Juvenile inflammatory rheumatic disease associated with higher antibody responses to seasonal coronaviruses

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen behind the current coronavirus disease 2019 (COVID-19) pandemic is a coronavirus of the betacoronavirus family. However, there are other human seasonal coronaviruses that cause endemic human infection, with mild common cold symptoms. The spectrum of SARS-CoV-2 infection also ranges from mild symptoms like a runny nose, nasal congestion or mild fever, to severe gastrointestinal or respiratory disease, sometimes terminating in multi-organ failure.

SARS-CoV-2 vs HCoV-OC43 infection

The complications of COVID-19 are observed in less than a tenth of patients, with risk factors for these including male sex, advanced age, ethnic background, lack of healthcare access, and pre-existing conditions. The majority of infections are asymptomatic.

Children are more likely to be asymptomatic. In contrast, they are at higher risk of harboring one of the seasonal human coronaviruses (HCoVs) and are more likely to have pre-existing antibodies and memory B cells.

Children have also been found to develop the multisystem inflammatory syndrome (MIS), thought to be a little-understood inflammatory complication reflecting the dysregulation of the antibody response following COVID-19.

Risk of COVID-19 in juvenile inflammatory conditions

Children with inflammatory rheumatic disorders, such as juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE), were thought to be at high risk of COVID-19 because of uncontrolled antibody and inflammatory responses, as well as the fact that they were often on immunosuppressive treatment. However, specific information was lacking.

A new study released on the bioRxiv* server compared the antibodies produced in young patients with these three conditions against the two immunodominant coronavirus antigens, the spike and the nucleocapsid antigens. The researchers chose to study patients with infection to one of the seasonal HCoVs, HCoV-OC43, which is quite common in this group, where SARS-CoV-2 infections are rare due to shielding.

The underlying premise is that HCoV-OC43 can elicit not only antibodies specific to its antigens, but also cross-reactive antibodies to SARS-CoV-2. The study aims to understand this antibody response as a proxy for the humoral response against coronavirus infections, in general.

It is thought that the currently circulating SARS-CoV-2 virus will likely become an endemic infection, similar to current HCoVs. In fact, HCoV-OC43 has a history of mutations that suggests it recently jumped the species barrier to infect humans. In that case, it would indicate the possibility that this virus did initially cause a major epidemic.

For this reason, the current study could help uncover the response to SARS-CoV-2 as well when this becomes endemic.

Antibody responses to HCoV-OC43 spike

The study shows that IgG was the primary antibody response to the spike antigen, making up almost 70% and 60% of all antibodies to HCoV-OC43 and SARS-CoV-2, respectively. The remainder was made up of IgM antibodies, with IgA being the least abundant.

Most healthy children and adolescents had IgGs to the HCoV-OC43 spike, but the proportion with detectable SARS-CoV-2 spike antibodies was small, and the titer was much lower. The same profile was found in patients with JIA, JDM and JSLE.

However, the proportion of JDM and JSLE patients with IgGs against HCoV-OC43 spike was much higher than controls. JSLE patients also had a higher prevalence of IgGs against SARS-CoV-2 spike compared to healthy controls.

After classifying JSLE by age into those 1-12 years old and 13-18 years, the researchers found that younger patients with JIA and JDM had higher anti-HCoV-OC43 spike IgGs relative to older patients and controls. Even though patients with JSLE were typically older than pediatric patients with the other two conditions, they also had higher total and IgG anti- HCoV-OC43 spike antibodies.

IgA anti- HCoV-OC43 spike antibodies increased in all JSLE patients and the older JIA patients.

Antibodies against SARS-CoV-2 spike

All three classes of patients showed antibodies to the SARS-CoV-2 spike, though the titer was lower and the correlation with HCoV-OC43 spike antibodies low. JSLE patients, and younger patients with JIA, had higher IgG titers against the SARS-CoV-2 spike. Older JIA patients had below average anti-SARS-CoV-2 antibody titers.

