COVID-19 Induces Expression Of Unique Autoantibodies – Males At Risk For Autoimmune


A new study by researchers from Cedars-Sinai Medical Center-California not only confirms that SARS-CoV-2 infections whether symptomatic (Be it Mild, Moderate or Severe) or even asymptomatic can generate distinct autoantibodies that can lead to a variety of autoimmune issues not only during the infection stage but also in the long term.

The study has also found that males tend to generate higher titers of these autoantibodies compared to females upon infection.

To date, emerging evidence has highlighted the potential importance of autoimmune activation in modulating not only the acute response but also recovery trajectories following SARS-CoV-2 exposure.

Given that immune-inflammatory activity can be sex-biased in the setting of severe COVID-19 illness, the study team deliberately examined sex-specific autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease.
The study team used a bead-based array containing over 90 autoantigens previously linked to a range of classic autoimmune diseases to assess autoantibody (AAB) titers in 177 participants.

All participants had confirmed evidence of prior SARS-CoV-2 infection based on presence of positive anti-nucleocapsid IgG serology results (Abbott Diagnostics, Abbott Park, Illinois).
The study team used multivariate analysis to determine whether sex-bias was associated with increased rates of AABs reactivity and symptom burden after SARS-CoV2 infection.
The study findings showed that 82.4% of AABs reactivity was associated with being male compared to 17.6% with female. The study found a diversity of AABs responses that exhibited sex-specific patterns of frequency distribution as well as associations with symptomatology and symptom burden.
The study findings reveal a remarkable sex-specific prevalence and selectivity of AAB responses to SARS-CoV-2. Further understanding of the nature of triggered and persistent AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19.
The study findings were published on a preprint server and are currently being peer reviewed.
It has already been known that the high degree of variability observed in COVID-19 severity is characterized by extreme dysregulation in the host immune response, with disruptive immune activation seen at each stage of disease progression.
Typically autoantibodies (AABs) mistakenly target the hosts’ own proteins. Recent reports have identified active AABs in those with severe COVID-19 that are clinically similar to those seen in classic autoimmune diseases, such as lupus and multiple sclerosis.
The COVID-19 Immunology study team besides exploring as to whether sex gender was a key factor also investigated the association between COVID-19 and autoimmunity at all levels of disease severity.
Shockingly the study team found that autoimmune responses are triggered following even mild and asymptomatic infection.< ;/strong>
For a study a total, 177 healthcare workers were enrolled and all had tested positive for SARS-CoV-2 immunoglobulin g (IgG) and had declared COVID-19 symptoms within the last six months. Each participant was categorized based on the time of sampling from the last reported symptoms and severity of symptoms.
Besides the 177 participants, an additional 6 patients with lupus were also admitted to the study as a positive control for AABs.
A novel AAB array bearing 91 protein antigens was developed, allowing the group to quantify a variety of cytokines, lung-specific proteins, and other proteins known to interact with SARS-CoV-2. These antigens were in addition to a selection of AAB-antigens observed in systemic sclerosis and other similar inflammatory conditions.
Alarmingly of the 177 healthcare workers enrolled in the study, the presence of at least one AAB was detected in 160. On average, each had 5.2 reactive AABs in their sera, where 9% had none, 36% had 1-2, 29% had 3-6, and 25% had more than 6.

