In an exciting immunological medRxiv* preprint paper, researchers from Germany and Russia analyzed adaptive immune response in severely affected patients with coronavirus disease (COVID-19). They demonstrated a protracted immune reaction characterized by egress of B lymphocytes into the blood.
The global COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has thus far affected more than 27 million people. Consequently, there is an urgent need to explore how adaptive immunity is established in individuals most severely affected by the disease.
Patients infected with the original SARS virus in 2003 have shown the research community that complete restitution of the immune system may necessitate a relatively long period. Comparably, studying the immune system in convalescent COVID-19 patients may facilitate our understanding of the recovery process, disease severity, and adaptive immune responses.
This was the primary goal of a group of German and Russian researchers, led by Dr. Marta Ferreira-Gomes from the Institute of the Leibniz Association in Berlin, Germany. More specifically, they turned their investigative eye to patients recently admitted to the intensive care unit (ICU) with severe forms of COVID-19, as reflected by activated B cells escaping into the blood.
Fundamental and clinical methodological approach
"To analyze the adaptive immune response triggered by SARS-CoV-2 in severely affected COVID-19 patients, we initially focused on activated B lymphocytes of the peripheral blood, considering them as biosensors of the ongoing immune reaction and effectors of humoral immunity", study authors explain the crux of their methodological approach.
In a nutshell, they have established a clinical cohort of 11 COVID-19 ICU patients. Then they have analyzed samples from six patients within the first week following ICU admission (all except from one patient that was seronegative for the SARS-CoV-2 spike glycoprotein) and from 7 patients who had been in the ICU for more than a week (9 to 59 days) and were seropositive by IgG antibodies for SARS-CoV-2 spike glycoprotein.
The techniques used were rather complicated, which explains a large number of researchers on this paper. More specifically, B cells were enriched from peripheral blood with the use of specific microbeads; moreover, the isolation of SARS-CoV-2 reactive effector/memory and regulatory CD4+ T lymphocytes has been pursued, and single-cell suspensions were obtained by cell sorting.
A 'distracted' immune reaction
The results show that early on (i.e., before seroconversion as a response to SARS-CoV-2 spike glycoprotein) activated peripheral B cells exhibit a type 1 interferon-induced gene expression signature.
After seroconversion, things change rather drastically, as activated B cells lose this specific signature. Instead, they show gene expression signatures induced by interleukin-21 and transforming growth factor-beta (TGF-β), and mostly IgG1 and IgA1 antibody response.
In the preserved and unabating immune reaction found in COVID-19, patients previously activated peripheral B cells moved to the expression of antibody class IgA2 until day 59 – reflecting, in turn, the instrumental role of TGF-β that acts as a salient 'switching driver.'
However, notwithstanding the persistent generation of activated B cells, they were not found in the lungs of COVID-19 patients that have died, nor did the IgA2 antibody class bind to dominant antigens of SARS-CoV-2. In severe COVID-19, SARS-CoV-2 hence triggers a chronic immune reaction diverted from itself and primarily instructed by TGF-β.
Implications for further research
"We demonstrate here that severely affected COVID-19 patients which required prolonged ICU care show a continued immune reaction reflected by egress of activated B lymphocytes into the blood", concludes study authors.
However, while it is quite apparent that SARS-CoV-2 triggers the continued immune reaction of COVID-19 patients in the ICU, it is less clear whether they are also exclusively directed against this virus.
Furthermore, the specificities of the antibodies generated in such immune reactions of COVID-19 patients still need to be explained, as most of them are not specific for the spike glycoprotein, and primarily its receptor-binding domain or nucleocapsid protein.
Whether or not such antibodies found in ICU patients are harmless, or may eventually cause dangerous and harmful immunopathology remains to be seen. In the meantime, we can hypothesize that therapeutic targeting of TGF-β may be a way forward towards ameliorating severe COVID-19 – particularly its affinity towards inducing lung fibrosis.
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.