Lymphatic coagulation and neutrophil extracellular traps in lung-draining lymph nodes of COVID-19 decedents

淋巴系统 淋巴 淋巴结 中性粒细胞胞外陷阱 纤维蛋白 医学 病理 髓过氧化物酶 免疫学 生发中心 淋巴管内皮 血栓调节蛋白 淋巴管 抗体 炎症 癌症 血小板 内科学 凝血酶 B细胞 转移
作者
Margo MacDonald,Rachel Weathered,Emma C Stewart,Alexandra I. Magold,Anish Mukherjee,Sandeep Gurbuxani,Heather Smith,Phillip McMullen,Jeffrey Mueller,Aliya N. Husain,Calixto Mateos Salles,Priscilla S. Briquez,Sherin J. Rouhani,Jovian Yu,Jonathan Trujillo,Athalia R. Pyzer,Thomas F. Gajewski,Anne I. Sperling,Witold W. Kilarski,Melody A. Swartz
出处
期刊:Blood Advances [American Society of Hematology]
卷期号:6 (24): 6249-6262 被引量:5
标识
DOI:10.1182/bloodadvances.2022007798
摘要

Abstract Clinical manifestations of severe COVID-19 include coagulopathies that are exacerbated by the formation of neutrophil extracellular traps (NETs). Here, we report that pulmonary lymphatic vessels, which traffic neutrophils and other immune cells to the lung-draining lymph node (LDLN), can also be blocked by fibrin clots in severe COVID-19. Immunostained tissue sections from COVID-19 decedents revealed widespread lymphatic clotting not only in the lung but also in the LDLN, where the extent of clotting correlated with the presence of abnormal, regressed, or missing germinal centers (GCs). It strongly correlated with the presence of intralymphatic NETs. In mice, tumor necrosis factor α induced intralymphatic fibrin clots; this could be inhibited by DNase I, which degrades NETs. In vitro, TNF-α induced lymphatic endothelial cell upregulation of ICAM-1 and CXCL8, among other neutrophil-recruiting factors, as well as thrombomodulin downregulation; in decedents, lymphatic clotting in LDLNs. In a separate cohort of hospitalized patients, serum levels of Myeloperoxidase-DNA (MPO-DNA, a NET marker) inversely correlated with antiviral antibody titers, but D-dimer levels, indicative of blood thrombosis, did not correlate with either. Patients with high MPO-DNA but low D-dimer levels generated poor antiviral antibody titers. This study introduces lymphatic coagulation in lungs and LDLNs as a clinical manifestation of severe COVID-19 and suggests the involvement of NETosis of lymphatic-trafficking neutrophils. It further suggests that lymphatic clotting may correlate with impaired formation or maintenance of GCs necessary for robust antiviral antibody responses, although further studies are needed to determine whether and how lymphatic coagulation affects adaptive immune responses.
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