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Authors:Yi-Lin Chiu et al.   

Journal/ Pre-Print:Research Square 

TagsBioinformaticsClinicalImmunology/Immunity 

Research Highlights

  1. Naïve B cell infiltration is increased in deceased COVID-19 patient lung tissue biopsies relative to idiopathic pulmonary fibrosis (IPF) donors and healthy controls 

  1. Plasma cells, CD8+ T cells, CD4+ naïve and activated memory T cells are also increased in COVID-19 donor tissue relative to healthy controls, similar to the response seen in IPF patients.   

  1. Pathway enrichment analysis suggests IL-12 and IL-4 signalling and LFA-1 and α4β1 integrin signalling is increased during severe COVID-19 disease.   

Summary  

The study takes a novel approach towards assessing immune cell infiltration in the lung within COVID-19 patients.  They perform an in-silico gene expression analysis of biopsy and pulmonary tissue sample from 16 deceased COVID-19 patients, against healthy controls and idiopathic pulmonary fibrosis (IPF) patients.  They observe that deceased COVID-19 donors demonstrate increased infiltration of CD8+ T cells, naïve B cells, plasma cells, monocytes and type I activated macrophages within their pulmonary tissues relative to healthy controls.  The infiltration of naïve B cells and lack of memory B cells within the lung was unique to deceased COVID-19 patients and distinguished them from IPF samples.  The authors suggest this may be a result of increased naïve B cell retention in the lung through activation of LFA-1 and α4β1 integrins. However, experimental approaches are needed to support this hypothesis. Moreover, since no difference was noted in the level of plasma cells in the lungs of COVID-19 and IPF patients, the mechanism by which naïve B cells, which do not secret antibodies, may contribute to disease progression is not clear.   

Impact for SARS-CoV2/COVID19 research efforts  

Understand the immune response to SARS-CoV2/COVID19: pathway enrichment analysis suggests Fc receptor and IFN-y signalling in deceased COVID-19 patients. 

Treatment of SARS-CoV2/COVID19 positive individuals: the authors propose that inhibition of naïve B cell proliferation and migration may help to reduce the risk of lung damage after SARS-CoV–2 infection (but requires experimental validation).  

Study Type  

  • Patient Case study (bioinformatic)

Strengths and limitations of the paper 

Novelty: The authors provide a novel way of assessing cellular infiltration into pulmonary tissue other than through BAL and PBMC analysis, granting very useful insight into the immune response in severe COVID-19 patients.   

Standing in the field:Additional studies have shown naïve B cells to infiltrate the BALF of COVID-19 patients, however this was suggested to be due to vascular leakage as a result of damage to the architecture of the alveoli during severe infection (not active retention of naïve B cells). 

The authors hypothesize that naïve B cells do not class switch and produce predominantly IgM, however COVID-19 literature reports that the acute and early humoral response is dominated by IgA and IgG with IgG being the predominant isotype found in BAL sample from individuals with severe disease. 

Appropriate statistics: The statistics are described, however some comparisons “between” COVID-19 and IPF samples are not made (ieFigure 2/6). FDR of <0.25 was selected cut off for gene set enrichment analysis which is a much higher false discovery rate than typically used for statistical analysis. While FDR <25% is acceptable for GSEA a more stringent cut-off of 5% is recommended for small numbers of samples and FDRs of <0.01 or <0.05 are more commonly used in reporting of GSEA. 

Viral model used:N/A 

Translatability:Limited – inhibition of naïve B cell proliferation as a treatment for COVID-19 is proposed. However, further experimental support is needed before translation.   

Main limitations:  

  • The authors suggest that infiltration of naïve B cells to the lungs of COVID-19 patients may in itself contribute to disease by leading to increase in local IgM concentrations. However, naïve B cells do not secret antibodies and since the plasma cells levels were not increased in these patients, the relevance of the mechanism suggested is not clear. 

  • The choice of IPF as a reference condition as opposed to a disease-causing lung fibrosis is not justified. IPF and COVID-19 have very different aetiologiesso it is not surprising that there are differences in cell infiltration and signalling gene expression profiles in the lung tissue between these conditions It would be useful to spend more time proposing alternative suggestions for the significance of these differences (i.e. is a longer accumulation time responsible for memory B cell development during IPF the reason for observed differences?) 

  • The presence of naïve B cells and monocytes in lung tissue of COVID-19 could also represent damage to the alveoli and vascular leakage, not necessarily naïve B cell retention. 

  • We don’t know if the controls are age-matched or assessed for comorbidities. 

  • For the enrichment maps – it would be nice to visualise the healthy donors as a control as well. 

  • The figure numbers are mismatched, and the figures are in reverse order.