The Interplay of Autoimmune Hepatitis and COVID-19 Vaccines: A Comprehensive Analysis of AIH Pathogenesis and mRNA Vaccine Technology


Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by autoimmunity to hepatocytes, leading to an increase in antinuclear antibodies (ANA).

Histologically, AIH is associated with clear-cut interface hepatitis and piecemeal necrosis at the boundary between portal areas and periportal hepatocytes.

The presence of a lymph-plasma cellular infiltrate in the portal tracts supports the diagnosis, and specific autoantibodies (ANA, smooth muscle antibodies [SMA], or anti-liver/anti-kidney microsome 1 [LKM1]) are often present in the blood.

Molecular Mimicry and Autoimmune Reactions:

Molecular mimicry occurs when the immune system mistakes a foreign antigen for a self-antigen due to structural similarities. This phenomenon has been hypothesized as a potential mechanism for autoimmune reactions after COVID-19 vaccination. The antibodies produced against the spike protein of SARS-CoV-2 may cross-react with human proteins, triggering autoimmune phenomena. In particular, the similarity between the SARS-CoV-2 spike glycoprotein and the human cardiac protein titin has raised concerns about myocarditis and other autoimmune cardiac reactions.

Autoimmune Hepatitis (AIH) and its Diagnostic Criteria

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by a clear-cut interface hepatitis and piecemeal necrosis located at the boundary between portal areas and periportal hepatocytes. The hallmark of AIH is the autoimmunity directed against hepatocytes, leading to an increase in the levels of antinuclear antibodies (ANA).

A lymph-plasma cellular infiltrate often populates the portal tracts with minimal injury to the central and mid-zonal regions (zones 3 and 2 of the Rappaport) of the liver acinus (Beer and Dienes, 2021; Covelli et al., 2021; Domerecka et al., 2021).

To diagnose AIH, physicians rely on a combination of laboratory findings and histological features. Common laboratory abnormalities in AIH include increased levels of alanine aminotransferase and aspartate aminotransferase, hypergammaglobulinemia, and elevated serum IgG values. Specific autoantibodies such as antinuclear antibodies (ANA), smooth muscle antibodies (SMA), or anti-liver/anti-kidney microsome 1 (LKM1) are often present in the blood. While plasma cells are not always abundant, their presence provides stronger evidence for the diagnosis of AIH than the mononuclear cell infiltrate (Figure 1).

The exact cause of AIH remains elusive in most cases, and the condition is often considered idiopathic. However, it is presumed to have an infectious trigger that initiates the inflammatory process in the liver. In some instances, a virus can stimulate an inflammatory response, and vitamin D supplementation, in combination with immunosuppressive therapy, has shown promising results (Domerecka et al., 2021; Sergi, 2022a).

COVID-19 Vaccines and their Technology

After the devastating SARS-CoV-2 pandemic hit several countries, various vaccines were developed and have become essential tools in the fight against the virus (Sergi, 2021; Sergi and Leung, 2021). It is essential to note that mild symptoms may occur with all vaccines due to the immune system’s local and systemic reactions to the foreign body being introduced into the body.

Two prominent types of COVID-19 vaccines are the mRNA vaccines and the AstraZeneca vaccine. The mRNA vaccines, such as Pfizer-BioNTech’s BNT162b2 and Moderna’s mRNA-1273, do not use prebuilt viruses to deliver the antigen. Instead, they utilize messenger RNA (mRNA) to instruct cells to produce a spike protein found on the surface of the SARS-CoV-2 virus. This, in turn, triggers an immune response, leading to the production of antibodies against the virus.

The AstraZeneca vaccine, on the other hand, uses a customized adenovirus to deliver parts of SARS-CoV-2 to the body and stimulate an immune response. This traditional vaccination method employs a hybrid adenovirus-coronavirus assembly to elicit antibody production against both viruses.

mRNA vaccines have gained traction because they prompt the immune system to generate antibodies more efficiently and effectively. While there have been occasional reports of vaccine-induced thrombophilia associated with the AstraZeneca vaccine, it has generally been successful worldwide with minimal side effects.

Immune Response and Memory

Studies have shown that in individuals who have recovered from COVID-19, the spike IgG (immunoglobulin G) antibody titer remains stable for over 6 months. Additionally, specific memory B cells capable of producing immunoglobulins are more abundant at 6 months after infection compared to 1 month. T CD4+ and T CD8+ lymphocytes that are specific to SARS-CoV-2 also exhibit a half-life of 3-5 months.

Regarding COVID-19 vaccines, the mRNA-1273 vaccine from Moderna has been found to induce higher levels of neutralizing specific antibodies compared to other vaccines. These antibody levels decrease slightly over time but provide lasting and consistent humoral immunity, better than that conferred by natural infection.

COVID-19 Vaccines and Myocarditis

Reports of myocarditis and pericarditis following COVID-19 vaccination have been documented. These reactions are rare but may be underreported, and their severity varies. Some patients with myocarditis have shown dysregulation of titin, a crucial protein for sarcomere assembly and cardiac function. The risk of autoimmune reactions may be influenced by factors such as the type of vaccine (mRNA vs. adenovirus-based), the number of doses, and individual immunocompetency.

COVID-19 Vaccines and Autoimmune Hepatitis

Recent reports have identified cases of COVID-19 vaccine-induced AIH-like syndrome. These patients developed symptoms of AIH following vaccination with mRNA-based vaccines, such as Pfizer-BioNTech and Moderna. The association between AIH and COVID-19 vaccination is still rare, and more research is needed to validate these findings. Proper pharmacovigilance and longitudinal studies are crucial in understanding the true incidence and mechanisms of vaccine-related AIH.

Addressing Vaccine Hesitancy

Despite the success and safety of COVID-19 vaccines, vaccine hesitancy and misinformation have been circulating on social media, major newspapers, and television broadcasts. Such misinformation has raised concerns and doubts about the validation process of vaccination programs, leading to the possibility of cohorts of children missing their traditional non-COVID-19 vaccine immunization (Sergi and Leung, 2021).

It is crucial to address vaccine hesitancy and promote accurate information about vaccines. The mRNA technology, in particular, has been wrongly associated with fears of host DNA mutation, but this remains groundless. The mRNA cannot cause infection as it does not penetrate the cell nucleus and cannot integrate into the nuclear DNA of host cells. Moreover, mRNA has an extremely low half-time and needs to be kept at low temperatures for transportation before being inoculated.

Future Prospects of mRNA Technology

The mRNA technology used in COVID-19 vaccines has shown great promise. Researchers predict that it may be crucial for developing potential vaccines against other infectious agents and possibly non-infectious diseases, including cancer. There is hope that personalized vaccines may be developed to generate precise immune responses when combined with drug adjuvants like checkpoint inhibitors, which could be effective in reducing tumor size (Chan et al., 2021; Thorp et al., 2022).

In conclusion, AIH is a complex liver inflammation characterized by autoimmunity to hepatocytes and specific histological features. On the other hand, COVID-19 vaccines have been a significant step in the fight against the pandemic, with mRNA technology proving effective and safe. Addressing vaccine hesitancy and spreading accurate information is crucial to ensure the success of vaccination programs and safeguard public health. The mRNA technology also holds promise for future vaccine development and potential applications in non-infectious diseases.

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