COVID-19 and Autoimmune Diseases

Yu Liu; Amr H. Sawalha; Qianjin Lu


Curr Opin Rheumatol. 2021;33(2):155-162. 

In This Article

Molecular Mimicry and SARS-CoV-2

The production of autoantibodies is a key feature of autoimmune diseases. However, the underlying mechanisms are complicated and still not fully understood. Molecular mimicry by infectious pathogens is believed to be one of the mechanisms.[39] Viral infection can disturb immunologic tolerance by exposure of antigen epitopes that elicit cross-reactive antibodies. There are a large number of reports indicating antigenic mimicry between viral and human proteins. Perhaps one of the most established examples of molecular mimicry in autoimmunity is the immune response to Epstein–Barr virus (EBV) in lupus patients.[40] An abnormal immune repose to Epstein–Barr virus Nuclear Antigen-1 (EBNA-1) can induce an autoimmune response targeting the Sm and Ro autoantigen systems.[41] Cross-reactivity between anti-EBNA-1 antibodies and myelin basic protein in patients with multiple sclerosis has also been demonstrated.[42] Moreover, EBNA-1 showed structural similarity with β synuclein, a brain protein implicated in multiple sclerosis, and predicted to bind HLA class II DR2b (HLA-DRB1*15 : 01).[43] In-silico analysis revealed that an envelope protein of human endogenous retroviruses (HERV) shares similar sequence with three myelin proteins that induced an autoimmune response in multiple sclerosis and was predicted to bind to HLA-DRB1*15 : 01. Basavalingappa et al.[44] demonstrated that Coxsackievirus B3 (CVB3) infection can induce the generation of autoreactive T cells for multiple antigens.

Some epitopes from SARS-CoV-2 were revealed to exhibit cross-reactivity with autoantigens. Anand et al.[45] reported that a unique S1/S2 cleavage site in SARS-CoV-2 identically mimicked a FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α), which plays a critical role in the homeostasis of airway surface liquid. Mimicry between SARS-CoV-2 and three proteins namely DAB1, AIFM and SURF1 that are present in the human brainstem pre-Bo[Combining Diaeresis]tzinger complex (preBo[Combining Diaeresis]tC) may contribute to the respiratory failure in COVID-19.[46] In addition, SARS-CoV-2 infection can elicit autoimmune responses through molecular mimicry. Marino Gammazza et al.[47] compared viral proteins with human molecular chaperones and postulated that the chaperones, most of which were heat shock proteins, could participate in molecular mimicry phenomena after SARS-CoV-2 infection. Furthermore, Lucchese and Flöel[48] compared viral amino acid sequence with human autoantigens associated with immune-mediated polyneuropathies and showed that peptides embedded in immunoreactive epitopes of SARS-CoV-2 shared the same sequence with human heat shock proteins 90 and 60 that are associated with Guillain-Barré syndrome and other autoimmune diseases. Venkatakrishnan et al.[49] reported 33 distinct 8-mer or 9-mer peptides with potential cross-reactivity between SARS-CoV-2 and the human reference proteome, among which 20 human peptides have not been observed in any previous coronavirus strains. Moreover, four of these human 8-mer/9-mer peptides mimicked by SARS-CoV-2 showed similarity with host pulmonary-arterial peptides and were predicted to bind with HLA-B*40 : 01, HLA-B*40 : 02, and HLA-B*35 : 01.[49] A recent study analysed sharing between hexapeptides that define minimal epitopic sequences of the virus and the human proteome, and documented numerous immunoreactive epitopes shared with human proteins.[50] The results of this study imply the possibility that SARS-CoV-2 might induce cross-reactivity with host autoantigens and offer hints to possibly explain the various clinical manifestations and pathologies involving different organs and systems after SARS-CoV-2 infection.