After adjusting for the female sex, older age, steroid use and the year of collection, HCoV-OC43 spike antibodies were still higher in JSLE patients, and IgG HCoV-OC43 spike in younger patients with any of the three conditions.

Females and those on steroids had higher antibody titers. Steroid use may indicate more severe rheumatic disease but may also indicate immune dysregulation, especially in patients with JSLE.

After adjusting for confounding factors, total antibodies to SARS-CoV-2 spike were lower in JDM, but IgG levels were higher in JSLE patients. Both total and IgG SARS-CoV-2 spike antibodies were higher in younger patients and those who had autoantibodies.

Association with autoantibodies

The association between SARS-CoV-2 spike and HCoV-OC43 spike antibodies, with the presence of autoantibodies, gains significance when the presence of a comparable association between these spike antibodies and antibodies to HERV-encoded envelope glycoproteins, also essentially autoantibodies, is taken into account. This could indicate that the higher spike antibody levels in these patients reflect a fundamental overactivity of adaptive immunity.

Neutralizing titers were similar for all three conditions when assessed in most sera with cross-reactive SARS-CoV-2 IgGs. Neutralizing capacity bore a weak relation to antibodies to the SARS-CoV-2 spike but not IgGs against the HCoV-OC43 spike.

“Our findings suggest that inflammatory rheumatic diseases do not impede humoral immunity to a seasonal HCoV in this age group and may even enhance it.”

Coronavirus nucleoproteins stimulate mostly IgM responses

Younger patients with any of these conditions had higher IgG responses to the spike protein, which could be the result of exaggerated immune responses or a higher viral load because of immunosuppressive therapy. To explore this, the researchers measured antibodies to the nucleoprotein (N), which typically does not produce neutralizing antibodies. This would therefore provide a clearer idea of viral replication.

They found that most anti-N antibodies belonged to the IgM subclass, at 82% and 67% of total antibodies to the HCoV-OC43 and SARS-CoV-2 N proteins, respectively. In contrast, healthy adult controls produced both IgG (30%) and IgM (62%) antibodies to the HCoV-OC43 N protein.

Healthy pediatric controls, conversely, produced only 9% IgG, but 85% IgM to the HCoV-OC43 N protein. This shows that the coronavirus N protein stimulates an IgM-dominated response with a slow class-switching to IgG with increasing age.

In younger patients with JDM and JIA, both total and IgM antibodies to the N protein were reduced.

These findings show the difference in the antibody response in younger patients exposed to the coronavirus spike and N protein. The two are not correlated strongly. This could mean that either could be immunodominant in each individual patient.

However, with all disease groups, spike antibodies were at a higher ratio to N antibodies, irrespective of the virus tested (HCoV-OC43 or SARS-CoV-2). This was more likely with females and steroid treatment but less with old age. This indicated lower viral exposure and less risk of an adverse outcome.

What are the implications?

This study looks at the differences in the antibody response to coronaviruses in adults and children and the impact of underlying immunosuppression. The researchers found that in younger patients with JIA, JDM and JSLE, the antibody responses were similar or stronger than in healthy controls.

With HCoV-OC43 spike, IgGs were dominant, but there were also cross-reactive IgGs against SARS-CoV-2. However, antibody production against these two virus nucleoproteins showed a slow class-switching that occurred with age, and was not elevated from the baseline in patients with these conditions.

This indicates that the reason for the higher antibody response in these patients was not increased exposure. The outcome was a favorable ratio of spike to nucleoprotein antibodies.

If the response to SARS-CoV-2 or vaccination can be inferred from the response to HCoV-OC-43, together with the presence of pre-existing cross-reactive antibodies to SARS-CoV-2, the data suggest that pediatric and adolescent patients with the most common inflammatory rheumatic diseases would mount a highly effective humoral response against SARS-CoV-2 infection or vaccination.”

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.