Artery tertiary lymphoid organs encode a pathogenic high-affinity autoantibody−autoantigen pair in atherosclerosis

Q: What is the clinical evidence from this study?

Population: Atherosclerosis and thoracic aortic calcification (n=495). Intervention: Circulating anti-histone 2B (H2B) autoantibodies (and H2B vaccination / A6 monoclonal autoantibody transfer in Apoe-/- mice) vs. Lower anti-H2B antibody titers (or PBS / isotype / adjuvant controls in mice). Primary outcome: Prevalence of thoracic aortic calcification (TAC) on chest CT in the human cohort (and aortic atherosclerotic plaque load in mice) (OR 2.43, p=0.023).

Q: What does this research mean for the field?

Artery tertiary lymphoid organ-derived anti-histone 2B (H2B) autoantibodies accelerate atherosclerosis in mice and correlate with aortic calcification in humans. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Chuankai Zhang; Xi Zhang; Yi Ran; Zhihua Wang; Liping Li; Shu Wang; Junjie Zheng; Yixin Zhang; Ting Sun; Yutao Li; Shu Lu; Mingyang Hong; Zhe Ma; Sabine Steffens; Michael Hristov; Xavier Blanchet; Jingpu Zhu; Xinwen Dou; Xinyi Deng; Klaus Dornmair; Desheng Hu; Shibojyoti Lahiri; Axel Imhof; Nadja Sachs; Lars Mäegdefessel; Jingyi Xiao; Jianning Zhang; Yan Wang; Hua Hong; Livia Habenicht; Xinyu Weng; Junbo Ge; Christian Weber; Donato Santovito; Rachael Bashford-Rogers; Sarajo K. Mohanta; Klaus Ley; Andreas J. R. Habenicht; Changjun Yin

doi:10.1038/s44161-026-00864-w

Key result

Artery tertiary lymphoid organ-derived anti-H2B autoantibodies accelerated atherosclerosis in mice and independently associated with thoracic aortic calcification in humans (OR 2.43, P=0.023).

Why the study?

Do artery tertiary lymphoid organ (ATLO)-derived anti-histone 2B (H2B) autoantibodies promote atherosclerosis progression in mice and associate with thoracic aortic calcification in humans?

Key Points

To determine whether disease-relevant autoimmune B cells arise in artery tertiary lymphoid organs (ATLOs) during atherosclerosis.
FACS-sorted CD45+ leukocytes from renal lymph nodes of aged wild-type and Apoe-/- mice, as well as ATLOs from Apoe-/- mice, analyzing 12,854 B cell transcriptomes with matched scRNA-seq and scBCR-seq.
Expression cloned 60 autoantibodies from germinal center B cells to test reactivity against the arterial wall, followed by histone 2B (H2B) vaccination and A6 antibody adoptive transfer in mice.
Assessed circulating anti-H2B autoantibody titers in a human clinical cohort to evaluate correlations with aortic calcification.
Identified high-affinity autoantibody A6 binding to H2B, with both H2B immunization and A6 adoptive transfer accelerating atherosclerosis in mice.
ATLO B cells showed altered transcriptomes with elevated activation markers (Nfkbia, Relb, Cxcr4) and decreased checkpoint and apoptotic genes (Cd22, Fas) compared to lymph node B cells.
Plasma cells in ATLOs exhibited significantly higher somatic hypermutations than renal lymph node plasma cells, and circulating anti-H2B antibody titers positively correlated with human aortic calcification.

Structured PICO

Do artery tertiary lymphoid organ (ATLO)-derived anti-histone 2B (H2B) autoantibodies promote atherosclerosis progression in mice and associate with thoracic aortic calcification in humans?

P

Population

Preclinical study in Apoe-/- and wild-type mice paired with a human cross-sectional screening cohort of 495 adults aged 30-70 years free of prior cardiovascular disease.

