Induction of autoimmunity by infection
Autoimmune conditions are on the rise in the United States as many astute clinicians have observed. The key point in recognizing the association of infection and autoimmunity as described here is that we are very likely too see an even steeper increase in autoimmune symptoms in the wake of the COVID-19 pandemic. This would include conditions with symptoms that are baffling if the practitioner fails to recognize their autoimmune etiology. An example of the evidence for the increase in autoimmunity is a study conducted by National Institutes of Health and their collaborators and recently published in the journal Arthritis & Rheumatology that examines the prevalence ofantinuclear antibodies (ANA). The authors state:
Increasing Prevalence of Antinuclear Antibodies in the United States
Growing evidence suggests increasing frequencies of autoimmunity and certain autoimmune diseases, but findings are limited by the lack of systematic data and evolving approaches and definitions. We investigated whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed over a recent 25‐year span in the U.S.
They analyzed measurements of ANA from three time periods: 1988‐1991, 1999‐2004, and 2011‐2012, to determine whether an increase could be detected and found that prevalence has risen steeply. This increase includes both genders and adolescents.
The prevalence of ANA was 11.0% (CI=9.7‐12.6%) in 1988‐1991, 11.5% (CI=10.3‐12.8%) in 1999‐2004, and 15.9% (CI=14.3‐17.6%) in 2011‐2012 (trend P<0.0001), which corresponds to 22, 27, and 41 million affected individuals, respectively. Among adolescents (ages 12‐19 years), ANA prevalence rose steeply, with odds ratios of 2.02 (CI=1.16‐3.53) and 2.88 (CI=1.64‐5.04) in the second and third time periods relative to the first (trend P<0.0001). ANA prevalence increased in both sexes (especially males), older adults (ages ≥50 years), and non‐Hispanic whites. These increases were not explained by concurrent trends in obesity/overweight, smoking, or drinking...The prevalence of ANA in the U.S. has increased considerably in recent years.
This implies an increase in the number of people with a dysregulated immune system and higher baseline of inflammation rendering them more at risk for serious lung injury from COVID-19. The marked increase in such vulnerable teenagers has been reflected in pandemic statistics. Considering the steep increase in people whose immune systems are already 'on the edge', it is a matter of immense public health concern that even a relatively mild version of COVID-19 can act as a trigger for autoimmunity.
Autoimmunity can be triggered by infection
It is a matter of immense public health concern that even a relatively mild version of COVID-19 can act as a trigger for an autoimmune condition when there is a pre-existing polarization of the immune system. This may occur with predictive antibodies that emerge prior to the experience of any symptoms.
A paper published in The Journal of Clinical Investigation reviews some of the basic mechanisms by which exposure to a pathogen can induce autoimmunity. Autoimmune disease entails the activation and clonal expansion of auto-reactive lymphocytes key to the autoimmune process. Key mechanisms related to infection discussed in this paper include:
Molecular mimicry.
Viral and bacterial superantigens.
Enhanced processing and presentation of auto-antigens during an infection.
Molecular mimicry occurs when the string of amino acids of microbial peptides are similar to peptides in self-tissues; T cells can then be activated to react to both.
Superantigens belonging to a number of pathogens bind to a wide variety of MHC class II molecules and activate large numbers of T cells irrespective of their MHC/peptide specificity, resulting in reactivity to multiple tissues.
Enhanced processing and presentation of auto-antigens during an infection is also called "epitope spreading". The inflammatory process in reaction to one tissue can result in the presentation of antigens from other affected tissues resulting in priming of the immune system to additionally react those additional tissues.
The author states:
Activation and clonal expansion of autoreactive lymphocytes is a critical step in the pathogenesis of autoimmune diseases. In experimental models of autoimmunity, disease can be transferred by activated, but not resting, autoreactive T cells (1), indicating that activation of autoreactive T cells is required for the development of autoimmune diseases. Infectious agents have long been considered as possible culprits in the activation of autoreactive T cells.
