Gut Autoimmunity via Spike: The Calm Before the Pathogenic Priming Storm?

Spike-induced cross-reactivity is known - gut, liver. Recommended reading highlighted.

As the COVID-19 pandemic unfolded, researchers identified troubling links between SARS-CoV-2, its spike protein, and the triggering of autoimmune diseases- a phenomenon called pathogenic priming, first brought to attention by Lyons-Weiler (2020). Pathogenic priming occurs when the immune system’s response to viral proteins cross-reacts with the body’s own proteins, leading to autoimmune disorders. Specifically, SARS-CoV-2’s spike protein has become a key player in this process, initiating autoimmune responses in tissues it closely resembles. As the gastrointestinal tract (GIT) appears to be a major target, there is a growing concern about the long-term impact of the virus on gut-related autoimmune diseases.

Recent studies by Lerner et al. (2023) have illuminated the specific vulnerabilities of the GIT to pathogenic priming, particularly as SARS-CoV-2 proteins mimic critical gut proteins. This mimicry can lead to the onset or exacerbation of diseases such as Crohn’s disease, celiac disease, and autoimmune hepatitis. With the gut being a central player in immune function, this intersection between pathogenic priming and autoimmunity warrants a deeper understanding of the molecular mechanisms involved and the potential for long-term consequences.

Pathogenic Priming and the Gut

Lyons-Weiler’s early articulation of pathogenic priming pointed to the spike protein’s sequence similarities with various human proteins, providing a blueprint for how immune cross-reactivity could lead to autoimmunity. This phenomenon is particularly concerning within the gastrointestinal tract, where proteins critical to gut function—such as zonulin, occludin, and actin—are susceptible to this immune misfiring (Vojdani et al., 2021). SARS-CoV-2-driven gut permeability, often referred to as "leaky gut," can exacerbate autoimmune responses as intestinal barriers break down, enabling a wider systemic immune activation.

As Lerner et al. (2023) elaborated, molecular mimicry plays a pivotal role in this process, where viral peptides imitate human proteins, tricking the immune system into targeting healthy tissues. In particular, the gut, being a frequent site of viral replication and immune cell activity, is highly susceptible to these inflammatory processes, with bystander activation and cross-reactive antibodies forming a deadly combination for gut health.

Molecular Mimicry in Action: Autoimmune Diseases of the Gut

As Lerner et al. (2023) demonstrated, specific epitopes of the SARS-CoV-2 spike protein exhibit sequence homology with human gut proteins, leading to autoimmune reactions. This process, facilitated by molecular mimicry, has been implicated in the onset of diseases such as Crohn’s disease, ulcerative colitis, and autoimmune hepatitis. Of particular interest is the discovery of 58 viral sequences that share similarities with proteins involved in gut function, raising red flags about the potential for chronic gut disorders post-infection.

The research of Vojdani et al. (2021) further expands on this, revealing that SARS-CoV-2 shares structural similarities with key gut proteins like myosin and keratin-18, both of which are involved in maintaining gut integrity and liver function. The viral assault on these proteins can lead to the development of autoimmune conditions, such as autoimmune hepatitis, thus supporting the theory that pathogenic priming plays a critical role in gut and liver autoimmunity.

Pathogenic Priming Beyond the Gut

While the gut is a primary site of immune misfiring, the effects of pathogenic priming are not confined there. As Lerner et al. (2023) pointed out, intestinal permeability opens the door for systemic inflammation, allowing autoimmunity to affect organs like the liver and pancreas. This connection, particularly through the gut-liver axis, provides a pathway for bacterial and viral antigens to translocate into the liver, sparking further autoimmune responses.

The spike protein’s capacity to trigger molecular mimicry in multiple organ systems, such as the liver, reveals the far-reaching effects of pathogenic priming. Liver dysfunction, observed in many COVID-19 patients, may be a direct result of this autoimmune cascade, with Vojdani et al. (2021) noting that cross-reactive antibodies can target liver antigens, precipitating conditions like primary biliary cirrhosis and autoimmune hepatitis.

