Artery tertiary lymphoid organs (ATLOs) harbor a dysregulated immune tolerance environment permissive for autoreactive B cells that express pathogenic autoantibodies promoting atherosclerosis, with a high-affinity anti-H2B autoantibody-autoantigen pair identified as disease-relevant.
Key Findings
Results
ATLO germinal center B cell-derived autoantibodies are skewed toward atherosclerosis-relevant autoantigens compared to their lymph node counterparts.
GC B cells were isolated from ATLOs and lymph nodes of both healthy and atherosclerosis-burdened mice.
60 autoantibodies were expression-cloned from ATLO GC B cells and screened for arterial wall reactivity.
ATLO GC B cell-derived autoantibodies showed preferential binding to atherosclerosis-relevant autoantigens versus counterparts in lymph nodes of both genotypes.
This skewing was specific to the ATLO microenvironment rather than a systemic lymphoid organ phenomenon.
Results
One ATLO GC B cell-derived autoantibody, termed A6, binds to histone 2B (H2B) with high affinity.
A6 was identified through systematic screening of 60 expression-cloned autoantibodies from ATLO GC B cells.
The A6 autoantibody demonstrated high-affinity binding specifically to histone 2B (H2B).
H2B was thereby identified as an atherosclerosis-relevant autoantigen encoded within ATLOs.
This represents a specific autoantibody-autoantigen pair identified in the context of atherosclerosis.
Results
Both vaccination with H2B and adoptive transfer of the A6 autoantibody accelerate atherosclerosis in mice.
H2B vaccination experiments were conducted in atherosclerosis-burdened mice to test antigen pathogenicity.
Adoptive transfer of the A6 autoantibody was used as an independent approach to establish pathogenicity.
Both experimental approaches resulted in accelerated atherosclerosis, confirming the A6-H2B pair as a pathogenic autoantibody-autoantigen pair.
These findings establish a causal role for anti-H2B autoimmunity in atherosclerosis progression.
Results
ATLOs specifically show distorted B cell activation and immune tolerance checkpoint-regulating gene expression profiles.
Mechanistic analyses revealed that ATLOs have a dysregulated immune tolerance environment.
Gene expression profiling identified distorted B cell activation pathways specifically in ATLOs.
Immune tolerance checkpoint-regulating genes showed altered expression profiles in ATLOs.
These molecular features were specific to ATLOs and are proposed to be permissive for autoreactive B cell emergence and survival.
Results
Circulating anti-H2B antibody titers positively correlate with aortic calcification in a human cohort.
A human cohort study was conducted to assess clinical relevance of the anti-H2B autoantibody finding.
Circulating anti-H2B antibody titers were measured and correlated with aortic calcification as a marker of atherosclerosis burden.
A positive correlation was found between anti-H2B antibody titers and aortic calcification.
This human data provides translational support for the pathogenic relevance of the anti-H2B autoimmune response identified in mice.
Discussion
ATLOs emerge in atherosclerosis and harbor a dysregulated immune tolerance environment permissive for disease-relevant autoreactive B cells.
ATLOs are structures that form in the adventitia of atherosclerotic arteries and contain organized lymphoid tissue including germinal centers.
The study establishes that ATLOs, not just peripheral lymph nodes, are sites where disease-specific autoreactive B cells are generated.
The dysregulated tolerance environment in ATLOs is proposed as the mechanism allowing escape of autoreactive B cells.
The findings add an autoimmune B cell component to the established chronic inflammatory pathogenesis of atherosclerosis.
What This Means
This research investigates a little-known aspect of atherosclerosis (hardening of the arteries): whether the immune system produces self-attacking antibodies directly within the diseased artery wall. Scientists have previously discovered that arteries affected by atherosclerosis develop small immune organ-like structures called artery tertiary lymphoid organs (ATLOs). This study found that these ATLOs produce antibodies that specifically target the body's own proteins — a hallmark of autoimmune disease. By isolating immune cells from ATLOs and creating copies of their antibodies in the lab, the researchers identified one antibody, called A6, that strongly binds to histone 2B (H2B), a protein normally found inside cell nuclei. When mice were either given this antibody or vaccinated with H2B protein, their atherosclerosis became worse, demonstrating that this antibody-protein pair actively drives disease progression.
The researchers also found that ATLOs have an unusual molecular environment: the genes that normally keep the immune system from attacking the body's own tissues appear to be dysregulated in ATLOs, potentially allowing these self-attacking immune cells to survive and multiply when they normally would be shut down. In a separate human patient cohort, people with higher blood levels of anti-H2B antibodies also had more aortic calcification, a measure of advanced atherosclerosis, suggesting this mechanism may be relevant in human disease as well.
This research suggests that atherosclerosis has a previously underappreciated autoimmune component, where structures that form within diseased arteries themselves act as factories for producing harmful self-targeting antibodies. The identification of H2B as a specific target, and the demonstration that blocking or neutralizing this immune response could slow disease progression, may open new avenues for understanding and potentially treating cardiovascular disease from an autoimmune perspective.
Zhang C, Zhang X, Ran Y, Wang Z, Li L, Wang S, et al.. (2026). Artery tertiary lymphoid organs encode a pathogenic high-affinity autoantibody-autoantigen pair in atherosclerosis.. Nature cardiovascular research. https://doi.org/10.1038/s44161-026-00864-w