A paper published in Clinical & Experimental Immunology adds to the conversation about infection as a trigger for autoimmune processes.
Pathogen infections induce several inflammatory cascades that result in the attraction, differentiation and expansion of cells of the innate as well as the adaptive immune system. Further, mechanisms such as bystander activation, pathogen‐induced necroptosis, superantigen cross‐linking and molecular mimicry have been reported to be involved in the breakdown of self‐tolerance.
In another paper in the same issue examines lymphatic system‐specific viral replication autoimmune disease the authors state:
Association of autoimmune disease with infections is evident from (1) autoimmune phenomena described during a chronic virus infection; (2) onset of autoimmune disease simultaneous to viral infections; and (3) experimental evidence. Involvement of virus infection during onset of type I diabetes is strongly evident. Epstein–Bar virus (EBV) infection was discussed to be involved in the pathogenesis of systemic lupus erythematosus.
Pathogens in Autoimmune Disease
A paper published in Clinical Microbiology Reviews focuses on the link between viral infections and autoimmunity.
Virus infections and autoimmune disease have long been linked. These infections often precede the occurrence of inflammation in the target organ. Several mechanisms often used to explain the association of autoimmunity and virus infection are molecular mimicry, bystander activation (with or without epitope spreading), and viral persistance. These mechanisms have been used separately or in various combinations to account for the immunopathology observed at the site of infection and/or sites of autoimmune disease, such as the brain, heart, and pancreas. These mechanisms are discussed in the context of multiple sclerosis, myocarditis, and diabetes, three immune-medicated diseases often linked with virus infections.
It is being observed that obesity and dysglycemia (blood glucose dysregulation) markedly increase the risk for poor outcomes in the COVID-19 pandemic; cardiovascular and hematological (clotting, with elevation of D-dimer associated with greatly heightened risk) effects are prominent among the afflicted, and manifestations of harm to the brain are emerging. Going forward, there is likely to be a tidal wave of autoimmunity among the survivors, some of which may not emerge until after a prolonged period of latency.
Molecular Mimicry, Bystander Activation, or Viral Persistence: Infections and Autoimmune Disease
It is relatively easy to envisage how molecular mimicry could induce autoimmunity...In a viral system, viruses have been shown to have cross-reactive epitopes with host self proteins (33)...An extension of this observation was published in a study by Srinivasappa et al. (125) showing that almost 4% of antiviral monoclonal antibodies also reacted with self proteins.
When APCs (antigen-presenting cells) are further activated by an inflammatory process, in this case viral infection, the trigger for autoimmunity is ready to be pulled. This is an important way that co-morbidities come into play...
Therefore, cross-reactive immune responses between viruses and host are relatively common; but, in order for autoimmune disease to occur, we predict that the cross-reaction takes place between the virus and host at a “disease-related” epitope. If this does not occur, autoimmunity may arise but no disease transpires.
Self antigens contained in dead or dying cells could then be presented by APCs to CD4+ or CD8+ T cells, leading to the autoimmune disease.
Nowadays with the steep increase in autoimmunity in general, more and more people are a "fertile field" for the activation of autoimmune disorders.
The fertile field concept has been recently reviewed (143) and may involve all three mechanisms: molecular mimicry, bystander activation and viral persistence. In brief, we proposed that any given individual may be repeatedly exposed to a potential immunogen without any untoward consequences; but that under some circumstances, for example, if the person had a viral infection at the time of exposure, infection would alter the immunological environment in which the antigen was encountered, leading to a profound immune response. In other words, the virus, even if it contained no cross-reactive antigens, would give rise to a fertile field in which immune responses to any exogenous antigen might flourish. A fertile field could be generated in other ways. For example, an infection with a virus having molecular mimicry to self CNS proteins can potentially prime autoreactive T cells but not to the point where they can initiate autoimmune inflammatory CNS disease; later events may trigger these cells to cause disease.
