COVID’s ‘comet tail’ of autoimmunity

SARS-CoV-2, like many other infections, can trigger latent or instigate new autoimmunity. It is exceptional compared to many other pathogens in…

…the large number of epitopes (the part of an antigen that an antibody attaches to) that mimic human antigens. This includes targets for brain inflammation. It is a major factor in the chronic sequelae of recovery from the acute infection, so-called ‘long COVID’. In a paper published in the World Journal of Clinical Cases, the authors discuss Autoimmunity as the comet tail of COVID-19 pandemic.

“COVID-19 indeed has at its base a complex immunological scenario, in which the immune system acts as a double-edged sword, being responsible for either viral clearance or excessive inflammation and autoimmunity.”

Infections and hyper-activation of the immune system

There are several mechanisms by which the immune response to the virus can result in autoimmunity…

“It is well known that viruses may trigger or exacerbate autoimmunity in genetically predisposed individuals, through aberrant activation of immunologic pathways involving either the innate or the adaptive immune response[10,11]. Mechanisms include molecular mimicry between viral and self-epitopes, breakdown of tolerance, non-specific bystander activation, super-antigen presentation, stimulation of inflammasome platforms and release of type I interferon (IFN)[10,11].”

Immunologic pathways activated by severe acute respiratory syndrome coronavirus 2

Autoantibodies

The production of antibodies targeting self-tissue as the immune system is activated against SARS-CoV-2 can result in immune-mediated neuropathy, blood disorders, myositis (muscle inflammation), myocarditis (heart inflammation), skin conditions, vasculitis (blood vessel inflammation) and pediatric inflammatory multisystem syndrome (MIS-C or PIMS: pediatric inflammatory multisystem syndrome).

Localization of autoimmune responses triggered by COVID-19

While acknowledging that “the jury is still out” regarding the dimensions of autoimmune sequelae to COVID-19 infections, the authors offer this “Core tip”:

“The immune system plays a central role in coronavirus disease 2019 (COVID-19), being responsible for clinical manifestations and prognosis. Hyper-activation of the immune response against severe acute respiratory syndrome coronavirus 2 may result, in some cases, in development of unwanted autoimmune disorders. COVID-19 has been associated with immune-mediated systemic or organ-selective manifestations, some of which fulfill the diagnostic or classification criteria of specific autoimmune diseases. Though it is still unknown whether these medical conditions represent transitory post-infectious epiphenomena, the use of therapeutic agents targeting the immune system may perhaps prevent their chronicization which leads to development of autoimmune diseases.”

Diverse functional autoantibodies in patients with COVID-19

A more recent paper published in Nature reveal a more expansive autoimmune response by applying a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling to screen 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins. They found both autoantibodies targeting immune-related proteins as well as targeting self-tissues.

“Our analysis…indicated that autoantibodies targeting immune-related proteins were increased in patients with severe COVID-19. These proteins included those involved in lymphocyte function and activation, leukocyte trafficking, the type I and type III IFN responses, type II immunity and the acute phase response. Confirming a previous report11, we identified autoantibodies against type I IFNs in 5.2% of patients who were hospitalized with COVID-19. Using an ELISA, we orthogonally validated a subset of 22 autoantibodies that target cytokines, chemokines, growth factors, complement factors and cell-surface proteins. These results demonstrate that patients with COVID-19 possess autoantibodies that may affect a wide range of immunological functions.”

Regarding antibodies targeting self-tissue, their findings suggest this is a fundamental part of COVID-19 infection pathology.

“The extent of autoantibody reactivities seen in patients with COVID-19 suggests that humoral immunopathology is an intrinsic aspect of the pathogenesis of COVID-19. Screening patient samples with the REAP platform, we have identified and validated numerous protein targets across a wide range of tissues and immunological and physiological functions. These autoantibodies had potent functional activities and could be directly correlated with various virological, immunological and clinical parameters in vivo within samples from patients with COVID-19. ..These results provide evidence that autoantibodies are capable of altering the course of COVID-19 by perturbing the immune response to SARS-CoV-2 and tissue homeostasis…Finally, our findings provide a strong rationale for the wider investigation of autoantibodies in the pathogenesis of infectious diseases.”

