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Authors: Matthew C. Woodruff et al., (2000)

Link to paper: https://www.medrxiv.org/content/10.1101/2020.04.29.20083717v1.full.pdf

Journal/ Pre-Print: medRxiv

Tags: Cell Biology (B cells), Clinical/Diagnostics, Immunology/Immunity

Research Highlights

1. The authors identify antibody-secreting cell (ASC) expansion in peripheral blood of 17/17 Covid-19 patients relative to 22 controls. ICU-admitted patients presented with significantly more ASCs than outpatient counterparts.

2. Critical COVID-19 patients’ circulating B cells clustered into two groups, the first with upregulated extrafollicular response pathway (EF-Cov), and the second with muted EF response but enhanced transitional B cell signal (Tr-COV), similar to what is seen in SLE patients.

3. Low frequency of transitional B cells and a high number of double negative (DN2) B cells across patients correlated inversely with plasma C-reactive protein (CRP) levels.

Summary

In this study, the authors set out to understand the B cell responses associated with the extra follicular (EF) pathway in SARS-Cov-2 patients. They observed an increased frequency of ASCs in the blood of EF-Cov cohort, which did not appear to correlate with protective immunity and in fact associated with poorer clinical prognosis. The authors did not assess whether the ASC produced neutralising antibodies, affecting the significance of previous finding. Expansion of transitional B cell subsets associates with better clinical prognosis. The EF-Cov cohort have similar double negative 2 B cell compartments akin to that of patients with systemic lupus erythematosus (SLE). The finding that EF-Cov cohort upregulated EF response and lose Tr B cell response correlating with poor poorer prognosis is weakened by the fact that healthy controls are not matched to the patients in regard to their pre-existing comorbidities.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19

Clinical symptoms and pathogenesis of SARS-Cov2/COVID19

Develop diagnostic tools for SARS-CoV2/COVID19

Study Type

· Patient Case study

· In vitro study

Strengths and limitations of the paper

Novelty: The prevalence of ASC expansion in Covid-19 patients’ PBMC may not correlate with protective immunity.

Upregulated extrafollicular B cell response and diminished transitional B cells observed in critical cases of COVID-19 is comparable to the B cell response observed in SLE.

Standing in the field: Double negative B cells are reported in the literature, further subsets of these cells are not well characterised outside of SLE.

Appropriate statistics: Overall appropriate, although not always present for comparison between all groups (ie. Fig 2d-f). There are no statistics for Figure 4b-f to support claim that EF pathway activation predicts poor disease outcomes.

Viral model used: N/A

Translatability: Potential for translation: loss of translational B cells may serve as a biomarker for poor prognosis, however the patient numbers are currently too low to support clinical translation.

Main limitations:

- The authors do not acknowledge in their interpretations the comorbidities and antibiotic/antiviral therapies listed within the “EF-COV” group compared to the “T-COV” group. For example, some patients in the EF-COV cohort also presented with diabetes, chronic renal failure, coronary disease, etc., which may affect the interpretation that this patient cluster associates tightly with biomarkers of poor outcomes and exhibits high rates of mortality.

- Figure 2c. The authors do not disclose at which time point patient blood was collected prior to the assessment of CD19+ ASC for vaccinated patients (flu, hepatitis, tetanus) or if they reported symptoms – this makes the comparison to EF-COV and T-COV unclear.

- The authors don’t always present full gating strategies for their flow cytometry. For example, it would have been helpful to see CD19 gating when analysing CD138+ ASCs (which have been shown to be CD19 low as well). Mis-labelled plot Figure 3i – no frequencies are displayed (gating strategy is needed here).

- DN1 subset appears to have a memory B cell chemokine phenotype, which could be addressed by the authors.

- Constrained by trial size of 17 Covid-19 patients.