A paper published in the Journal of Autoimmunity zeroes in on molecular mimicry.
As previously reported in this review, there clearly appears to be a link between exposure to infectious disease agents and the role of immune tolerance. Thus, exposure to antigens of infectious agents leads to host immune responses that in some cases cross-react with normal human tissue proteins and imply the breaking of self tolerance.
Points highlighted by these authors include the role of environmental pollution as a contributor to the increase in autoimmunity:
Molecular mimicry occurs when similarities between foreign and self-peptides favor an activation of autoreactive T or B cells
Host genetics, exposure to microbiota and environmental chemicals influence molecular mimicry
Autoreactive T cells play a paramount role in molecular mimicry
Another study in the same journal considers autoimmune myocarditis (heart inflammation) induced by viral infection.
We have investigated two models of virally-induced autoimmune myocarditis in mice using widely different infectious agents. Infection of susceptible BALB/c mice with either Coxsackievirus or murine cytomegalovirus results in the development of acute myocarditis from day 7–14 after infection, and chronic myocarditis from day 28 onwards...although infectious virus cannot be detected past day 14 of infection...Many researchers have investigated the role of molecular mimicry in the development of myocarditis after viral infection. This review explores the ‘adjuvant’ effect of infection on the innate immune response and how this determines the progression to autoimmune disease.
And of key clinical importance demonstrate that supporting innate immunity--NK (natural killer) cells--has a protective effect.
We show that NK cells protect against the development of disease, while complement and complement receptors are involved in the development of autoimmune myocarditis induced by inoculation with virus or cardiac myosin, respectively. Our results suggest that the innate immune response to viral and self-antigens may determine whether susceptible strains of mice progress to chronic autoimmune disease. These findings have broad implications for understanding the role of infection in inducing autoimmune disease.
This is also explored in a paper published in Immunologic Research. The authors state:
Revisiting the old link between infection and autoimmune disease with commensals and T helper 17 cells
Alongside...genetic defects in central or peripheral tolerance mechanisms, which can confer increased susceptibility to autoimmune diseases, autoimmunity has also been epidemiologically linked to infections...Many theories have been proposed to explain how microbes could initiate or predispose to autoimmunity (Fig. 1a), and these include bystander activation of autoreactive T cells by pathogen encoded superantigens or inflammatory cytokines produced by APC responding to infection. The dominant theory is “molecular mimicry”, or more specifically “epitope mimicry”, where self-reactive B or T cells are activated inappropriately upon recognition of peptides derived from pathogens that share sequence or structural homology with peptides derived from self-antigens
The authors cite numerous examples of autoimmune diseases known to be triggered prior infection, including the well-known association of MS (multiple sclerosis) and SLE (lupus) with EBV (Epstein-Barr virus).
In MS, clinical studies have shown that infection with EBV is a consistent and strong risk factor. In fact, it has been reported that in individuals infected with EBV in early childhood, the risk of MS is about tenfold higher compared to EBV-negative individuals, and at least 20-fold greater if they also have developed mononucleosis [55, 56]. SLE is also associated with prior viral infection. Prior to clinical onset of SLE, the initial autoantibodies that develop in patients to the 60KDa protein Ro, a common target in SLE, were found to cross-react with a peptide from the latent EBV viral protein Esptein-Barr virus nuclear antigen-1 (EBNA-1) [35]. Rabbits immunized with either Ro or the cross-reactive EBNA-1 peptide developed autoantibodies that bound to multiple epitopes of Ro, and the animals progressively developed symptoms of lupus [35].
Bottom line: autoimmune conditions were steeply on the rise, even in adolescents, prior to the COVID-19 pandemic; autoimmunity can be induced by infection; practitioners should be alert to a possible surge of conditions with an autoimmune etiology in the years following the pandemic. See also Balancing immunity and inflammation in lung disease.