E

Exposure

In mice: vaccination with recombinant histone 2B (H2B) plus adjuvant at 8 weeks with a boost at 12 weeks, or passive intraperitoneal transfer of 100 ug recombinant ATLO-derived anti-H2B monoclonal autoantibody (A6) every 7 or 10 days starting at 12 weeks. In humans: exposure to elevated circulating serum anti-H2B autoantibody titers.

C

Comparator

In mice: PBS control, adjuvant-alone control, or irrelevant isotype control antibody. In humans: lower serum anti-H2B autoantibody titers.

O

Outcome

In mice: atherosclerotic plaque size/load in the whole aorta (en face staining, aortic root, thoracic and abdominal segments) at 16 or 32 weeks. In humans: prevalence of thoracic aortic calcification (TAC) assessed by 3D chest computed tomography (CT).surrogate

Main Result

Odds Ratio: 2.43

p-value: p=0.023

Limitations

Limited number of B cell receptor and antibody sequences cloned for functional characterization
Further work is needed to fully elucidate the molecular mechanisms of A6 autoantibody pathogenicity
Human clinical validation was conducted in a cross-sectional screening cohort
Limited number of BCR/antibody sequences cloned and screened (60 recombinant antibodies)
More work is needed to understand the exact downstream mechanisms of A6 autoantibody pathogenicity in vivo
Human data are derived from a cross-sectional preventive screening cohort rather than a longitudinal prospective study

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Implication

Identifies histone 2B (H2B) and its high-affinity autoantibody (A6) originating from artery tertiary lymphoid organs as a novel pathogenic autoimmune pair driving atherosclerosis in mice and correlating with aortic calcification in humans independent of lipid levels and hsCRP.

Abstract

Artery tertiary lymphoid organs (ATLOs) emerge in atherosclerosis, which is a chronic inflammatory artery disease with an autoimmune component. However, whether disease-relevant autoimmune B cells emerge in ATLOs remains unknown. In this study, we isolate germinal center (GC) B cells from ATLOs and lymph nodes from healthy and atherosclerosis-burdened mice, expression clone 60 autoantibodies and screen them for arterial wall reactivity. ATLO GC B cell-derived autoantibodies skew to atherosclerosis-relevant autoantigens versus their counterparts in lymph nodes of both genotypes. One ATLO GC B cell-derived autoantibody (termed A6) binds to histone 2B (H2B) with high affinity. Both vaccination with H2B and adoptive transfer of A6 accelerate atherosclerosis, revealing a pathogenic autoantibody−autoantigen pair. Mechanistically, ATLOs specifically show both distorted B cell activation and immune tolerance checkpoint-regulating gene expression profiles. In a human cohort, circulating anti-H2B antibody titers positively correlate with aortic calcification in humans. We suggest that ATLOs harbor a dysregulated immune tolerance environment permissive for autoreactive B cells that express pathogenic autoantibodies promoting atherosclerosis.

Discussion

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Cite This Study

Zhang et al. (2026) studied Atherosclerosis and thoracic aortic calcification (n=495). Circulating anti-histone 2B (H2B) autoantibodies (and H2B vaccination / A6 monoclonal autoantibody transfer in Apoe-/- mice) vs. Lower anti-H2B antibody titers (or PBS / isotype / adjuvant controls in mice) was evaluated on Prevalence of thoracic aortic calcification (TAC) on chest CT in the human cohort (and aortic atherosclerotic plaque load in mice) (OR 2.43, p=0.023). Artery tertiary lymphoid organ-derived anti-H2B autoantibodies accelerated atherosclerosis in mice and independently associated with thoracic aortic calcification in humans (OR 2.43, P=0.023).

synapsesocial.com/papers/6a9fd82f58e84d0ff5b47800 https://doi.org/10.1038/s44161-026-00864-w

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Artery tertiary lymphoid organs encode a pathogenic high-affinity autoantibody−autoantigen pair in atherosclerosis

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Artery tertiary lymphoid organs encode a pathogenic high-affinity autoantibody−autoantigen pair in atherosclerosis

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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