However when compared to healthy controls, this difference did not meet the threshold of statistical significance (5.2 AABs per person compared to 2.3). As expected, the participants with lupus exhibited much greater odds of bearing significantly more AABs with an average of 17.3 AABs.
It was found that age, sex, and timing of reported symptoms did not correlate with IgG levels in the participants.
Interestingly, the reactivity of IgG towards 12 of the 91 antigens included in the panel differed significantly from healthy controls. The identified antigens have previously been implicated in a number of immune-mediated inflammatory diseases, and also included organ-specific autoantibody targets in the thyroid and islet cells.
Importantly the prevalence of certain antibodies correlated with symptoms, finding that the presence of AABs against CHD3 was associated with skin changes.
Also the AABs against CHD3 were reported in 19% of those positive for these AABs, as compared to 5% without.
The study findings also found other correlations that include shortness of breath, where 56% of those with anti-SRP19 AABs reported the symptom as compared to 28% of those without. Additionally, diarrhea was present in 52% of those with anti-IFNA4 AABs and only 27% of those without. Interestingly, positivity for anti-INS AABs correlated with the early reporting of symptoms, but negatively with the development of fever.
Also increased reactivity to interferon and S100A8/S100A9 was also found amongst those with prior SARS-CoV-2 infection at a greater incidence than naïve individuals. Notably, S100A8/S100A9 is expressed by immune cells in response to environmental triggers and cellular damage.
It was noted that the presence of these cytokines was strongly associated with poor clinical outcomes in patients with severe pulmonary disease. Several other indicators of inflammation were also upregulated in those with prior COVID-19.
Past studies have already demonstrated that the immune response is disrupted and modulated by COVID-19, and that the generation of AABs occurs and may contribute significantly to severe disease states.
The study findings has further demonstrated that AABs associated with other autoimmune diseases may also be detected in those with a prior mild infection, which could be a precursor to underlying autoimmune disease as a direct result of COVID-19.
The presence of AABs may have no clinical significance for positive individuals; however, the researchers of the current study highlight the need for ongoing surveillance of AABs induced by COVID-19 in long-term studies.
Corresponding author, Dr Justyna Fert-Bober ,PhD from the Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center told Thailand Medical News, “Accordingly, males in our study had a greater than 1.5-fold odds of AABs reactivity after adjusting for age.

For classic autoimmune disease, clinical prevalence and incidence of autoimmune diseases tends to follow a male versus female pattern based on pathology. Male-predominant autoimmune diseases usually manifest clinically (i.e., show signs and symptoms of clinical disease) prior to age 50 and are characterized by acute inflammation and a Th1-type response, whereas autoimmune diseases with a greater incidence in females that occur early in life have a clearer antibody-mediated pathology.

Autoimmune diseases that have a greater incidence in females and also appear clinically later in life tend to present with evidence of chronic pathology, fibrosis, and increased numbers of autoantibodies are present.”
The study team concluded, “This comprehensive study of AABs to a wide array of antigens found that male sex carries the risk of diverse autoimmune activation following symptomatic COVID-19 illness, whereas female sex carries risk for a distinct profile of autoimmune activation following asymptomatic SARS-CoV-2 exposure.

Importantly, both sets of sex-specific AAB reactivity patterns were found to persist up to 6 months following associated symptomatology. Further understanding the nature of triggered and persistent AAB activation among individuals who are exposed to SARS-CoV-2 and vulnerable to its potentially morbid clinical sequelae will be essential for developing effective interventions and therapeutics.”

Impairment of health after overcoming the acute phase of COVID-19 is being observed more and more frequently. Here different symptoms of neurological and/or cardiological origin have been reported. With symptoms, which are very similar to the ones reported but are not caused by SARS-CoV-2, the occurrence of functionally active autoantibodies (fAABs) targeting G-protein coupled receptors (GPCR-fAABs) has been discussed to be involved.

We, therefore investigated, whether GPCR-fAABs are detectable in 31 patients suffering from different Long-COVID-19 symptoms after recovery from the acute phase of the disease.

The spectrum of symptoms was mostly of neurological origin (29/31 patients), including post-COVID-19 fatigue, alopecia, attention deficit, tremor and others. Combined neurological and cardiovascular disorders were reported in 17 of the 31 patients. Two recovered COVID-19 patients were free of follow-up symptoms. All 31 former COVID-19 patients had between 2 and 7 different GPCR-fAABs that acted as receptor agonists.

Some of those GPCR-fAABs activate their target receptors which cause a positive chronotropic effect in neonatal rat cardiomyocytes, the read-out in the test system for their detection (bioassay for GPCR-fAAB detection). Other GPCR-fAABs, in opposite, cause a negative chronotropic effect on those cells.

The positive chronotropic GPCR-fAABs identified in the blood of Long-COVID patients targeted the β2-adrenoceptor (β2-fAAB), the α1-adrenoceptor (α1-fAAB), the angiotensin II AT1-receptor (AT1-fAAB), and the nociceptin—like opioid receptor (NOC-fAAB).

The negative chronotropic GPCR-fAABs identified targeted the muscarinic M2-receptor (M2-fAAB), the MAS-receptor (MAS-fAAB), and the ETA-receptor (ETA-fAAB). It was analysed which of the extracellular receptor loops was targeted by the autoantibodies.

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