COVID-19—A Theory of Autoimmunity Against ACE-2 Explained

Abstract

The COVID-19 pandemic caused by the coronavirus SARS-COV-2 has cost many lives worldwide. In dealing with affected patients, the physician is faced with a very unusual pattern of organ damage that is not easily explained on the basis of prior knowledge of viral-induced pathogenesis. It is established that the main receptor for viral entry into tissues is the protein angiotensin-converting enzyme-2 [“ACE-2”, (1)]. In a recent publication (2), a theory of autoimmunity against ACE-2, and/or against the ACE-2/SARS-COV-2 spike protein complex or degradation products thereof, was proposed as a possible explanation for the unusual pattern of organ damage seen in COVID-19. In the light of more recent information, this manuscript expands on the earlier proposed theory and offers additional, testable hypotheses that could explain both the pattern and timeline of organ dysfunction most often observed in COVID-19.

Pathophysiology of COVID-19-associated acute kidney injury

“…sACE2, which is present in the blood and in extracellular fluids, is thought to act as a dummy receptor and an inactivator molecule for SARS-CoV-2, as has been described for other soluble receptors for other pathogenic viruses 98 . However, the high affinity of the SARS-CoV-2 spike protein for ACE2 may lead to the formation of SARS-CoV-2–sACE2 complexes and to the development of anti-ACE2 autoantibodies that might target tissue ACE2 — the receptor that allows viral entry into cells — creating vasculitis-like lesions after the early infective phase of the virus 99 , 100 . Thus, although targeting ACE2 may be useful in the initial stages of disease to prevent viral uptake by cells (discussed later), the presence of ACE2-targeted autoantibodies after the infective phase may be harmful and result in organ damage.…”

“…Of note, anti-ACE2 IgM production has been associated with a robust anti-SARS-CoV-2 spike protein IgG response, suggesting the presence of an anti-idiotype IgM response cross-reacting with ACE2 (ref. 100 ). Given the wide expression of ACE2 in different organs including the kidney, a role for anti-ACE2 autoantibodies in COVID-19 pathogenesis cannot be excluded, in which autoantibody production may lead to an imbalance in the ratio of ACE to ACE2 (because ACE2 is a negative regulator of ACE), resulting in worsening of tissue oedema, inflammation and damage 102 .…”

Investigating the relationship between serum ACE 2 level and COVID-19 patients’ prognosis: a cross-sectional study

“…It was suggested that, Measurement of serum ACE2 antibody titers would help to identify who is likely to progress into acute respiratory distress, particularly in patients with cardiovascular disease and hypertension [21], Therefore, it might be possible to use serum ACE2 as indicator of ARDS.…”

Role of ACE2 in pregnancy and potential implications for COVID-19 susceptibility

“…Autoimmune responses may play a role on regulating ACE2 in COVID-19 pregnancies. The binding of soluble ACE2 with SARS-CoV-2 can induce a series of conformational alterations in both proteins that may result in the exposure of new epitopes [141]. It has been shown that the SARS-COV-2/ACE2 complex when recognized by antigen presenting cells can stimulate the production of autoantibodies targeting ACE2 [141].…”

“…The binding of soluble ACE2 with SARS-CoV-2 can induce a series of conformational alterations in both proteins that may result in the exposure of new epitopes [141]. It has been shown that the SARS-COV-2/ACE2 complex when recognized by antigen presenting cells can stimulate the production of autoantibodies targeting ACE2 [141]. If confirmed, this mechanism could explain the higher risk of patients with diseases known to induce higher levels of soluble ACE2, such as hypertension, heart disease and diabetes [132,141].…”