Neutrophils—Important Communicators in Systemic Lupus Erythematosus and Antiphospholipid Syndrome

Abstract

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are two autoimmune diseases that can occur together or separately. Insights into the pathogenesis have revealed similarities, such as development of autoantibodies targeting subcellular antigens as well as a shared increased risk of cardiovascular morbidity, potentially due to mutual pathologic mechanisms. In this review, we will address the evidence implicating neutrophils in the pathogenesis of these conditions, highlighting their shared features. The neutrophil is the most abundant leukocyte, recognized for its role in infectious and inflammatory diseases, but dysregulation of neutrophil effector functions, including phagocytosis, oxidative burst and formation of neutrophil extracellular traps (NETs) may also contribute to an autoimmune process. The phenotype of neutrophils in SLE and APS differs from neutrophils of healthy individuals, where neutrophils in SLE and APS are activated and prone to aggregate. A specific subset of low-density neutrophils with different function compared to normal-density neutrophils can also be found within the peripheral blood mononuclear cell (PBMC) fraction after density gradient centrifugation of whole blood. Neutrophil phagocytosis is required for regular clearance of cell remnants and nuclear material. Reactive oxygen species (ROS) released by neutrophils during oxidative burst are important for immune suppression and impairment of ROS production is seen in SLE. NETs mediate pathology in both SLE and APS via several mechanisms, including exposure of autoantigens, priming of T-cells and activation of autoreactive B-cells. NETs are also involved in cardiovascular events by forming a pro-thrombotic scaffolding surface. Lastly, neutrophils communicate with other cells by producing cytokines, such as Interferon (IFN) -α, and via direct cell-cell contact. Physiological neutrophil effector functions are necessary to prevent autoimmunity, but in SLE and APS these are altered.

Are the cutaneous manifestations during or due to SARS-CoV-2 infection/COVID-19 frequent or not? Revision of possible pathophysiologic mechanisms

“…Inadequate negative or positive regulation of innate immune receptors, may lead to signals that stimulate nucleic acid and subsequent protein transcription, which can occur as monogenic genetic disorders, with gain in function (GOF) or loss of function (LOF). These are known as type I interferonopathies or other autoinflammatory diseases [76][77][78][79][80][81].…”

In vivo evidence for extracellular DNA trap formation

“…Systemic lupus erythematosus (SLE) is considered to be a prototypic systemic autoimmune disease and is characterized by loss of tolerance to self-antigens, abnormal T-and B-cell responses, and autoantibody production [66][67][68][69][70] . Its pathogenesis involves defective clearance of immune complexes and debris containing nucleic acids, excessive innate immune activation involving Toll-like receptors (TLR) and type I interferons, as well as aberrant lymphocyte activation 71 .…”

Immunosuppressive Treatment in Antiphospholipid Syndrome: Is It Worth It?

“…Neutrophils, short lived and terminally differentiated cells, are the most abundant circulating leukocyte and contribute to autoimmune dysregulation in APS, with a phenotype that differs from that observed in healthy subjects [ 56 ]. Among peripheral blood mononuclear cells (PBMC), a subset of low-density neutrophils with different properties from normal density granulocytes can also be found.…”

“…Neutrophil-platelet interactions play an important role in thrombo-inflammation, and it has been hypothesized that they are also involved in the cardiovascular manifestations observed in APS. LGDs and platelets can release mitochondria and mitochondrial DNA (mtDNA), which are strongly involved in inducing pro-inflammatory cytokines, including type I IFN, IFNγ, IL-6, IL-8, and TNFα, all actors in the context of the autoimmune pathogenesis of APS [ 56 ].…”