Sex differences in the chronic autoimmune response to myocardial infarction

Myocardial infarction (MI) causes a robust inflammatory response, which is necessary for remodeling and scar formation of the infarcted left ventricle (LV). However, this can lead to chronic systemic inflammation and persistent autoimmune responses. In this study, we analyzed sex differences in the inflammatory autoimmune response to chronic MI. MI was induced by permanent left coronary artery ligation in adult male and female C57BL/6J mice for one, four, and eight weeks. Both sexes exhibited similar declines in LV function. Females had higher levels of total immune cells and T cells in the infarct and remote area at D7 post-MI, and B cells at D56. MI increased levels of pro-inflammatory cytokines (Il1b, Il6, Tnf, Ccl2, Ifng, Il18) in the LV infarct that peaked at one week, which was exaggerated in females for Il6, Ifng, and Il10. In the remote LV, females had higher levels of Il6, Tnf, Ccl2, and Il18. MI increased spleen mass in females only, and splenic cytokines were higher in females at several time points, including Il1b, Il12a, Il10, Ifng, Il18, Ccl2, and Il4. IgG and IgM deposition in the LV infarct increased over time in both sexes, but more so in females. In the remote area, both sexes had increased IgG and IgM at eight weeks. Plasma IgM was higher in females at one, four, and eight weeks post-MI compared with males. Plasma IgG and IgM autoantibodies were detected in males and females after MI, but the number of autoantibodies displaying reactivity to autoantigens was much higher in females, particularly at week 8. In summary, MI leads to the development of systemic and myocardial autoimmune activation, which is more pronounced in females.