Abstract
Although initial immunophenotypical studies on peripheral blood and bronchoalveolar lavage samples have provided a glimpse into the immunopathology of COVID-19, analyses of pulmonary draining lymph nodes are currently scarce. 22 lethal COVID-19 cases and 28 controls were enrolled in this study. Pulmonary draining lymph nodes (mediastinal, tracheal, peribronchial) were collected at autopsy. Control lymph nodes were selected from a range of histomorphological sequelae [unremarkable histology, infectious mononucleosis, follicular hyperplasia, non-SARS related HLH, extrafollicular plasmablast activation, non-SARS related diffuse alveolar damage (DAD), pneumonia]. Samples were mounted on a tissue microarray and underwent immunohistochemical staining for a selection of immunological markers and in-situ hybridization for Epstein Barr Virus (EBV) and SARS-CoV-2. Gene expression profiling was performed using the HTG EdgeSeq Immune Response Panel. Characteristic patterns of a dysregulated immune response were detected in COVID-19: 1. An accumulation of extrafollicular plasmablasts with a relative paucity or depletion of germinal centers. 2. Evidence of T-cell dysregulation demonstrated by immunohistochemical paucity of FOXP3+, Tbet+ and LEF1+ positive T-cells and a downregulation of key genes responsible for T-cell crosstalk, maturation and migration as well as a reactivation of herpes viruses in 6 COVID-19 lymph nodes (EBV, HSV). 3. Macrophage activation by a M2-polarized, CD163+ phenotype and increased incidence of hemophagocytic activity. 4. Microvascular dysfunction, evidenced by an upregulation of hemostatic (CD36, PROCR, VWF) and proangiogenic (FLT1, TEK) genes and an increase of fibrin microthrombi and CD105+ microvessels. Taken together, these findings imply widespread dysregulation of both innate and adoptive pathways with concordant microvascular dysfunction in severe COVID-19.
Highlights
The COVID-19 (Coronavirus Disease 2019) pandemic, caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), has rapidly evolved into the greatest public health crisis of the 21st century
As previously described in systematic histomorphological analyses on the same autopsy cohort [6], pulmonary draining lymph nodes of lethal COVID-19 displayed the following characteristics compared to controls: 1. vascular changes such as capillary stasis and edema and presence of fibrin microthrombi (6/19 vs. 0/14; p=0.027) (Figure 1A); 2. absence or paucity of germinal centers (16/21 vs. 4/14; p=0.013) (Figure 1B); 3. increased extrafollicular accumulation of plasmablasts (Figure 1C); 4. an overall increased presence of histiocytes with hemophagocytic activity (Figure 1D)
Our dataset comprises COVID-19 patients from the first wave (March-July 2020) in Switzerland during which the use of high dose dexamethasone, which could have potentially served as a confounder, was limited, potentially generating more robust evidence, and utilizes representative controls with a carefully selected spectrum of histological sequelae
Summary
The COVID-19 (Coronavirus Disease 2019) pandemic, caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), has rapidly evolved into the greatest public health crisis of the 21st century. Follicular hyperplasia, the histological correlate of an adequate immune response with immunologic memory, was rarely observed, replaced by an expansion of the abovementioned plasmablasts indicative of a transient humoral response in the absence of germinal center formation [8, 9]. Taken together, these features suggest extensive dysregulation in antigen presentation and B-cell activation and response in severe disease, both essential for the development of long-term immunity [10, 11]
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