Severe COVID-19 linked to self-attacking antibodies


Hospitalized COVID-19 patients are substantially more likely to harbor autoantibodies – antibodies directed at their own tissues or at substances their immune cells secrete into the blood – than people without COVID-19, according to a new study.

Autoantibodies can be early harbingers of full-blown autoimmune disease.

“If you get sick enough from COVID-19 to end up in the hospital, you may not be out of the woods even after you recover,” said PJ Utz, MD, professor of immunology and rheumatology at Stanford Medicine.

Utz shares senior authorship of the study, which will be published Sept. 14 in Nature Communications, with Chrysanthi Skevaki, MD, Ph.D., instructor of virology and laboratory medicine at Philipps University Marburg in Germany, and Eline Luning Prak, MD, Ph.D., professor of pathology and laboratory medicine at the University of Pennsylvania.

The study’s lead authors are Sarah Chang, a former technician in Utz’s lab; recent Stanford undergraduate Allen Feng, now a technician in the Utz lab; and senior research investigator Wenshao Meng, Ph.D., and postdoctoral scholar Sokratis Apostolidis, MD, both at the University of Pennsylvania.

The scientists looked for autoantibodies in blood samples drawn during March and April of 2020 from 147 COVID-19 patients at the three university-affiliated hospitals and from a cohort of 48 patients at Kaiser Permanente in California. Blood samples drawn from other donors prior to the COVID-19 pandemic were used as controls.

The researchers identified and measured levels of antibodies targeting the virus; autoantibodies; and antibodies directed against cytokines, proteins that immune cells secrete to communicate with one another and coordinate their overall strategy.

Upward of 60% of all hospitalized COVID-19 patients, compared with about 15% of healthy controls, carried anti-cytokine antibodies, the scientists found.

This could be the result of immune-system overdrive triggered by a virulent, lingering infection. In the fog of war, the abundance of cytokines may trip off the erroneous production of antibodies targeting them, Utz said.

If any of these antibodies block a cytokine’s ability to bind to its appropriate receptor, the intended recipient immune cell may not get activated. That, in turn, might buy the virus more time to replicate and lead to a much worse outcome.

Tracking down autoantibodies

For about 50 patients, blood samples drawn on different days, including the day they were first admitted, were available. This enabled the researchers to track the development of the autoantibodies.

“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,” Utz said. “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, Utz said. 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, Utz said.

“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,” he said. “If any of these viral pieces too closely resemble one of our own proteins, this could trigger autoantibody production.”

The finding bolsters the argument for vaccination, he added. Vaccines for COVID-19 contain only a single protein—SARS-CoV-2’s so-called spike protein—or the genetic instructions for producing it.

With vaccination, the immune system is never exposed to—and potentially confused by—the numerous other novel viral proteins generated during infection.

In addition, vaccination is less intensely inflammatory than an actual infection, Utz said, so there’s less likelihood that the immune system would be confused into generating antibodies to its own signaling proteins or to the body’s own tissues.

“Patients who, in response to vaccination, quickly mount appropriate antibody responses to the viral spike protein should be less likely to develop autoantibodies,” he said.

Identifying autoantibody triggers

Indeed, a recent study in Nature to which Utz contributed showed that, unlike SARS-CoV-2 infection, the COVID-19 vaccine produced by Pfizer doesn’t trigger any detectable generation of autoantibodies among recipients.

“If you haven’t been vaccinated and are telling yourself, ‘Most people who get COVID get over it and are OK,’ remember that you can’t know in advance that when you get COVID-19 it will be a mild case,” Utz said.

“If you do get a bad case, you could be setting yourself up for a lifetime of trouble because the virus may trip off autoimmunity. We can’t say yet that you’ll definitely get an autoimmune disease – we haven’t studied any patients long enough to know whether these autoantibodies are still there a year or two later, although we hope to study this – but you certainly might. I wouldn’t want to take that chance.”

Utz intends to study blood samples from SARS-CoV-2-infected people who are asymptomatic or who’ve had mild COVID-19 symptoms. That could help determine whether the massive hyperactivation of the immune system, which doesn’t occur in mildly symptomatic or asymptomatic people, is what causes trouble, or whether the mere molecular resemblance of SARS-CoV-2 proteins is enough to trigger autoantibody generation.

Utz is a member of Stanford Bio-X, the Stanford Institute for Immunity, Transplantation and Infectionand the Stanford Maternal and Child Health Research Institute.

The immune system is a highly regulated entity which functions to recognise and eliminate foreign material including infections and tumours. The effector cells involved in adaptive immunity are comprised of B and T lymphocytes, cells which express unique receptors on their surface which recognise specific regions of antigens called epitopes [10].

Epitopes between B and T cells differ. B cells will directly recognise free, exposed antigens. In contrast, T cells recognise a complex consisting of antigen peptide fragments within a molecule known as molecular histocompatibility complex (MHC), which is presented by other cells.

