Researchers have measured the antibody levels and types in hospitalized coronavirus disease 2019 (COVID-19) patients with different disease severity. Their results suggest gut immune pathways could play a role in reducing virus-based inflammation and recovery.
COVID-19, the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), affects people differently. Some patients are asymptomatic, while in others, the disease can be fatal. However, the reasons for this diversity in symptoms are not yet fully understood. Studies suggest a person’s immune response to the virus could be important in determining how the disease progresses.
Infection of SARS-CoV-2 causes the immune system to produce neutralizing antibodies against the virus spike protein or the nucleocapsid protein. Higher levels of antibodies are seen in patients with severe disease symptoms, suggesting antibody response affects not only virus clearance but also immunopathology. Apart from their neutralizing properties, antibodies could also have properties that can lead to increased inflammation or antibody-dependent infection enhancement.
Of the four types of IgG antibodies, IgG1 and IgG3 are considered pro-inflammatory as they can initiate complement cascade and deliver powerful immune-activating signals. Characterizing the different types of antibodies can provide information on the immune response.
Antibody types differ with disease severity
To do that, researchers characterized serum antibodies to the spike protein and the nucleocapsid protein obtain from hospitalized COVID-19 patients with moderate to severe disease. They reported their results in a paper published on the medRxiv* preprint server.
The authors collected serum samples from 38 patients between March and May 2020, within 44 days of symptom onset. They characterized the types of antibodies by isotyping for IgG, IgA, and IgM and subtyping into IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2 using ELISA.
They found higher amounts of receptor-binding domain (RBD) antibody classes and subclasses in the COVID-19 patients than pre-pandemic control samples. The majority of patients had predominantly IgG1 and IgG3 subclasses. RBD-specific IgA response included IgA1 and IgA2 subclasses. In the nucleocapsid-specific antibodies, they found IgG1 and IgG3 in a majority of the patients.
Next, the authors grouped the patients based on antibody titers to RBD and nucleocapsid protein, along with patient demographic data. They found that RBD-specific IgA antibodies clustered together with non-inflammatory RBD-specific IgG2 and IgG4 antibodies and away from nucleocapsid protein-specific antibodies clustered with RBD-specific IgG1, IgG3, and IgM.
They found four clusters of COVID-19 patients when clustering according to antibody levels. Patients in the early stage of infection had RBD-specific IgA and low RBD-specific IgG1 and IgG3. The next cluster of patients with moderate disease showed low or no RBD-specific IgG1 and IgG3 antibodies. Patients with more severe disease had sustained RBD-specific IgG responses. Patients with severe infection had IgG response to both RBD and nucleocapsid protein along with IgA antibodies.
Possible of gut immune system
Further analysis of the results revealed that larger levels of RBD-specific IgG1, and to a lesser extent IgG3 levels, are associated with higher disease severity. The authors used machine learning modeling to find the minimum number of variables that could differentiate patients based on disease severity. They found RBD-specific IgG levels to determine disease severity. IgG2 and IgG4 subclasses were not associated with disease severity. They also found the IgA response, seen mainly in patients with gastrointestinal symptoms, was associated with good clinical outcomes.
Previous studies have reported higher SARS-CoV-2 neutralizing antibody levels in hospitalized patients. The higher IgG1 and IgG3 levels seen in severe disease could likely be because they can worsen inflammation during advanced infection stages. The authors found that these antibodies also correlated with serum LDH and ferritin, which are biomarkers for inflammation. Antibodies to nucleocapsid protein do not correlate with disease severity, but the reasons for this are not clear yet.
Apart from the IgG antibodies, the authors also detected RBD-specific and nucleocapsid protein-specific IgA and IgM antibodies. However, there was no correlation between IgA1 and IgM and disease severity or inflammation biomarkers. IgA1 is found in both the intestines and respiratory tract, while IgA2 is found mainly in the intestines. The observations of IgA2 in some COVID-19 patients suggest a gut immune response.
Recent observations show gastrointestinal symptoms of COVID-19 have favorable clinical outcomes and increased survival. The authors also found a negative correlation between RBD-specific IgA2 titers and days of hospitalization. These results suggest gut immunity can reduce COVID-19 disease severity and improves recovery. Because there is considerable interaction between the gut and respiratory mucus membranes, gut immune responses could reduce lung inflammation in COVID-19 patients. However, this hypothesis needs to be validated further.
medRxiv 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.