In a recent study published in the journal Viruses, researchers describe the pathological mechanisms of virus-induced autoimmune diseases (AIDs).
Study: The Role of Viral Infections in the Onset of Autoimmune Diseases. Image Credit: successfulalexey78 / Shutterstock.com
What are AIDs?
Several decades of research have been committed to elucidating the various mechanisms through which viruses contribute to the development of AIDs; however, the relationship between these two health conditions is highly complex and constantly evolving.
AIDs, affecting about 5% of the global population, arise from dysregulated immune responses that may be sustained for extended periods, cannot be downregulated, or are more intense than necessary.
AIDs are typically classified by the specific organs affected by these diseases, such as inflammatory bowel disease (IBD), multiple sclerosis (MS), and type 1 diabetes. AIDs can also be systemic, as evident in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjörgen syndrome.
Genetic factors contribute to the development of several autoimmune diseases; however, most autoimmune diseases arise due to a combination of both genetic and non-genetic factors. In addition, environmental factors such as pathogens, toxic chemicals, and dietary composition, for example, can directly impact the immune system and, as a result, cause certain people to be more vulnerable to developing AIDs.
Chronic viral infections also increase the risk of autoimmunity. In fact, the growing number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections that have been diagnosed throughout the coronavirus disease 2019 (COVID-19) pandemic has been accompanied by a more significant number of AIDs subsequently diagnosed in these individuals.
Immune tolerance and AIDs
When the immune system loses its ability to tolerate the activity of self-antigens, autoimmune diseases can occur. The two different mechanisms by which this loss of immunological tolerance can arise through altered central tolerance selection or insufficient peripheral suppressive functions.
Central tolerance refers to the different selection processes that exist in the thymus and bone marrow to remove autoreactive T- and B-cells, respectively, before they leave this organ and enter the bloodstream. Previous studies have shown that viral thymus infections, such as those caused by roseoloviruses, can interrupt the maturation and selection of T-cells and, as a result, lead to autoimmunity.
Despite the effectiveness of central tolerance, some reactive T- and B-cells can still enter the bloodstream and join the peripheral lymphocyte pool. At this point, peripheral tolerance is responsible for limiting the duration, intensity, and location of immune responses through various immune cells, the most prominent of which include regulatory T-cells (Tregs). Notably, Treg dysfunction is associated with various autoimmune diseases, including type 1 diabetes, RA, MS, SLE, and myasthenia gravis.
Inflammation and AIDs
Prolonged inflammatory responses to infections have been shown to increase the risk of developing autoimmune diseases. Some of the different proinflammatory cytokines that participate in both inflammatory responses and the initiation of autoimmune reactions include type 1 interferon (IFN), IFN-γ, interleukin 1β (IL-1β), IL-12, IL-17, and tumor necrosis factor α (TNF-α).
Inflammasomes are intracellular components that participate in the innate immune response and comprise several subtypes activated by different pathogens, including bacteria, viruses, fungi, and parasites.
Notably, the dysregulated activation of inflammasomes has been implicated in RA, SLE, ankylosing spondylitis, and Sjörgen syndrome. The core protein of hepatitis C, the SARS-CoV-2 viroporin, the influenza virus M2 ion channel, and the encephalomyocarditis viroporin have also been shown to activate the NLRP3 inflammasome in macrophages.
How does COVID-19 cause autoimmunity?
Throughout the COVID-19 pandemic, a vast amount of scientific research has been conducted to better understand the pathophysiology of this infection. These large datasets have allowed researchers to identify several characteristics of COVID-19 that closely resemble those that occur in autoimmune diseases.
COVID-19 is associated with the overactivation of mature natural killer cells and CD8+ T-cells. Furthermore, this infection is characterized by dysregulated B- and T-cells and inflammatory cytokines, including TNF-α, IL-1, and IL-6, all of which are elevated during COVID-19. Whereas leukocyte and neutrophil counts are also increased during COVID-19, lymphocyte, monocyte, eosinophil, and basophil counts appear to decline in SARS-CoV-2-infected patients.
Several autoimmune diseases have been reported in patients who have recovered from COVID-19, some of which include multisystemic inflammatory syndrome in children (MIS-C), Guillain-Barre, and SLE. In fact, one large cohort study found that in the first six months after recovering from COVID-19, patients are at a significantly greater risk of developing RA, ankylosing spondylitis, SLE, dermatopolymyositis, systemic sclerosis, Sjörgen syndrome, mixed connective tissue disease, IBD, celiac disease, type 1 diabetes, psoriasis, vasculitis, and polymyalgia rheumatica.
Additional clinical research is needed to determine the precise molecular mechanisms by which different viral infections can lead to autoimmune conditions. More population-based epidemiological studies on autoimmune diseases that collect long-term data from the period before the disease onset to after its onset are also urgently needed.
Large-scale data acquisition that accrued during the COVID-19 pandemic from across the world could serve as a valuable resource to monitor the trajectory of multiple AIDs with SARS-CoV-2 infections. Nevertheless, future AID studies should include an extensive assessment of trends, risk factors, co-prevailing morbidities, and disease burden while identifying variations across different population subsets.
- Sundaresan, B., Shirafkhan, F., Ripperger, K., & Rattay, K. (2023). The Role of Viral Infections in the Onset of Autoimmune Diseases. Viruses. doi:10.3390/v15030782