Autoimmune diseases related to post-SARS-CoV-2 vaccination: A rheumatology perspective

Dear Editor,

The new coronavirus 2019 (COVID-19) disease emerged as a form of atypical pneumonia in Wuhan, China late in 2019. As of May 2023, WHO accounted over 750 million laboratory-confirmed cases as well as almost seven million deaths caused by the SARS-CoV-2 infection. Angiotensin converting enzyme 2 (ACE2) plays a critical role in the SARS-CoV-2 virus cleavage to respiratory tract cells. The widespread expression, as well as tissue distribution of ACE2 is responsible for extra-pulmonary COVID-19 related symptoms e.g., gastrointestinal, blood vessels, muscles, and synovial membrane [1]. There are several evidences related to clinical relevance of SARS-CoV-2 infection in autoimmune diseases i.e., thrombosis, reactive arthritis, vasculitis, systemic sclerosis, systemic lupus erythematosus, myositis, Sjögren syndrome, and even Multi-system inflammatory syndrome [1,2]. In this scenario, SARS-CoV-2 is primarily associated to induction of hyperinflammatory responses; Furthermore, SARS-CoV-2 infected-individuals may shed virions for longer time, than previously expected [1]. Thus, long persistence of COVID-19 symptoms, particularly in individuals affected by immune disorders, may predispose these patients to develop autoimmune disease by reactivation of the virus in periods of immune suppression [1]. Fortunately, since early 2020, vaccination against SARS-CoV-2 was available and highly effective worldwide [3]. Thus, vaccination is one of the most critical strategies in establishing a strong barrier in general population to attenuate the speed of spread of SARS-CoV-2 infection, reducing the virus transmission from symptomatic and asymptomatic carriers, as well as hindering poor clinical outcomes in the current global crisis [4]. WHO accounted about 72.3% of the world population received at least one dose of a SARS-CoV-2 vaccine [5]. There are two main SARS-CoV-2 vaccine platforms including mRNA (i.e. Pfizer-BioNTech and Moderna) and vector virus vaccine (i.e. Johnson & Johnson and AstraZeneca) that, when administrated, elicit robust immune response against SARS-COV-2 at a global scale. Unfortunately, randomized human trials postulated various SARS-CoV-2 vaccine related-adverse events ranging from local symptoms to systemic symptoms such as de-novo autoimmune manifestations i.e. thrombotic thrombocytopenia, autoimmune­liver­diseases, Guillain–Barré syndrome, IgA­nephropathy, Inflammatory­arthritis, Systemic lupus erythematosus, Graves' disease, Autoimmune polyarthritis, Type 1 diabetes mellitus, etc., [5,6]. However, the accurate impact of SARS-CoV-2 vaccines in triggering autoimmune diseases remains nebulous.

In mRNA based-vaccines, the SARS-CoV-2 spike protein was translated from the mRNA enters via ribosomes. Subsequently, the spike translated protein was recognized and binds to the ACE2. Through the following antigen translation process, the robust CD8 + and CD4 + T-cell-mediated response i.e., memory lymphoid cells as well as neutralizing antibodies were generated. Whereas in adenoviral vector based-vaccines, SARS-CoV-2 antigens are delivered to the host cells by their vectors. The spike protein is expressed on the cell surface and triggers T-cell-mediated immune response [8]. According to available literature, the main explanations for the impact of SARS-CoV-2 vaccines in initiation of de-novo autoimmune disease consists in 1) molecular mimicry, 2) trigger of auto-antibodies, 3) adjuvants, and 4) bystander activation [8,9].

In relation to this, the SARS-CoV-2 spike glycoprotein are partially homologous to lung surfactant proteins, by sharing 13 of 24 pentapeptides [9]; Furthermore, cross-reaction between SARS-CoV-2 antigens with various human-tissue antigens can render immune system to trigger autoimmunity against the cardiovascular, gastrointestinal and nervous system tissues [10]. Production of autoantibodies by B cells was also an unfavorable outcome reported in the context of autoimmune hepatitis following hyper-inflammatory responses to SARS-CoV-2 vaccines [9]. Adjuvants are essential components of both mRNA and adenovirus-based SARS-CoV-2 vaccines that include a mixture of different lipid substances. Adjuvants can be responsible for development of hypersensitivity reactions after vaccination which have been confirmed through animal investigations [11]. Bystander activation is another mechanism for development of autoimmune disease related to post-SARS-CoV-2 vaccination. Bystander activation is defined as a situation that both of B and T lymphocytes subset are activated in an antigen-independent manner. Therefore, this phenomenon could be occurring as a result of SARS-CoV-2 vaccine administration as a possible result non-specific immune-stimulation [7].

To sum, there are several reviews regarding de-novo autoimmune symptoms post-SARS-CoV-2 vaccination. However, this evidence should not encourage vaccine discontinuation in general population. There are still major gaps and limitations regarding main mechanisms involved in pathogenesis of autoimmune disease as an adverse effect of SARS-CoV-2 vaccines that should be elucidated. There are no standard guidelines regarding continuation of further SARS-CoV-2 vaccine doses in population with autoimmune manifestations after the first dose. In addition, there is no guide for diagnosis or treatment of SARS-CoV-2 vaccine-induced autoimmune manifestations. Clinicians should be aware as to the potential autoimmune manifestations of COVID-19 vaccines. In the light of existing evidence, there is need for broad surveillance regarding countermeasures for autoimmune diseases developed after SARS-CoV-2 vaccination in general population. There is also need for further investigation to establishing suitable criteria for diagnosis as well as management of de-novo autoimmune manifestations post-COVID-19 vaccination.