Infections and epitope spreading

In a recent edition of Nature Outlook focusing on autoimmune disease, the author comments on How pandemics strengthen links between viruses and autoimmunity. He describes the important principle of ‘epitope spreading’ by which the immune system acquires new self-tissue targets when confronted with inflammatory debris.

“Sometimes, however, B cells erroneously generate antibodies against the body’s own proteins. When people are exposed to Epstein–Barr virus (EBV) for the first time, for instance, “a number of autoantibodies arise”, says Gregg Silverman, an immunologist at NYU Grossman School of Medicine in New York City.

One reason for this misbehaviour by B cells is that in the heat of the battle, the correct targets can become unclear — and more intense fights generate greater confusion. “The more cells killed by an infection, the more autoantigens are released,” says Silverman. In the case of infection with the virus SARS-CoV-2, there can be so much tissue injury that “the immune system cannot figure out initially whether it should be recognizing the virus or self-antigens that are being released from our own cells”, he explains. This phenomenon, known as epitope spreading, leads to both friend and foe being hit.”

Brain Autoimmunity

Antibodies targeting the brain in reaction to a viral infection are of special importance considering the potentially global effects on health, cognition, and mood. COVID-19 as a Trigger of Brain Autoimmunity published in ACS Chemical Neuroscience examines how COVID-19 triggers brain autoimmune disorders. The authors describe how this occurs through molecular mimicry, bystander activation, and as noted above, epitope spreading.

“Molecular mimicry involves structural similarity of a pathogen’s antigens to self-antigens, which in turn activates T- and B-lymphocytes and leads to a cross-reactive response involving conformationally similar human proteins, thereby causing autoimmune disease. Molecular mimicries between SARS-CoV-2 and several neuronal autoantigens in brain and CSF from individuals afflicted with COVID-19 have been identified (Table 1).(1)”

Bystander activation occurs as the consequence of an overzealous immune inflammatory reaction. A pre-existing baseline level of chronic, non-purposeful, non-resolving inflammation raises the risk.

“As an acute first line of defense, the innate immune system mounts a forceful response to SARS-CoV-2 infection resulting in elevated levels of proinflammatory cytokines (e.g., interleukin (IL)-1β, IL-6, IL-8, TNF-α, interferon (IFN)γ) and chemokines (e.g., granulocyte colony stimulating factor (G-CSF), interferon γ-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1α (MIP-1α)). This nonspecific and over-reactive antiviral immune response produces a “cytokine storm” characterized by an exaggerated proinflammatory environment which further initiates self-tissue (blood–brain barrier, myelin sheath, axonal membrane) damage along with production of self-antigens that mimic COVID-19 antigens. These self-antigens are ultimately taken up by antigen presenting cells (APCs), simulating surrounding autoreactive T-cells and further triggering the ongoing autoimmune response.”

As noted above, the resulting debris containing self-tissue antigens increase the risk of epitope spreading. Moreover, this includes antibodies that attack the brain and nervous and remain persistent due to the ‘immortalization’ of B-cells.

“Along with immune-targeting autoantibodies and antiphospholipid antibodies, people with COVID-19 also sometimes exhibit high prevalence of other CNS-tissue associated autoantibodies (e.g., neuronal injury marker NINJ1, metabotropic glutamate receptor GRM5, orexin receptor HCRT2R enriched in the hypothalamus). Moreover, immunological memory enabled by effector B-cells against self-antigens fosters ongoing antibody production against diverse CNS tissue targets in the BBB and myelin sheath. These diverse and varied self-targeting CNS tissue autoantibodies result in targeted, longer-term damage and may result in neurodegenerative disease severity in post-COVID-19 patients in coming decades. The SARS-CoV-2 virus therefore has the capacity to damage the human brain via complex indirect mechanisms, resulting in autoantibodies, predominantly against brain-based antigens as has been clinically demonstrated in cerebrospinal fluid samples from patients with COVID-19 neurological complications.(2)”

Potential autoimmune neurodegenerative disorders promoted by COVID-19 include multiple sclerosis (MS) or Guillain–Barré syndrome (GBS), optic neuritis, MS-like demyelination, long-term protein-misfolding neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease. There are also possibilities for diffuse neurological, cognitive and mood disorders that defy easy labeling complicated by mitochondrial dysfunction.

