Sex Differences in Autoimmune Signatures After Myocardial Infarction in Mice

Abstract

Myocardial infarction (MI) is caused by ischemic injury to the left ventricle (LV), leading to an acute inflammatory response, scar formation, and loss of LV function. The role of the antibody-mediated response and autoimmune (AI) development during MI is not well understood. AI disease is highly prevalent in females, which increases risk of MI and worsens MI outcomes. Thus, we hypothesized that females would exhibit increased susceptibility to MI-induced development of AI signatures, including B cell activation and autoantibody (AAB) production. Permanent MI was induced by left coronary artery ligation in adult male and female C57BL/6J mice, which were followed for 7, 28, or 56 days, using no MI (D0) as controls. LV function was tracked using echocardiography (VEVO 3100). LV infarct cytokines were measured by qPCR. LV infarct and blood leukocytes were measured by flow cytometry. LV IgG and IgM antibody deposition was measured by immunofluorescence. Plasma AABs (IgG and IgM subclasses) were measured with an autoantigen (AAN) microarray (128 AANs). In both sexes, MI led to progressive LV hypertrophy, increased end-diastolic diameter and volume, anterior/posterior wall thinning, and decreased ejection fraction. Survival was significantly higher in females for each time point (100% vs 50% at D7, 83% vs 57% at D28, 94% vs 39% at D56). MI increased spleen mass/tibia length in D7, 28, and 56 females, but decreased spleen mass in D28 and 56 males. LV inflammatory cytokines (IL-1β, IL-6, IL-18, IFN-γ, TNF, CCL2, IL-10) were increased at D7. In both sexes, IL-6 and IL-18 remained elevated at D28 and 56. Blood and LV myeloid cells were increased at D7 in both sexes, while B and T cells were decreased. At D28, myeloid cells returned to D0 levels; LV activated B cells (CD80+) and T cells (CD3+) were increased. At D56, only B cells remained elevated in the LV. IgG deposition was increased in the female LV at D7 (14.1±1.2% area fraction vs 6.3±1.5% D0) and further at D28 (40.4±3.6%), but only at D28 in males (20.4±4.0% vs 3.1±0.7% D0). Both sexes exhibited increased LV IgM at D7 and 28, however, the IgM response at D7 was higher in females (21.1±2.8% vs 8.3±1.6% in males). In plasma, MI increased AABs against several AANs (p<0.05 vs D0). Compared to D0, D7 females had elevated IgG AABs 1 AAN (dsDNA, a classical AI marker) vs 0 for males, and elevated IgM AABs against 4 different AANs versus 1 for males. D28 females had elevated IgG AABs against 1 AAN vs 4 for males, and elevated IgM AABs against 5 AANs vs 0 in males. D56 females had elevated IgG AABs against 34 AANs vs 9 in males, and elevated IgM AABs against 30 AANs versus 1 for males. For both IgG and IgM AABs in D56 females, several were against AANs highly expressed in the heart, including ACE2, mitochondrion, and myosin. Furthermore, D56 female IgM AABs were increased against IL-6 (9.8±0.8 fold change), which as mentioned earlier, remained elevated in the LV at all post-MI time points. In summary, MI promotes development of AI signatures, including LV B and T cell activation, IgG and IgM antibody deposition, and increased circulating AABs, which is exacerbated in females. NHLBI R01 HL166737 (Mouton), AHA Career Development Award CDA856365 (Mouton), NIH/NHLBI R00 HL146888 (Taylor), U54 HL169191 (Taylor), NIGMS P20 GM104357 (Hall), P30 GM149404 (Hall), U54 GM115428 (Hall), NHLBI R01 HL1630376 (da Silva), NIDDK R01 DK121411 (do Carmo), AHA Postdoctoral Fellowship 835218 (Omoto). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.