The COVID-19 pandemic has raised many questions about the effects of the SARS-CoV-2 virus on long-term health. One area of interest has been whether COVID-19 can trigger or exacerbate autoimmune conditions. Autoimmune diseases occur when the immune system mistakenly attacks the body’s own tissues. There are over 80 different autoimmune conditions, including type 1 diabetes, rheumatoid arthritis, lupus, and multiple sclerosis. Understanding the potential link between COVID-19 and autoimmunity is important for managing patient care during and after the pandemic.
Can acute COVID-19 infection cause autoimmune issues?
There is some evidence that acute COVID-19 infection can lead to autoimmune issues in some patients. A few mechanisms have been proposed:
Molecular mimicry
SARS-CoV-2 shares similar protein sequences with host tissues. This molecular mimicry may confuse the immune system and trigger autoantibody production against host cells and proteins. Studies have detected autoantibodies in COVID-19 patients that can bind to and damage host tissues such as the brain, blood vessels, heart, kidneys, and liver.
Inflammation
The severe inflammation and cytokine release syndrome triggered by COVID-19 may nonspecifically activate autoreactive T cells and B cells that target host proteins. This may lead to tissue damage and autoimmunity.
Bystander activation
The activation of innate and adaptive immune responses to SARS-CoV-2 may nonspecifically activate quiescent autoreactive T and B cells through bystander activation. This may provoke autoimmune reactions.
Overall, acute COVID-19 infection can disrupt immune tolerance and trigger autoimmune activity through multiple mechanisms. Whether this leads to enduring, clinically-evident autoimmune disease is still under investigation.
What autoantibodies have been detected in COVID-19 patients?
Several autoantibodies targeting host proteins and organs have been detected in COVID-19 patients, including:
Antiphospholipid antibodies
These antibodies attack phospholipids and phospholipid-binding proteins. They can lead to blood clots and have been found in over 50% of hospitalized COVID-19 patients.
Anti-Ro antibodies
Anti-Ro antibodies target Ro60 and La proteins. They have been detected in approximately 15% of COVID-19 patients and can cause skin rashes and swelling.
Anti-endothelial cell antibodies
These autoantibodies attack endothelial cells lining blood vessels and have been found in 14-40% of hospitalized COVID-19 patients. They may contribute to some of the vascular complications of COVID-19.
Antineuronal antibodies
Autoantibodies targeting the brain and nervous system proteins have been reported in up to 30% of severely ill COVID-19 patients. They may be implicated in the neurological effects of COVID-19.
Antithyroid antibodies
One study found antithyroid antibodies targeting thyroid peroxidase and thyroglobulin emerged in 37% of COVID-19 patients. These can lead to thyroid dysfunction.
The development of these autoantibodies may precede the onset of autoimmune disease in a subset of patients after COVID-19. Their presence needs to be monitored, though not all patients with these antibodies will go on to develop overt autoimmune pathology.
Does COVID-19 increase the risk of specific autoimmune diseases?
Some population studies have found associations between COVID-19 and an increased risk of developing particular autoimmune conditions, including:
Type 1 diabetes
Multiple studies have reported new onset type 1 diabetes after COVID-19, even in adults. One study found a 72% increase in new type 1 diabetes cases in children after the COVID-19 pandemic started. The pathogenesis may involve molecular mimicry between the virus and insulin-producing pancreatic cells.
Guillain-Barré syndrome (GBS)
GBS is an acute autoimmune neuropathy that leads to paralysis. Incidence of GBS was 3-6 times higher after the COVID-19 pandemic compared to pre-pandemic levels. Antibodies against gangliosides have been found in COVID-19 patients with GBS.
Immune thrombocytopenia (ITP)
ITP causes a low platelet count and increased risk of bleeding. A study in Wuhan, China found a 47-fold increased incidence of ITP after COVID-19 compared to pre-pandemic rates. Antiphospholipid antibodies likely mediate COVID-19-associated ITP.
Kawasaki disease
This childhood vasculitis transiently inflames blood vessels. Reports indicate Kawasaki disease is more common and severe in children after COVID-19. Antibodies against endothelial cells may be the link between COVID-19 and Kawasaki disease.
Rheumatoid arthritis (RA)
Worsening of RA symptoms has been reported after COVID-19. One study also found COVID-19 patients had a 63% higher risk of new-onset RA. The underlying mechanisms need more research.
So while acute COVID-19 can cause transient autoantibody production in many patients, some may subsequently develop overt autoimmune disease, likely mediated by these autoantibodies. Careful monitoring of these at-risk patients is important.
Can post-acute COVID-19 or long COVID cause autoimmune issues?
Many patients with post-acute COVID-19 syndrome or ‘long COVID’ also report debilitating symptoms like fatigue, ‘brain fog’, pain, and headaches that persist for months. There are a few mechanisms by which post-acute COVID-19 may potentially drive autoimmunity:
Persistent elevation of autoantibodies
While most COVID-19 patients see a reduction in autoantibodies after recovery, some patients have persistently elevated levels even after viral clearance. This may maintain aberrant immune activation.
