The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, the subsequent pandemic, and the continuous emergence of novel variants continues to make coronavirus disease 2019 (COVID-19) a matter of global public health concern.
There is an imminent need to understand how the human body responds to novel infections and this has been highlighted by the recent outbreak episodes of SARS, MERS, Zika, and Ebola. This knowledge will help develop better treatments and control the emergence and spread of novel viruses.
In the context of the current pandemic, initial studies involving serum antibody titers, showed that while total antibody titers decrease, SARS-CoV-2-specific memory responses were persistently present. This mitigates concerns over the nature and duration of B cell memory.
B cell response and repertoire analysis
Immunoglobulins (Ig) have huge variability in antigen binding, owing to which they can mediate immunity against multiple pathogens, both as secreted antibodies and as B Cell Receptors (BCRs). The variability is brought about by V-D-J recombination. Upon a specific challenge, B cells with Ig genes encoding disease-specific antibodies are expanded. This causes the skewing of the repertoire to make greater use of the antigen-specific genes corresponding to the challenge.
The terminal deoxynucleotidyl transferase (TdT) and the imprecise joining of gene segments give rise to a highly diverse complementarity determining region (CDR) region. This region is essential for antigen binding, and can be used to identify “clones” of B cells within a repertoire. Thus repertoire analysis can help scientists identify changes in the memory/effector B cells compartments and characterize genes that may have use in antibody therapeutics.
A new study
A new study has been published on the bioRxiv* preprint server, which takes a long-read repertoire amplification approach to better understand, compare and contrast B cell responses to emerging or endemic viruses.
Samples were obtained from COVID-19 patients during and after infection, Ebola virus disease (EBOV) survivors from West Africa and the UK, and volunteers challenged with respiratory syncytial virus. The samples were compared with samples from healthy donors. In this study, scientists documented the variation in repertoire across disease states and paid special attention to the elderly, who are known to be more vulnerable to infection.
The team found a general increase of IGHV4-39 use of the repertoire of COVID-19 and Ebola. They explained that there are possibly unannotated IGHV4-39 SARS-CoV-2 binders and that one cluster does not explain the larger expansion in IGHV4-39 across the COVID-19 and Ebola repertoires.
IGHV4-39 may be promiscuously binding to self-proteins or may be supporting a wide array of specific binding properties. Among all the sequence clusters considered, 14 were dominated by COVID-19/COVID-19 recovered sequences and only 5 matched known binders. This led scientists to conclude that there were previously unknown SARS-CoV-2 specific binders present.
Previous studies have shown that T-independent activation is driven by CD40-independent TLR/TACl activation. In the current study, scientists observed early switching to IgG1 without extensive hypermutation. The COVID-19 IgA1 sequences also indicated a lower level of hypermutation than the control group, and the diversity analyses showed expansion of unmutated IgM clones.
The CDRH3 region maturation of IgG1 and IgG3 genes in the COVID-19 patients were less removed from the IgM state than healthy IgG1 and IgG3 or any other class-switched repertoires. In the case of COVID-19, the picture was of an early immature response of IgM switching first to IgG1 and then to IgA1.
Previous research has shown that healthy older people generally have more antibodies capable of binding self-proteins. Scientists observed a higher frequency of known spike binders clustering with COVID-19 repertoires in the younger cohort. The increased use of IGHV3-30 was only seen in older COVID-19 patients and that of IGHV4-39 only in the younger group.
In the Ebola data, even 2-3 months after recovery with negative PCR tests, there were abnormally high proportions of class-switched clones with little or no direction towards a particular sub-class. Scientists opine that this could be unique to Ebola infection. It was also observed that the Ebola survivor’s memory B cell populations were more diverse than the control group.
In this study, the scientists have shown that while the specifics of B cell responses are unique to a particular infection, the human immunoglobulin gene repertoire can have similar responses across two or more different diseases. More research is needed to understand the balance of beneficial versus bystander responses in acute inflammatory diseases. The fact that genes, such as IGHV4-39, appear in two completely different diseases lends credence to the hypotheses that the emergency humoral immune response to challenge can evade normal regulation. This may, subsequently, allow the production of autoimmune antibodies.
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.