Antibody-Fc-mediated innate immunity shapes COVID-19 severity

The pandemic of coronavirus disease 2019 (COVID-19) has plagued the world for over a year now. In most cases, infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes asymptomatic or very mild disease. However, in a significant minority, the infection results in severe or even critical disease. A short paper that appeared recently on the preprint bioRxiv* server pointed to a link between specific characteristics of anti-SARS-CoV-2 antibodies associated with the severity of COVID-19.

Non-neutralizing functions of specific antibodies

Severe COVID-19 is associated with hyper-inflammation and increased activation of the complement system. Neutralizing antibodies targeting the virus are also found at higher titers in severe disease. However, it is already known that antibodies play other roles than the neutralization of pathogens.

For instance, antibodies can cause many actions via their Fc portion. These include antibody-dependent complement deposition (ADCD), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). In all these cases, antibody binding triggers other pathways of immune activation, leading to the destruction of the antibody-bound target cells or particles.

On the other hand, these innate immune functions mediated by Fc binding can also promote hyperintense inflammation, leading to systemic damage.

Exploring qualitative differences in specific antibodies

The current study aimed to explore the possibility that specific anti-SARS-CoV-2 antibodies have distinct features that influence disease severity. The researchers looked at immunoglobulin G (IgG) antibodies targeting the S1 subunit of the spike protein and the receptor-binding domain (RBD).

These were isolated from 40 COVID-19 patients with disease severe enough to be hospitalized, as well as 20 patients with less severe disease. There were also 20 control patients. The median age of the group was 52.5 to 58.5 years, with 45–60% female. All samples were collected at the time of admission.

Higher ADCD, lower ADCP and ADCC in severe COVID-19

The researchers found that IgG from hospitalized COVID-19 patients produced substantially higher ADCD when directed against S1- and RBD-coated target cells when compared to IgG from non-hospitalized individuals. On the other hand, ADCP activity was higher with IgG from non-hospitalized COVID-19 patients compared to hospitalized patients. In fact, the most significant activity was seen in the non-COVID-19 group.

NK cell degranulation and intracellular cytokine production are effects that accompany and can be used to measure ADCC. These were found to be higher when cells were exposed to anti-S1 antibodies from hospitalized patients than from non-hospitalized patients. The reverse effect was seen with anti-RBD antibodies, which showed higher activity when retrieved from non-hospitalized patients compared to those from patients with more severe COVID-19.

This seems to indicate that severe COVID-19 is accompanied by specific antibodies with distinctive actions. One of the most critical differences is higher complement deposition and lower phagocytosis in response to antibodies found in hospitalized COVID-19 patients. This finding correlates well with earlier research showing that complement activation is associated with a worse outcome in COVID-19.

Higher antibody titers correlate with ADCP

The researchers then compared the titers of antibodies in hospitalized vs. non-hospitalized patients. They found that both anti-S1 and anti-RBD antibodies were similar in titer in both groups of patients. However, when the ADCD, ADCP, and ADCC activity was compared with the titers of specific antibodies, they found that patients with higher ADCP activity had higher S1 and RBD antibody titers, corresponding to more severe disease.

This still leaves the difference in ADCC and ADCD activity independent of antibody titer. This suggests that the antibodies in hospitalized patients are qualitatively different from those in non-hospitalized patients, rather than simply being higher in titer.

ADCD associated with greater inflammation

The researchers also found that higher ADCD in response to anti-S1 and anti-RBD antibodies was linked to higher levels of inflammatory markers and immune activation markers. On the other hand, ADCP associated with these antibodies was associated with lower inflammatory activity. ADCC activity in response to anti-S1 antibodies was negatively linked with inflammation, while with anti-RBD antibodies, it was linked to increased inflammation. This supports the deleterious effects of ADCD in the disease process.

Implications and future directions

The study points to the need to examine other antibodies in COVID-19, notably anti-nucleocapsid (N) IgG, IgM and IgA, and the underlying mechanisms. For instance, Fc-linked immune functionalities are known to be modulated by glycosylation as well as by antibody subclass. Strikingly, COVID-19 is associated with increased glycosylation of IgGs. The role played by glycosylation on antibody-mediated innate immunity needs to be clarified.

Further research must use larger patient cohorts from a wider geographic setting and a larger span of demographic characteristics. The effect of specific antibody properties on the functioning of natural, vaccine-induced, and therapeutic antibodies is an important area of study given the need to balance potent neutralization with innate immune functions without causing antibody-dependent adverse effects.

*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.

Journal reference:
Dr. Liji Thomas

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.


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