Due to the diverse repertoire of receptors created during development, these epitopes may be self-antigens (autoantigens). The present review focuses on adaptive immunity, with an emphasis on B cells, as well as autoreactivity (attacking of self) that occurs during, or as a long-term consequence of, exposure to SARS-CoV-2 or its component macromolecules.

In COVID-19, B and T cell responses to the SARS-CoV-2 proteins have been studied in acute and convalescent infections [11,12]. Serological assays to measure the increased presence of antibodies to the spike and nucleoprotein have been used to

1. understand seroconversion (the appearance of specific antibodies),

2. identify neutralising antibodies (i.e., those that prevent viral infection of host cells) and

3. correlate the immune response with disease severity (systematically reviewed in [11]).

There have also been reports of increased antibody responses to other SARS-CoV-2 proteins (such as open reading frame (ORF)3b and ORF8) after infection [13]. Similarly, T cell responses to multiple SARS-CoV-2 proteins have been identified [14], and responses elicited in COVID-19 patients have been studied (systemically reviewed in [12]).

By studying and measuring T cell responses, insights into the role of T cells for the resolution of primary infection, as well as the establishment of long-term immunological memory able to react effectively to subsequent infections, can be gained. This is therefore also key for the development of both therapeutic and vaccine strategies.

Viral Infections and Autoimmunity

A key pillar of the adaptive immune system is its ability to recognise and react to external pathogens (such as SARS-CoV-2), but not to self-antigens. This is controlled by immune tolerance, mechanisms which regulate an immune response, as well as the built-in unresponsiveness of a lymphocyte when its antigen-specific receptor engages with a cognate self-antigen [15,16].

Tolerance is particularly important in the context of self-antigens since it is undesirable to have an immune response to self. High frequencies of self-reactive immune cells can be found circulating in our bodies, although they usually remain suppressed [17,18,19].

These self-reactive immune cells can be activated by the dysregulation of immune tolerance mechanisms [20] or through inflammatory signals [21,22]. This can result in the immune system going awry, resulting in immunopathology and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis (MS) [23,24].

The triggering of autoimmune diseases is defined by a ’mosaic of autoimmunity’, a term that describes the combination of multiple contributory factors [25]. These factors can be grouped into the following four groups: genetic predisposition, immune defects, hormonal factors and environmental factors [25].

Amongst the environmental factors, viral infections are known to promote and exacerbate autoimmune diseases. Two of the key mechanisms proposed for viral-induced autoimmunity include molecular mimicry and bystander activation (Figure 1) [26].

Molecular mimicry occurs when the same lymphocyte receptor recognises both a foreign pathogen antigen and a self-protein due to their structure similarity, which can result in immune cross-reactivity. In contrast, bystander activation occurs when autoreactive immune cells become activated due to the liberation of self-antigens which are otherwise not exposed to the immune system.

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Figure 1
Mechanisms of virally induced autoimmunity. (A) In the normal situation, B cells will release antibodies upon activation that can bind to the extracellular virus [27]. Infected cells will present viral antigens on MHC class 1 (MHC-I) to cytotoxic T cells, resulting in the activation of the T cells and killing of these virus-infected cells [28]. (B) Molecular mimicry occurs when the viral antigen is structurally similar to human-derived proteins [26]. Antibodies may bind to both viruses and self-proteins (e.g., on healthy cell surfaces). T cells may become activated by the viral protein and target a virus-infected cell but also recognise and attack self. (C) Bystander activation. (1) Release of self-antigens into an inflammatory environment. (2) Antigen uptake and presentation by an antigen presenting cell (APC) to an autoreactive T cell. (3) Activated autoreactive T cell recognises and attacks healthy cells.

Associations between various viral infections and autoimmune diseases have been reported repeatedly in the literature (reviewed by Smatti et al. [26]). Active human cytomegalovirus (HCMV) infection is often found in patients diagnosed with immune thrombocytopenic purpura (ITP, an autoimmune blood disorder), and HCMV infection results in a more severe form of this autoimmune disease which is also resistant to treatment [29].

Antibody responses to HCMV have been found to be significantly elevated in SLE patients in comparison to healthy controls [30]. Another virus with a reported association with SLE is the Epstein−Barr virus (EBV) [31,32]. In comparison to healthy controls, EBV viral burden is abnormally elevated in SLE patients [31], and they have higher titres of anti-EBV antibodies [32].

High titres of anti-EBV antibodies are also present in rheumatoid arthritis (RA) patients [32]. Other examples of viral infections linked to autoimmune diseases include enteroviruses (e.g., coxsackievirus A4, coxsackievirus A2 and coxsackievirus A16) with islet autoimmunity [33] and measles, mumps and rubella with type 1 diabetes [34].

Several coronaviruses have additionally been linked to autoimmunity. Two of the common human coronaviruses, HCoV-229E and HCoV-OC43, have been linked with autoimmunity, specifically MS [35,36,37,38]. Antibodies to HCoV-OC43 and HCoV-229E were found intrathecally in 41% and 26% in people with MS, respectively [35]. This was in comparison to control subjects where no antibodies to either virus were detected.