The Role of Vaccination in Pathogenic Priming

COVID-19 vaccines, particularly those targeting the spike protein, may also contribute to pathogenic priming. Early warnings from Lyons-Weiler (2020) highlighted the possibility that vaccines could inadvertently prime the immune system to attack the body’s own tissues. Although vaccines are designed to prevent infection, they share a common target with the virus—the spike protein—which may also initiate cross-reactive immune responses.

Research by Vojdani et al. (2021) has provided evidence that antibodies generated against the spike protein can cross-react with human tissues, potentially triggering autoimmune reactions. They also reported autoreactogenic epitopes from other SARS-CoV-2 proteins.

The study specifically identified several cross-reactive epitopes within the SARS-CoV-2 spike glycoprotein that share sequence similarity with human proteins implicated in autoimmune diseases. The key epitopes in the spike glycoprotein are:

1. VSETNDTK – This epitope in the spike glycoprotein was found to cross-react with keratin, type I cytoskeletal 18, which is associated with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC).

2. EELDKYW – This epitope cross-reacts with the same keratin, type I cytoskeletal 18, which is also linked to AIH and PBC.

3. GDGVTHNV – This epitope was identified as cross-reacting with actin, alpha skeletal muscle, a protein involved in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC).

4. ATRFAAAY – This epitope cross-reacts with pyruvate dehydrogenase E1 component subunit alpha, which is associated with primary biliary cholangitis (PBC).

5. PATPAGPK – This epitope was found to cross-react with dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, another antigen involved in primary biliary cholangitis (PBC).

6. DVPIGAIIC – This epitope shares sequence similarity with human antigens and was identified as being involved in cross-reactivity, although the specific human target is not listed in this section.

These cross-reactive epitopes in the spike protein contribute to molecular mimicry, potentially leading to autoimmune responses in individuals with a predisposition to conditions such as AIH, PBC, and other gut-associated autoimmune diseases.

Autoimmunity against the six cross-reactive epitopes identified in the SARS-CoV-2 spike glycoprotein might contribute to several autoimmune diseases. Here’s a breakdown of the potential autoimmune conditions associated with each epitope and the corresponding human antigens:

1. VSETNDTK and EELDKYW (Keratin, type I cytoskeletal 18)

   • Autoimmune Hepatitis (AIH): Keratin-18 is involved in liver function, and autoantibodies targeting this protein can contribute to AIH. This condition causes chronic inflammation of the liver, leading to liver damage if untreated.

   • Primary Biliary Cholangitis (PBC): This autoimmune condition affects the bile ducts in the liver, potentially leading to liver cirrhosis. Cross-reactivity with keratin-18 may contribute to the immune system attacking bile duct cells.

2. GDGVTHNV (Actin, alpha skeletal muscle)

   • Autoimmune Hepatitis (AIH): Actin autoantibodies are commonly found in AIH type 1. Actin is part of the cellular cytoskeleton, and autoimmunity against it can result in liver damage due to an attack on liver cells.

   • Primary Biliary Cholangitis (PBC): Like AIH, PBC patients may show autoantibodies against actin, contributing to liver inflammation and damage.

3. ATRFAAAY (Pyruvate dehydrogenase E1 component subunit alpha)

   • Primary Biliary Cholangitis (PBC): Autoantibodies targeting the pyruvate dehydrogenase complex, particularly the E1 alpha subunit, are hallmark markers of PBC. This autoimmune liver disease primarily affects the bile ducts, leading to their destruction and progressive liver damage.

4. PATPAGPK (Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex)

   • Primary Biliary Cholangitis (PBC): This component of the pyruvate dehydrogenase complex is another target of autoantibodies in PBC. The immune system’s attack on this mitochondrial enzyme can disrupt energy metabolism in liver cells and lead to bile duct inflammation and destruction.

