Autoimmune reactions to ACE2 triggered by SARS-CoV-2 S protein and their histopathological consequences

SARS-CoV-2 has been shown to induce autoimmunity. Due to the idiotype-antiidiotypic interactions between lymphocytes to SARS-CoV-2 S protein and lymphocytes to angiotensin converting enzyme 2 (ACE2), the immune response to S protein can cause induction of anti-ACE2 lymphocytes. The ubiquity of ACE2 within the human body endows autoimmune reactions to ACE2 with the role of the main factor causing injuries of various tissues. Immunization of Wistar rats with S protein caused hyperplasia and dedifferentiation of type II pneumocytes, extensive injury of the proximal tubules, infiltration of CD4+ T, CD45RA+ B lymphocytes in the lungs and CD4+ T, CD8+ T lymphocytes in the kidneys. Both type II pneumocytes and proximal tubule epithelium express ACE2. Damage to ACE2 expressing cells in the absence of other lesions in the studied organs suggests that ACE2 might be the target of an autoimmune attack induced by S protein. Our findings clarify the mechanism of multiple tissue damage in COVID-19. © The Author(s) 2025.