“ACE2-mediated accelerated production of neurotoxic proinflammatory cytokines with subsequent pathological innate and adaptive immune activation leads to CNS cellular organelle (mitochondria, lysosomes) impairment (as has been observed in so-called COVID-19 long-haulers) and may be the start of a neurodegenerative cascade.”

Alzheimer’s disease

In their conclusion, the authors comment on the significance for Alzheimer’s disease risk, adding COVID-19 to the list including other human herpes viruses and the oral pathogen Porphyromonas gingivalis.

“The possibility that COVID-19 might culminate (after a latent phase) in AD is suggested by diverse accumulating data, including the neurotropic properties of SARS-CoV-2 and the neurological clinical features of COVID-19. Innate-immune activation, such as that instigated by SARS-CoV-2, is an early event in AD pathogenesis, occurring possibly 20–30 years prior to the first symptoms. This activation is triggered by pathogen-associated molecular patterns (PAMPs) which induce cytotoxic proinflammatory cytokine release. Long-past infections have thus been proposed as triggers of AD and include human herpes viruses and most recently Porphyromonas gingivalis. We are proposing that SARS-CoV-2 is a trigger similar to Porphyromonas gingivalis. In response to such PAMPs the subsequent sustained released of proinflammatory cytokines and activated microglia heralds a chronic autoimmune neurotoxic state creating the substrate for AD’s persistent preclinical progressive neuronal death over subsequent decades. Long-term cognition assessment and overall neurological competence are recommended in acute COVID-19 patients, specifically for patients having any history of autoimmune disorders.”

And just the other day a paper published in Nature Communications documents the presence of new-onset IgG autoantibodies in hospitalized patients with COVID-19.

The authors developed arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in 147 hospitalized COVID-19 patients and found autoantibodies in approximately 50% of patients but in less than 15% of healthy controls.

They conclude…

Our studies have begun to quantify the impact of SARS-CoV-2 on autoimmunity, identifying which antigens and specific autoimmune diseases to surveil in patients who have been infected, and contributing to our mechanistic understanding of COVID-19 pathogenesis. These studies provide a starting point for large-scale epidemiology studies to determine the extent of autoimmunity that results from SARS-CoV-2 infection, and its long-term impacts on the health care system and the economy. While the COVID-19 pandemic is leaving a wake of destruction as it progresses, it also provides an unprecedented opportunity to understand how exposure to a new virus could potentially break tolerance to self, potentially giving rise to autoimmunity and other chronic, immune-mediated, diseases.

The corresponding author Paul J. Utz of Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, is quoted in DG News:

“Within a week after checking in at the hospital, about 20% of these patients had developed new antibodies to their own tissues that weren’t there the day they were admitted,” said Dr. Utz. “In many cases, these autoantibody levels were similar to what you’d see in a diagnosed autoimmune disease.”

In some cases, the presence of those newly detected autoantibodies may reflect an increase, driven by the immune response, of antibodies that had been flying under the radar at low levels, said Dr. Utz. It could be that inflammatory shock to the systems of patients with severe COVID-19 caused a jump in previously undetectable, and perhaps harmless, levels of autoantibodies these individuals may have been carrying prior to infection. In other cases, autoantibody generation could result from exposure to viral materials that resemble our own proteins.

“It’s possible that, in the course of a poorly controlled SARS-CoV-2 infection -- in which the virus hangs around for too long while an intensifying immune response continues to break viral particles into pieces -- the immune system sees bits and pieces of the virus that it hadn’t previously seen,” said Dr. Utz. “If any of these viral pieces too closely resemble one of our own proteins, this could trigger autoantibody production.”