Intravascular adipocytes and tertiary lymphoid structures in human aneurysmal autoimmunity 3366

Abstract Description Abdominal aortic aneurysm (AA) is a disease in which the aorta is abnormally dilated and may rupture causing sudden death. As surgery is the only treatment option, there is a great need to understand the pathogenesis of AAs. Inflammaging and B cell-activating factor (BAFF) are crucial for the growth of AAs, however, the role of adaptive immunity in AA is poorly understood. BAFF can promote the formation of tertiary lymphoid structure (TLS) in non-lymphoid organs, supporting its role in autoimmunity. We found that BAFF-enriched non-classical and classical TLSs are present in human AAs. Unexpectedly, intravascular adipocytes (IVAs) are formed in the AA tissues, but not in healthy aortas, and are associated primarily with non-classical TLSs. Our single-nucleus RNA sequencing identified IVA as the primary producer of thrombospondin 1 in a human AA specimen. Thrombospondin 1 is a haptotactic-chemotactic matricellular protein suggesting IVAs function as a TLS inducer. NanoString spatial analyses revealed increased ERK1/2 signaling in non-classical TLS naive B cells, whereas, antigen-specific B cells, highly mutated germinal center B cells, and memory T cells pertain to classical TLSs. Additionally, AA explants produced multiple autoantibodies against the aorta. Altogether, our results support a model in which IVA-produced factors promote non-classical TLS formation, and BAFF promotes the maturation of the non-classical TLSs to classical and initiates autoimmunity in the AAs. Funding Sources Supported by NIH/NHLBI R01HL146685 and funds from East Carolina University. Topic Categories Basic Autoimmunity (BA)