Fri. Jan 21st, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the current COVID-19 (Coronavirus Disease 2019) pandemic, has left public health systems worldwide broken.

Intensive efforts have been made internationally to develop prophylactic vaccines and neutralizing antibodies (NAbs) against the virus. However, there is limited information on the SARS-CoV-2 virus-induced B-cell immune response. Thus, understanding the principles of the B cell response to the virus is crucial for the development of antiviral vaccines and NAbs.

In a new study published in the journal Human immunology, researchers sought to better understand how the B-cell immune repertoire changes over time during SARS-CoV-2 infection by extensively characterizing the dynamics of the immunoglobin heavy chain (IGH) repertoire in COVID-19 patients.

Study: Landscapes and dynamic diversifications of B-cell receptor repertoires in COVID-19 patients.  Image credit: NIAID
Study: Landscapes and dynamic diversifications of B-cell receptor repertoires in COVID-19 patients. Image credit: NIAID

Background

B cell surfaces have immunoglobin molecules called B cell receptors (BCRs). They recognize and bind foreign antigens. B cells become activated, multiple and can differentiate into different cells when they meet their specific antigen. B cells can be differentiated into short-lived efficient antibody-secreting plasma cells or long-lived plasma and memory cells. Researchers have stated that analysis of BCR sequences is of great interest, as repertoires may have similar features by exposing individuals to the same pathogen, thereby giving rise to converging antibodies.

Recent developments in high-throughput sequencing have enabled the characterization of the IGH repertoire in a large number of samples. Researchers use these tools to gain insight into the humoral reactions of healthy individuals and a wide range of diseases. They are now able to understand how the antibody repertoire can change in response to disorders arising from a viral infection, viral development and vaccination. BCR repertoire analysis has been used in cases of various viruses (eg influenza virus, human immunodeficiency virus, etc.), but the dynamics of antibody response elicited by SARS-CoV-2 infection still need to be determined.

A new study

In the current study, researchers sought to understand how the B-cell immune repertoire changed over time during SARS-CoV-2 infection. For this purpose, IGH repertoires from the peripheral blood samples were collected several times from five COVID-19 patients (longitudinal data).

First, the sequences were classified into clones by lineage cluster analysis. The next step was to track the development of certain traits, such as the unique number of CDR3, Shannon index, the number of high frequency clones, cumulative frequency of the 100 best clones and V, J gene segment use. In addition to the above, researchers also performed clonotype overlap, line extension, and CDR3 sequence network structure. This was done to study the similar and dissimilar trends in IGH repertoire status over time.

Key findings

Researchers found that a period of 2-3 weeks after the onset of symptoms is of great importance for the B cells’ immune response. It was observed that each individual’s frequency of use of different V and J gene segments remained relatively stable over time, suggesting that the use of V, J segments may not be significantly altered by SARS-CoV-2 infection. The use of V-components showed a differentiated preference, which could mean that the human immune system is quite variable across individuals, but relatively stable over time within a given individual. This result is in line with a previous study showing that IGHV3-23 was highly represented in patients and healthy controls. Contrary to the above results, another reported that IGHV3-23 was overrepresented in patients compared to the control group. Researchers also documented that IGHV4-34 is used more frequently in COVID-19 patients compared to healthy donors.

Bulk BCR sequencing could be more suitable for BCR recycling rate assessment, and this is an advantage with large amounts of sequencing data. However, the current study treated only five patients; therefore, this small sample size could certainly limit the power of analysis.

The current study reported that the BCR repertoire composition of all patients for 2-3 weeks after onset was quite different than in other periods.

There were many more common clones and clear lineage expansion. In addition, it was observed that each patient’s average degree and diameter indicators peaked around the said time frame.

It should be noted that this 2-3 week timeline is consistent with an antigen-induced B-cell differentiation and maturation. Researchers believed that the above observations could be due to strong neutralizing antibody responses and a significant expansion of virus-specific B cell clones.

Collaboration between researchers from different countries has contributed to the advances in the development of COVID-19 therapy.

Research by the scientists in the current study revealed that there is a clear preference for sequence homology between clones and antibodies with neutralizing potential.

Clone expansion was observed early in one patient (the only severe case and at the age of 85 years). This led to the as yet untested hypothesis that the previous clone expansion may be correlated with the severity of clinical symptoms and the age of the patients being considered.

Conclusion

In this study, researchers provided a comprehensive B-cell deep immune profiling of COVID-19 patients.

The results of this research should help advance our understanding of the immune response in COVID-19 patients and provide the necessary basic knowledge for the development of new vaccines and nAbs.

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