Work

Spatial multi-omics implicates vascular adipocytes proximal to tertiary lymphoid structures in human aortic aneurysm and B-cell autoreactivity

Year: 2026

Type: preprint

Abstract: Objective Perivascular Adipose Tissue (PVAT), tertiary lymphoid structures (TLS), and the B lymphocytes they harbor have been implicated in regulating vascular diseases, including abdominal aortic aneurysm (AAA). Yet, the relationship of adipose tissue to TLS and B-cell responses is poorly understood. Approach and Results Here, using multi-omics approaches, we characterized the potential interplay of vascular adipocytes and TLSs in shaping microenvironments conducive to pathogenic B-cell immunity in human AAA pathology. Single-nucleus RNA sequencing identified white adipocytes expressing transcripts for lipogenesis, lipolysis, and extracellular remodeling. Unexpectedly, these adipocytes expressed haptotactic and chemotactic factors such as thrombospondin 1 and autotaxin, and extracellular matrix proteins with potential to recruit CD44+ leukocytes within AAAs. Immunohistology revealed two anatomical compartments for the adipocytes within AAAs: PVAT and the medial-adventitial region. Medial-adventitial adipocytes were frequently associated with CD44+ TLSs and were largely absent from control non-aneurysmal abdominal aortas. Visium HD spatial transcriptomics revealed mature TLSs recapitulated the organization of functional secondary lymphoid structures, with multiple B-cell follicles clustered to form a nodular structure partly covered by a layer of smooth muscle cells. The TLSs harbored isotype-switched B cells expressing IgG1, IgG3, or IgA, with dominant kappa chain usage and IgG antibodies to the aortic wall. Myeloid cells in AAA were implicated in promoting B-cell effects, as they were the primary producers of B-cell activating factor (BAFF), a cytokine that promotes B-cell infiltration, survival, and function. Conclusion Altogether, our results support a model in which new adipocytes in the medial-adventitial layer elicit inflammatory pathways that promote early TLS formation, and BAFF produced by myeloid cells promotes the survival and maturation of vascular wall-antigen-exposed B cells, leading to mature TLS formation, production of antibodies to AAA antigens, fueling inflammation and AAA growth. Graphical Abstract Clinical Implications Despite multiple drugs showing efficacy in preclinical animal models, no non-surgical treatments are available for AAAs. Therefore, we re-evaluated human aortic aneurysm pathology using new technologies to better understand human aneurysm pathogenesis. The results revealed formation of novel adipocytes in the medial-adventitial region of human AAAs. These vascular adipocytes exacerbate inflammation by attracting an arsenal of immune cells to the medial-adventitial region. B-cell activating factor (BAFF) further exacerbates the B-cell immune response by supporting the formation of mature tertiary lymphoid structures (TLSs) and production of antibodies against AAA tissue. While more studies are needed to confirm these findings, this work opens new avenues of investigation for potential therapeutics for treating small AAAs. Particularly, repurposing anti-adipogenesis drugs and anti-BAFF therapeutics may attenuate B-cell immune responses, inflammation, and AAA growth.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.13.758932