Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody

Area of Science:

• Immunology
• Vascular Biology
• Infectious Diseases

Background:

• Subclinical vascular impairment can worsen with sustained inflammation post-COVID-19.
• The role of autoantibodies in vascular dysfunction among COVID-19 survivors is understudied.

Purpose of the Study:

• To investigate the prevalence and impact of autoantibodies, specifically anti-ACKR1, on vascular dysfunction in healthy COVID-19 survivors.
• To explore the association between anti-ACKR1 autoantibodies and vascular disease outcomes.
• To elucidate the mechanism by which these autoantibodies affect endothelial cells.

Main Methods:

• Analysis of anti-ACKR1 autoantibodies, systemic cytokines, and endothelial cells in COVID-19 survivors.
• Longitudinal follow-up of an independent cohort for vascular disease outcomes.
• Single-cell transcriptome analysis of mouse endothelial cells to identify ACKR1 expression patterns.
• Functional assays using purified IgG from patient plasma on human vein endothelial cells and peripheral blood mononuclear cells (PBMCs).

Main Results:

• COVID-19 survivors had significantly elevated anti-ACKR1 autoantibodies correlating with cytokines and endothelial dysfunction.
• These autoantibodies were linked to increased vascular disease in a long-term follow-up cohort.
• ACKR1 expression was enriched in venous regions of mouse brain and soleus muscle.
• Patient IgG enhanced antibody-dependent cellular cytotoxicity (ADCC) via PBMCs, which was mitigated by ACKR1 blocking agents.

Conclusions:

• Elevated anti-ACKR1 autoantibodies in COVID-19 survivors contribute to vascular dysfunction and disease.
• ACKR1-targeting autoantibodies may play a role in COVID-19-associated venous thromboembolism.
• Therapeutic strategies targeting autoantibody reactivity to ACKR1 could mitigate chronic vascular inflammation.