Is molecular mimicry the culprit in the autoimmune haemolytic anaemia affecting patients with COVID‐19?

The British Journal of Haematology recently published two papers describing autoimmune haemolytic anaemia (AIHA) associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. ¹ , ² AIHA is characterised by the destruction of red cells by autoantibodies, but the mechanism underpinning autoimmunity in patients with coronavirus disease 2019 (COVID‐19) has yet to be elucidated.

We recently postulated that molecular mimicry could be at the basis of the most severe complications observed in SARS‐CoV‐2‐induced disease (COVID‐19). ³ , ⁴ For example, antibodies elicited against viral proteins could very well cross‐react with vascular endothelial proteins if they shared antigenic epitopes. This would trigger extensive vasculitis followed by thrombosis and widespread intravascular coagulation with multi‐organ failure. ⁵

Here, we would like to posit the hypothesis that molecular mimicry is also a determinant factor in AIHA in patients with COVID‐19, with Ankyrin 1 (ANK‐1) and the viral protein Spike being the central players.

ANK‐1 is an erythrocyte membrane protein that is important for red cell differentiation and function, providing the primary connection between the membrane skeleton and the plasma membrane. ⁶ It is defective in patients with hereditary spherocytosis, a common cause of haemolytic anaemia. ⁶

We found that ANK‐1 shares a putative immunogenic‐antigenic epitope (amino acids LLLQY) with 100% identity with the SARS‐CoV‐2 surface glycoprotein named Spike protein (Table I). We established that this epitope is part of the Spike’s predicted immunogenic epitope 750‐SNLLLQYGSFCTQL‐763 for B cells by using the immune epitope database and analysis resource [Immune Epitope Database (IEDB), https://www.iedb.org/]. This database contains experimentally validated epitopes and tools to predict epitopes recognisable be T and B cells and is used also in the design of vaccines. ⁷

Table I.

Shared identical epitope between Ankyrin 1 and SARS‐CoV‐2 surface glycoprotein¹

Protein	Accession number	Epitope amino acids	Identity percentage, %
SARS‐CoV‐2 surface glycoprotein	NCBI ID: YP_009724390·1	752‐LLLQY‐756	100
Ankyrin 1	UniProt ID: P16157	323‐LLLQY‐327

ID, identifier; NCBI, National Center for Biotechnology Information.

¹ We used for comparative analyses BlastP (available at: https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE=Proteins) and the whole virus proteome (available at: https://www.ncbi.nlm.nih.gov/nuccore/MN908947).

With this Letter, we would like to call the attention of the scientific community to the structural similarity between ANK‐1 and the viral protein Spike. We hope it will prompt further research aiming at determining if the potential immunological cross‐reactivity between ANK‐1 and Spike contributes to the pathogenesis of AIHA in patients with COVID‐19. Information on this topic may open new avenues toward designing efficacious therapies.