Infections and Pathogens as Triggers of Autoimmune Disease
One of the most powerful and well-supported environmental contributors to autoimmune disease is infection. In their 2022 publication in Pathophysiology, Aristo Vojdani and colleagues detailed the complex relationship between infectious agents and the immune system, explaining how pathogens can serve as potent triggers for autoimmune reactions, especially in genetically susceptible individuals.
The paper outlines several mechanisms by which infections can contribute to immune dysregulation, as well as specific pathogens most frequently associated with autoimmune disease.
How Infections Can Trigger Autoimmunity
Multiple immune mechanisms may be set into motion when the body encounters an infection:
Molecular mimicry
Structural similarities between microbial and self-proteins can mislead the immune system, causing it to attack the body’s own tissues.
Epitope spreading
Initial tissue damage from infection can expose hidden self-antigens, broadening the autoimmune response.
Viral persistence
Chronic or latent infections can keep the immune system in a constant state of low-level activation.
Bystander activation
Nearby immune cells may become activated in response to inflammation, even if they are not specific to the pathogen.
Polyclonal activation
Some infections trigger widespread immune cell activation, increasing the likelihood of autoreactive cells becoming active.
Innate immune activation
Infections can overstimulate pattern recognition receptors like Toll-like receptors (TLRs), driving prolonged inflammation.
Dysregulation of immune homeostasis
Repeated or chronic immune stimulation may erode the body’s normal checks and balances, tipping the immune system into self-reactivity.
Key Pathogen Groups Linked to Autoimmunity
Oral Pathogens
Oral bacteria such as Porphyromonas gingivalis—often involved in periodontal disease—have been shown to:
- Translocate from the mouth to the gut, disrupting the gut microbiome.
- Increase intestinal permeability (also known as “leaky gut”).
- Contribute to systemic inflammation and autoantigen formation.
These disturbances can drive the immune system to produce autoantibodies and fuel systemic autoimmunity. Oral pathogens have been implicated in diseases such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease.
SARS-CoV-2
The virus that causes COVID-19 has earned the nickname “the autoimmune virus” due to its extensive and well-documented connections to immune dysregulation:
- Molecular mimicry: The virus’s spike and nucleocapsid proteins share similarities with human proteins, leading to cross-reactivity.
- Antibody cross-reactions: Studies show that antibodies against SARS-CoV-2 can bind to human autoantigens, and vice versa.
- Autoantibody development: Elevated levels of autoantibodies have been found in people infected with COVID-19—even in those without prior autoimmune disease.
- Immune profile overlap: The lymphocyte subpopulation patterns seen in COVID-19 mirror those found in certain autoimmune conditions.
This may explain the post-COVID development or worsening of diseases like lupus, type 1 diabetes, autoimmune encephalitis, and antiphospholipid syndrome.
Herpesviruses
The human herpesvirus (HHV) family includes Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), and others. These viruses are known for their ability to establish lifelong latency and reactivate periodically, presenting a unique challenge to the immune system.
Epstein-Barr virus
EBV has been linked to numerous autoimmune diseases, including:
- Multiple sclerosis (MS)
- Systemic lupus erythematosus (SLE)
- Rheumatoid arthritis (RA)
- Sjögren’s syndrome
- Type 1 diabetes
- Autoimmune thyroid disease
- Celiac disease
HHV-6 and related viruses have been associated with:
- MS and ME/CFS
- Guillain-Barré syndrome
- Encephalitis and epilepsy
- Neurodegenerative diseases like Parkinson’s and Alzheimer’s
- Collagen vascular diseases
These viruses may contribute to autoimmunity by integrating into host genomes, modifying immune signaling, and triggering recurrent inflammatory episodes.
Implications for Autoimmune Disease Prevention and Management
The exposome model proposed by Vojdani reframes autoimmune disease as the result of cumulative lifetime exposures, with infections representing one of the most prominent and modifiable risk factors. Understanding the link between pathogens and autoimmunity may help:
- Identify at-risk individuals after infection
- Improve post-infection monitoring for autoimmune activity
- Inform treatment decisions for those with lingering inflammatory symptoms
- Guide future vaccine development with attention to immune cross-reactivity
By recognizing infectious agents as central to immune dysfunction in autoimmunity, clinicians and researchers can move toward more precise, preventive, and personalized approaches to autoimmune care.
Citation
Vojdani, A.; Vojdani, E.; Rosenberg, A.Z.; Shoenfeld, Y. The Role of Exposomes in the Pathophysiology of Autoimmune Diseases II: Pathogens. Pathophysiology2022, 29, 243-280. https://doi.org/10.3390/pathophysiology29020020