IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function

Area of Science:

• Immunology
• Vascular Biology
• Infectious Diseases

Background:

• Severe COVID-19 involves blood vessel damage from immune responses to SARS-CoV-2.
• Angiotensin-converting enzyme 2 (ACE2) is the SARS-CoV-2 receptor on vascular endothelium.
• Autoantibodies against ACE2 may play a mechanistic role in COVID-19 pathogenesis.

Purpose of the Study:

• To investigate the presence and significance of autoantibodies against ACE2 in COVID-19 patients.
• To determine if anti-ACE2 autoantibodies are associated with severe COVID-19 outcomes.
• To explore the functional impact of anti-ACE2 autoantibodies on endothelial cells.

Main Methods:

• ELISA was used to detect autoantibodies against ACE2 in 118 COVID-19 inpatients.
• Biolayer interferometry analyzed the binding properties of anti-ACE2 IgM.
• A tissue-engineered pulmonary microvessel model assessed complement activation and endothelial function.

Main Results:

• Anti-ACE2 IgM autoantibodies were significantly more prevalent in severe COVID-19 (27.2%) compared to moderate disease (3.8%).
• These IgM autoantibodies were rare in non-COVID-19 ARDS patients and did not class-switch to IgG.
• Anti-ACE2 IgMs activated complement and altered endothelial cell function in microvessels.

Conclusions:

• Anti-ACE2 IgM autoantibodies are a mechanism-based biomarker strongly associated with severe COVID-19.
• These autoantibodies contribute to the angiocentric pathology observed in SARS-CoV-2 infection.
• The findings have potential therapeutic implications for managing severe COVID-19.