Epitope spreading
The initial immune response to SARS-CoV-2 may activate B cells and T cells specific to cryptic self-epitopes. These can provoke secondary autoimmune cascades.
Reactive oxygen species
The oxidative stress from prolonged inflammation may expose neoantigens that can be targeted by autoreactive lymphocytes.
Mitochondrial autoantigens
The mitochondrial injury associated with long COVID may release mitochondrial autoantigens, inciting further autoreactivity through epitope spreading.
While the chronic symptoms of long COVID likely have multifactorial origins, autoimmunity may be a contributory factor in a subset of patients. Careful autoantibody profiling and monitoring may reveal clinically-relevant autoimmune pathologies in long COVID patients with severe, persistent symptoms.
Evaluating autoimmunity in COVID-19 patients
Based on the current evidence, experts recommend considering these tests to evaluate for autoimmunity in COVID-19 patients:
Complete blood count
To check for cytopenias that may indicate impaired bone marrow function or cell destruction mediated by autoantibodies.
Inflammatory markers
Such as C-reactive protein and erythrocyte sedimentation rate to assess inflammation that may be driven by autoreactive cells.
Kidney and liver tests
To evaluate organ injury that may result from autoantibody activity.
Coagulation studies
These include D-dimer, fibrinogen, and antiphospholipid antibodies to assess for COVID-19-associated coagulopathy linked to autoantibodies.
Autoantibody tests
These include ANA, RF, anti-CCP, and antibodies against organ-specific antigens. Serial monitoring for emerging autoantibody production is recommended.
Type 1 diabetes antibodies
Measure antibodies against glutamic acid decarboxylase (GAD), insulinoma-associated antigen 2 (IA-2), and zinc transporter 8 (ZnT8) in patients with hyperglycemia.
Careful monitoring for clinical and laboratory evidence of autoimmunity is important for at-risk COVID-19 patients. This can facilitate early diagnosis and treatment if overt autoimmune disease eventually develops.
Can COVID-19 vaccines trigger autoimmune issues?
There is no compelling evidence that the COVID-19 vaccines increase the risk of developing autoimmune conditions in most people. However, vaccine-induced autoimmunity is theoretically possible through a few mechanisms:
Molecular mimicry
If epitopes on vaccine antigens share homology with self-proteins, this can lead to cross-reactivity and loss of self-tolerance. However, vaccine antigens are designed to minimize this risk.
Nonspecific activation
The vaccine response may nonspecifically activate innate and adaptive immune cells through bystander activation. In susceptible individuals, this can reveal self-reactivity.
Adjuvants
Adjuvants enhance vaccine immunogenicity but may also induce autoimmunity in predisposed individuals through excessive stimulation of innate immune pathways like TLRs. However, vaccine adjuvants have not been definitively linked to autoimmunity.
Pre-existing susceptibility
Those with genetic risk variants or who already have autoreactive lymphocyte clones may mount autoimmune responses to vaccines more readily than healthy individuals. But vaccines are not thought to be substantial autoimmune triggers in those without pre-existing susceptibility.
After hundreds of millions of COVID-19 vaccine doses administered worldwide, population-level signals consistently indicate no increased risk of autoimmune diseases like multiple sclerosis, rheumatoid arthritis, or type 1 diabetes. Reports of autoimmune reactions have been rare. While the possibility exists, current evidence indicates the COVID-19 vaccines do not commonly trigger autoimmune conditions in most recipients. However, more long-term monitoring is warranted. Those with concern may consider consulting their healthcare provider before vaccination.
Key Takeaways
– Acute COVID-19 can lead to transient autoantibody production through mechanisms like molecular mimicry and bystander activation. Whether this translates to increased autoimmune disease is still under study.
– Population studies indicate increased incidence of some autoimmune diseases like type 1 diabetes and Guillain-Barré syndrome after COVID-19. Monitoring at-risk patients is important.
– Post-acute COVID-19 and long COVID may potentially drive autoimmunity through persistent autoantibody elevation, epitope spreading, and release of mitochondrial antigens.
– Autoantibody tests, blood counts, inflammatory markers, and organ function tests can help detect COVID-19-associated autoimmune activity.
– Current evidence suggests the COVID-19 vaccines are unlikely to trigger autoimmunity in most people, though surveillance is ongoing. Those at high risk may consider consultation before vaccination.
– More research is needed to clarify the mechanisms linking COVID-19 with autoimmunity and establish the long-term autoimmune risks after SARS-CoV-2 infection.
Conclusion
The SARS-CoV-2 virus has intricate immunological effects that we are still unraveling. While COVID-19 appears capable of inducing transient autoantibody production and likely raises the risk of some autoimmune conditions in a subset of patients, our current understanding suggests this is not happening on a wide scale. However, long-term data is limited, and careful monitoring of patients at high risk is prudent. For the general population, the risk of autoimmune disease attributable to COVID-19 or COVID-19 vaccination currently seems low. Continued research in this area will shed more light on the complex interplay between COVID-19 and autoimmunity.