In a separate study, viral RNA for HCoV-229E was detected in central nervous system tissue in 36% of MS patients, but not in control subjects [36], suggesting a potential role of coronavirus infection in disease aetiology. Similarly, a statistically significant increase in the prevalence of viral RNA for HCoV-OC43 has been reported in MS patients in comparison to controls [37].

Furthermore, T cell immune cross-reactivity between myelin and HCoV-229E antigens has been reported in MS patients, in contrast to control subjects [38]. Of interest is a case report linking ITP to an infection with the common human coronavirus, HCoV-HKU1 [39], although more evidence will need to be accumulated to establish this association.

Thrombocytopenia, which occurred in patients following infection with the previous epidemic causing coronavirus, SARS-CoV-1, has been suggested to be caused by an immune mechanism [40,41].

Another association between SARS-CoV-1 and autoimmune diseases has been identified through immune cross-reactivity [42]. Patients with autoimmune diseases (SLE, Sjögren’s syndrome, RA and mixed connective tissue disease) tested positive for antibodies to SARS-CoV-1 antigen, despite no previous SARS-CoV-1 infection [42]. Given these associations between coronaviruses and autoimmunity, as well as the sequence similarity of SARS-CoV-2 to these viruses, a link between SARS-CoV-2 and autoimmunity is plausible.

Autoantibodies Identified in COVID-19 Positive Patients

COVID-19 positive patients with more severe disease have increased levels of autoantibodies, including those that have known associations with autoimmune diseases [43,44,45,46,47,48]. One of the earliest studies showing this autoimmune phenomenon in severe COVID-19 cases investigated the antibody responses to 12 autoimmune-related targets in a cohort of 21 severe and critical patients [43].

Of these 12 antigen targets, 5 antigens were targeted in at least one patient; antinuclear antigen (ANA) antibodies (50%), anti-60 kDa SSA/Ro antibodies (25%), anti-52 kDa SSA/Ro antibodies (20%), anti-scl-70 antibodies (5%) and anti-U1-RNP antibodies (5%). Similarly, ANA antibodies were reported in 34.5% of severely ill COVID-19 cases in a separate cohort [44].

Within this second cohort, it was stated that no patients had a history of systemic autoimmunity, yet nearly 70% had autoantibodies relating to at least one systemic autoimmune rheumatic disease [44]. Amongst this cohort, anti-phospholipid antibodies (aPLs) were also common (cardiolipin (CL) and β2 glycoprotein I (β2GPI), 24.1% and 34.5%, respectively).

APLs associated with antiphospholipid syndrome (an autoimmune disorder that can result in a variety of symptoms such as blood clots and chronic headaches) have been reported to be associated with SARS-CoV-2 infection in several studies [46,47,48,49,50]. Two studies identified that more than 50% of their subjects had antibodies to at least one type of phospholipid [46,48].

One of these reported that higher titres of aPLs were associated with more severe disease [46] whereas the other reported that thrombosis events only occurred in the aPL positive patients but not those without any detectable aPL. In contrast, Gatto et al. [50] found no association between aPL positivity and thrombosis among the patients they studied. Therefore, the role of these autoantibodies in co-morbid events in COVID-19 patients is still unclear.

In addition to autoantibodies with known associations to autoimmune diseases, other autoantibodies to self-proteins, including cytokines and nervous system-related proteins, have also been found in COVID-19 patients [45,47]. Type I interferons (IFNs) are key cytokines in anti-viral immune responses [51]. The presence of autoantibodies to type I IFNs (-ω, -α or both) have been reported in 13.7% of patients with life threatening COVID-19 pneumonia [45].

These autoantibodies were specific to severe disease and not found in any COVID-19 patients with asymptomatic or mild infection. In 10.2% of patients with detectable anti-IFN antibodies, the antibodies had neutralising capabilities and were shown to neutralise the corresponding IFN’s ability to block SARS-CoV-2 infections in vitro [45]. Additionally, 15 (11.1%) of the 135 subjects positive for at least one type of anti-type I IFN also had autoantibodies to other cytokines including: IFN-γ, GM-CSF, IL-6, IL-10 and/or others [45].

Only in 4 of these 15 did the autoantibodies to other cytokines have neutralising capabilities, thus demonstrating that not all autoantibodies have potentially pathogenic roles. Furthermore, some patients presenting with neurological symptoms in severe COVID-19 have autoantibodies to neuronal targets [47]. In a cohort of 11 patients, anti-Yo antibodies were found in the serum and cerebral spinal fluid (CSF) of one patient, anti-myelin antibodies in the serum of two patients, and one patient had high levels of anti-NMDA receptor antibodies [47]. Three separate patients in this study were found to have aPLs [47].

The presence of autoantibodies highlights the state of dysregulation of the immune system in SARS-CoV-2 infection, particularly in severe cases. With COVID-19 presenting as a multi-organ disease, these autoantibodies are hypothesised to be playing a role in the pathology. However, in some cases, such as for anti-phospholipids and thrombosis, this remains unknown and further research into the role of these autoantibodies is required.

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reference link : Journal information:Nature Communications



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