, with SE ; pLdlr-/- mice (Grade 1: 22.22%, Grade 3: 77.77%) compared to IgA-/-Ldlr-/- mice (Grade 1: 22.2%, Grade 2: 44.4%, Grade 3: 33.3%). We detected an increased number of leukocytes in Ldlr-/- mice compared to the IgA-/-Ldlr-/- control mice in the omentum (by 61.4%) and carotids (by 71.7%) (pIgA-/-Ldlr-/- mice were substantially increased by 90.5% and 96.5%, respectively, compared to their Ldlr-/- counterparts. IgG2b plasma levels in HFD and chow fed IgA-/-Ldlr-/- mice were also increased by 18.0% and 39.4%, respectively, compared to their Ldlr-/- counterparts. IgM plasma levels in HFD fed IgA-/-Ldlr-/- mice were decreased by 10.9% compared to the Ldlr-/- mice, whereas increased by 39.8% in the chow fed IgA-/-Ldlr-/- mice. Further analysis of flow cytometry and histology data is underway.
CONCLUSION: Our data so far suggests IgA plays an unexpected pro-atherogenic role, likely by altering the local immune composition and reshaping the ability of B cells to produce other immunoglobulins. Future work will focus on identifying the mechanisms by which IgA-deficient B cells regulate plaque development and plaque stability.