Adaptive immune response to the autoantigen LL-37 differentiates atherosclerotic cardiovascular disease phenotypes.

UNLABELLED: Atherosclerosis is the common underlying pathology in atherosclerotic cardiovascular disease (ASCVD) phenotypes of myocardial infarction (MI), stroke or peripheral artery disease (PAD). Single immune cell profiling of atherosclerotic plaques demonstrates a site-specific immune profile associated with the ASCVD phenotype, and LL-37 is a reported autoantigen in atherosclerosis. OBJECTIVE: To investigate whether the immune response to LL-37 would be common among different ASCVD phenotypes. METHODS: Peripheral blood mononuclear cells (PBMCs) and plasma were collected from stable ASCVD patients enrolled within 12 months after MI or stroke or diagnosed with PAD. A subgroup of post-acute patients provided PBMCs at follow-up (14.7 ± 3.6 months). T-cell response to LL-37 was profiled using activation-induced markers. LL-37 IgG, immune complex (IC) levels and subclass were evaluated with ELISA. LDL is a reported binding partner of LL-37 in plasma. Therefore, cross-reactivity of LL-37 IgG-ICs with native LL-37 or LL-37 complexed with LDL (LL-37_LDL) was assessed using immune depletion. RESULTS: LL-37 provokes increased CD4CD25CD134T-cell response in stable post-MI patients whereas CD8CD25CD69T cells were reduced in PAD. CD4T-cell response to LL-37 in post-MI patients persisted at follow-up with increased CD4CD25CD69FoxP3T regulatory cells while post-stroke patients had increased CD8CD134T cells. LL-37 IgG-ICs were significantly increased in ASCVD patients with IgG3 subclass reduced in post-MI compared to post-stroke. Immune-depletion showed cross-reactivity of LL-37 IgG-ICs with both native LDL and LL-37_LDL only in post-MI plasma. CONCLUSION: LL-37 antigen specific profiling of immune response may differentiate various ASCVD phenotypes and provide mechanistic insight in pathophysiology.