Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis

Abstract

It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117⁺ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.

Keywords: COVID 19; SARS-CoV-2; cell-mediated immunity; immune responses; interleukin-4 (IL-4); mast cells (MC).

Figure 1

Graphs demonstrate the IL-4 tissue expression (percentage per HPF), the number of MCs (TB), and the number of CD117⁺ cells (IHQ) in the alveolar septa of the COVID-19 group compared to the H1N1 and Control groups. Non-parametric Kruskal Wallis test. Values of p < 0.05 indicated statistical significance. Histological section (H&E—A) shows evidence of microvascular involvement through endothelial activation (black arrow) and increased vascular permeability manifested by the formation of perivascular edema (asterisk). (B) (TB) shows thrombosis (asterisk) and perivascular MC (black arrow). (C,D) (TB) show evidence of degranulating (C—black arrow) and intact MCs (D—black arrows) and in the alveolar septa and perivascular spaces, in patients of COVID-19 (C), H1N1 (D—upper) and Control (D—under) groups. (E) Of the COVID-19 group sample shows the massive presence of CD117⁺ nucleated cells (black arrows) compared to photomicrograph (F) of the H1N1 group sample (black arrow). Scale bar −50 μm. Scanned by the Axio Scan Scanner. Z1 (Carl Zeiss, Germany) with 40× (A–D) and 20× (E,F) objectives.