5. DVPIGAIIC

   • Celiac Disease: Though the specific human target for this epitope isn’t clearly listed in the section, celiac disease often involves cross-reactive antibodies targeting proteins like tissue transglutaminase. The spike glycoprotein’s cross-reactivity might contribute to the autoimmune attack on the small intestine in genetically predisposed individuals, exacerbating celiac disease.

Summary of Potential Diseases

• Autoimmune Hepatitis (AIH): Involves chronic liver inflammation and damage caused by autoantibodies against liver antigens, such as keratin and actin.

• Primary Biliary Cholangitis (PBC): An autoimmune disease of the liver, where bile ducts are attacked by the immune system, often involving autoantibodies against pyruvate dehydrogenase components and actin.

• Celiac Disease: A condition where the immune system attacks the lining of the small intestine, potentially exacerbated by molecular mimicry with SARS-CoV-2 spike protein epitopes like DVPIGAIIC.

• Inflammatory bowel disease (IBD): A group of autoimmune disorders, including Crohn’s disease and ulcerative colitis, where the immune system attacks the gastrointestinal tract, leading to chronic inflammation.

In May of 2024, Indian researchers published a case series of patients with new onset of inflammatory bowel disease and exacerbations after ChAdOx1-nCoV-19 and inactivated COVID-19 vaccines (Kaur et al., 2024)

The cross-reactivity between SARS-CoV-2 spike epitopes and human proteins may contribute to these autoimmune diseases by inducing molecular mimicry, where the immune system mistakenly attacks human tissues after responding to viral infection.

This raises important questions about how the widespread use of mRNA vaccines, which does not prevent infection and may induce autoimmunity, could influence the development of autoimmune diseases via vaccine priming and infection confirming the autoimmunity, particularly in individuals already at risk for such conditions. It is essential to investigate how we might mitigate the risks associated with vaccine-induced pathogenic priming.

Future Directions and the Need for Vigilance

The phenomenon of pathogenic priming is a potential ticking time bomb in our understanding of long-term COVID-19 and vaccine-induced immune responses. The work of Lyons-Weiler (2020), Lerner et al. (2023), and Vojdani et al. (2021) all point to the critical need for further research into how SARS-CoV-2’s spike protein—and its vaccines—may affect gut health and autoimmune disease development.

While the pandemic’s immediate threat has been mitigated in many parts of the world, the long-term consequences of pathogenic priming are only just beginning to surface. Continued vigilance and robust scientific investigation are necessary to fully understand the risks, particularly regarding the gastrointestinal and systemic autoimmune effects that may arise in the years to come.

Lerner et al (2023) is recommended reading.

References

1. Lyons-Weiler J. (2020). Pathogenic priming likely contributes to serious and critical illness and mortality in COVID-19 via autoimmunity. Journal of Translational Autoimmunity, 3, 100051.

2. Lerner A., Benzvi C., & Vojdani A. (2023). SARS-CoV-2 gut-targeted epitopes: Sequence similarity and cross-reactivity join together for molecular mimicry. Biomedicines, 11(7), 1937.

3. Vojdani A., Kharrazian D. (2021). Reaction of human monoclonal antibodies to SARS-CoV-2 proteins with tissue antigens: Implications for autoimmune diseases. Frontiers in Immunology, 11, 617089.

4. Kaur et al., 2024. A descriptive study of patients with new onset of inflammatory bowel disease and exacerbations after ChAdOx1-nCoV-19 and inactivated COVID-19 vaccines in a tertiary hospital of North India https://www.researchgate.net/publication/380361584_A_descriptive_study_of_patients_with_new_onset_of_inflammatory_bowel_disease_and_exacerbations_after_ChAdOx1-nCoV-19_and_inactivated_COVID-19_vaccines_in_a_tertiary_hospital_of_North_India