NET Formation in Systemic Lupus Erythematosus: Changes during the COVID-19 Pandemic

Abstract

The severity of the coronavirus disease in 2019 (COVID-19) is strongly linked to a dysregulated immune response. This fuels the fear of severe disease in patients with autoimmune disorders continuously using immunosuppressive/immunomodulating medications. One complication of COVID-19 is thromboembolism caused by intravascular aggregates of neutrophil extracellular traps (NETs) occluding the affected vessels. Like COVID-19, systemic lupus erythematosus (SLE) is characterized by, amongst others, an increased risk of thromboembolism. An imbalance between NET formation and clearance is suggested to play a prominent role in exacerbating autoimmunity and disease severity. Serologic evidence of exposure to SARS-CoV-2 has a minor impact on the SLE course in a Swedish cohort reportedly. Herein, we assessed NET formation in patients from this cohort by neutrophil elastase (NE) activity and the presence of cell-free DNA, MPO-DNA, and NE-DNA complexes and correlated the findings to the clinical parameters. The presence of NE-DNA complexes and NE activity differed significantly in pre-pandemic versus pandemic serum samples. The latter correlated significantly with the hemoglobin concentration, blood cell counts, and complement protein 3 and 4 levels in the pre-pandemic but only with the leukocyte count and neutrophil levels in the pandemic serum samples. Taken together, our data suggest a change, especially in the NE activity independent of exposure to SARS-CoV-2.

The prevalence of neutropenia and association with infections in patients with systemic lupus erythematosus: a Swedish single-center study conducted over 14 years

“…Impaired handling of apoptotic cells with exposure of modified self-antigens from dying cells, including NETs in a proinflammatory environment, affects immune tolerance with subsequent development of autoimmunity and deterioration of already established autoimmune disease [29,48]. Exposure to the immune system of otherwise hidden molecules, such as DNA and nuclear constituents, logically represents a starting step for autoimmunity, and in SLE and antiphospholipid syndrome (APS), a functional neutrophil is important for preventing loss of tolerance via immune regulation and clearance [41,[49][50][51]. In support of this, NETs have been shown to contribute to inflammation and tissue damage in a number of other organs in patients with SLE, such as the brain, heart, and lung [52][53][54].…”

Internalisation of neutrophils extracellular traps by macrophages aggravate rheumatoid arthritis via Rab5a

“…This is possible because the NETs-DNA can be recognised with macrophage surface receptors like Toll-like receptors and thus cause NFκB activation. 39 Other studies also suggest that NETs-DNA could aggravate inflammation in various diseases via cGas-sting or ERK/ JNK mitogen-activated protein kinase pathways. 37 38 40 Moreover, proteins in NETs can be post-translational modified to alter structure, which leading more potential immune responses.…”

Formation and Clearance of NETs in Health and Disease

“…Interestingly, the levels of SARS-CoV-2 immunoglobulin G antibodies were similar in all patient groups, whereas SARS-CoV-2 IgA2 antibodies were restricted to patients in the intensive care unit and correlated with CRP and ecDNA levels. In the second paper, Knopf et al investigated changes in NET formation during the COVID-19 pandemic in a well-characterized Swedish cohort of patients with Systemic Lupus Erythematosus (SLE) [ 9 ]. COVID-19 and SLE are characterized, amongst others, by dysregulated type I interferon responses, an increased risk for thromboembolism, the robust activation of the complement system, and an imbalance in NET formation and clearance.…”