We sought to determine whether immune reactivity occurs between anti-SARS-CoV-2 protein antibodies and human tissue antigens, and whether molecular mimicry between COVID-19 viral proteins and human tissues could be the cause. We applied both human monoclonal anti-SARS-Cov-2 antibodies (spike protein, nucleoprotein) and rabbit polyclonal anti-SARS-Cov-2 antibodies (envelope protein, membrane protein) to 55 different tissue antigens. We found that SARS-CoV-2 antibodies had reactions with 28 out of 55 tissue antigens, representing a diversity of tissue groups that included barrier proteins, gastrointestinal, thyroid and neural tissues, and more. We also did selective epitope mapping using BLAST and showed similarities and homology between spike, nucleoprotein, and many other SARS-CoV-2 proteins with the human tissue antigens mitochondria M2, F-actin and TPO. This extensive immune cross-reactivity between SARS-CoV-2 antibodies and different antigen groups may play a role in the multi-system disease process of COVID-19, influence the severity of the disease, precipitate the onset of autoimmunity in susceptible subgroups, and potentially exacerbate autoimmunity in subjects that have pre-existing autoimmune diseases. Very recently, human monoclonal antibodies were approved for use on patients with COVID-19. The human monoclonal antibodies used in this study are almost identical with these approved antibodies. Thus, our results can establish the potential risk for autoimmunity and multi-system disorders with COVID-19 that may come from cross-reactivity between our own human tissues and this dreaded virus, and thus ensure that the badly-needed vaccines and treatments being developed for it are truly safe to use against this disease.
Introduction
Coronavirus disease (COVID-19) has become one of the greatest global public health concerns of our century. The COVID-19 pandemic has placed an immediate call to action for medical researchers to investigate how SARS-CoV-2 can impact the worldwide human population. While, naturally, the search for a successful vaccine and efficient treatment protocols are paramount, immunologists who focus on autoimmunity have been concerned whether the infection or even a newly developed vaccine itself can trigger autoimmunity via cross-reactivity. Cross-reactivity occurs when amino acid sequence homology exists between a pathogen and self-tissue proteins (1). In this mechanism, antibodies formed against SARS-CoV-2 would also bind to human tissue proteins leading to autoimmune reactivity. An insufficiently vetted vaccine might mean trading freedom from COVID-19 to an autoimmune assault in the future.
There are three important questions regarding the role of cross-reactivity with SARS-CoV-2. First, does cross-reactivity play a role in the multi-system disorders associated with SARS-CoV-2 infection? Second, how does cross-reactivity contribute to the pathophysiology of SARS-CoV-2–induced autoimmunity? Third, are there any concerns for autoimmune development with either infection or vaccination with SARS-CoV-2?
We will begin with the first question of whether cross-reactivity can be involved in the multi-system response of COVID-19 infection. We believe the answer is probable, since some of the systemic disease clinical manifestations of COVID-19 cannot be explained solely by the binding of SARS-CoV-2 spike proteins with cell membranes of tissues that exhibit angiotensin-converting enzyme 2 (ACE2). For example, a significant deadly expression of the infection is the development of disseminated intravascular coagulopathy. Coagulopathy has become a key indicator of mortality in infected subjects (2). In a recent correspondence in the New England Journal of Medicine, the serology of infected patients suffering from coagulopathy demonstrated significantly elevated levels of anti-cardiolipin and anti–β2-glycoprotein autoantibodies (3). These findings suggest the possibility of autoimmune reactivity that may be part of the SARS-CoV-2 pathophysiological sequela. It is possible that some of the clinical manifestations of central nervous system, skin, gastrointestinal, and organ diseases may also be associated with autoimmune reactions.
The second important question is whether SARS-CoV-2 infection can lead to cross-reactivity. The development of pathogen-induced cross-reactivity requires two key criteria. First, the viral pathogen must exhibit sequence homology with human tissue proteins, and second, there must be loss of immune tolerance (4). Lyons-Wieler recently mapped out the immunogenic epitopes of SARS-CoV-2 proteins and compared them to human proteins in search of patterns of significant homologous matching in order to establish the possibility of viral-induced autoimmunity. He identified substantial cross-reactive mapping with many SARS-CoV-2 spike and nuclear proteins to human tissue protein sequences (5). There have also been several findings of immune dysregulation associated with loss of immune tolerance with COVID-19 infection. Giamarellos-Bourboulis described complex immune dysregulation in COVID-19 patients with severe respiratory failure (6). The unique pattern of immune dysfunction included: immune dysregulation or major decrease in HLA-DR14 on monocytes; macrophage activation syndrome; and lower absolute count for CD3+/CD4+/CD45+ T-lymphocytes, CD3−/CD16+/CD56+/CD45+ NK cells, and CD19+/CD45+ B-lymphocytes among patients with COVID-19 when compared to healthy subjects. These immunological shifts in combination with SARS-CoV-2 amino acid sequence homology mapping with human tissue proteins orchestrate a combination of immune variables that suggest cross-reactivity can potentially occur with patients infected with SARS-CoV-2.
