Tin Kyaw1,2, Paula Loveland1, Peter Kanellakis1, Anh Cao1,2, Axel Kallies3, Alex L Huang4,5, Karlheinz Peter4,5,6, Ban-Hock Toh2, Alex Bobik1,2,6. 1. Vascular Biology and Atherosclerosis, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia. 2. Centre for Inflammatory Diseases, Department of Medicine, Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia. 3. Department of Microbiology and Immunology, University of Melbourne, 792 Elizabeth Street, Melbourne, Vic 3000, Australia. 4. Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia. 5. Department of Cardiology, Alfred Hospital, 55 Commercial Rd, Melbourne, VIC 3004, Australia. 6. Department of Immunology, Central Clinical School, 99 Commercial Rd, Melbourne, VIC 3004, Australia.
Abstract
AIMS: Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI. METHODS AND RESULTS: We used an apolipoprotein-E-deficient (ApoE-/-) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE-/- mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis. CONCLUSION: Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI. METHODS AND RESULTS: We used an apolipoprotein-E-deficient (ApoE-/-) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE-/- mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis. CONCLUSION: Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Upendra Chalise; Mediha Becirovic-Agic; Jocelyn R Rodriguez-Paar; Shelby R Konfrst; Sharon D B de Morais; Catherine S Johnson; Elizabeth R Flynn; Michael E Hall; Daniel R Anderson; Leah M Cook; Kristine Y DeLeon-Pennell; Merry L Lindsey Journal: J Cardiovasc Transl Res Date: 2022-10-05 Impact factor: 3.216
Authors: Texali C Garcia-Garduño; Jorge R Padilla-Gutierrez; Diego Cambrón-Mora; Yeminia Valle Journal: Int J Mol Sci Date: 2021-07-01 Impact factor: 5.923