Recent research has shown that neutrophil cells have critical roles in the onset and progression of systemic autoimmune disorders and in the development of complex inflammatory responses that cause organ damage. Particularly, their product called neutrophil extracellular traps (NETs) released upon activation are now recognized to play a pivotal role. The intricacy of neutrophil biology and its dysregulation can now be better understood as a result of novel technologies that enable better assessments of neutrophils. Autoantigens can be altered and presented to the adaptive immune system due to dysregulated neutrophil cell death. By targeting tissues to foster an inflammatory environment and produce neoepitopes, neutrophils play crucial roles in the onset and progression of autoimmune diseases. In a recent Nature Reviews Immunology journal study, researchers assess the role of NETs in systemic autoimmune and autoinflammatory disorders.
NETs in systemic autoimmune diseases
In systemic autoimmune diseases, the immune system cannot distinguish between self and non-self and subsequently responds to and harms several tissues and organs, including joints, kidneys, and blood vessels. Numerous studies have linked neutrophils to the pathogenesis of systemic autoimmunity. In both human and animal disease models, these immune cells are frequently located at the areas of tissue inflammation where they support inflammatory response. In particular, the formation of NETs has attracted attention due to their association with autoimmunity. Many of the autoantigens generated by neutrophils in NETs, including DNA and its fragments, histones, citrullinated peptides, myeloperoxidase (MPO) and proteinase 3 (PRTN3) are known to be attacked by the adaptive immune system observed in systemic autoimmunity.
As the most common systemic autoimmune illness, rheumatoid arthritis causes a heavy strain on both the patient and society. In addition to frequently affecting extra-articular tissues like the lungs and vasculature, this condition specifically targets the synovial joints, which, if not adequately treated, can result in considerable disability. Since neutrophils produce enzymes like peptidylarginine deiminase 4 (PAD4) that catalyze the conversion of arginine to citrulline, they are a key source of citrullinated antigens. Particularly in the initial phases of the disease, rheumatoid arthritis patients have an abundance of neutrophils in their inflamed joints that might produce NETs locally. Patients with rheumatoid arthritis have elevated amounts of NETs in their blood, which are correlated with levels of anti-citrullinated protein antibodies (ACPAs) and other systemic inflammatory markers.
Systemic lupus erythematosus (SLE)
SLE is a type I interferon response-heavy systemic autoimmune disease that displays high autoreactivity against nucleic acids and other nuclear and intracellular components. The skin, synovial joints, kidneys, lungs, blood vessels, and heart are some of the many organs affected by this broad inflammation, making it the classic systemic autoimmune disorder. As the condition worsens, neutrophil-specific gene expression is enriched in the neutrophil populations of SLE patients relative to healthy controls. In addition, neutrophils from people with SLE have aberrant oxidative metabolism, increased apoptosis, and decreased phagocytic clearance. Compared to NETs made from neutrophils with normal density, low-density granulocytes from individuals with SLE show a higher propensity to produce NETs ex vivo. They have higher concentrations of modified autoantigens and immunostimulatory molecules.
Idiopathic inflammatory myopathies (IIMs)
Also known as myositis, IIMs are a group of heterogeneous autoimmune disorders affecting both children and adults that classically present with muscle weakness but can also cause damage to skin, joints, lungs and heart. Autoantibodies targeting various molecules are commonly found in these patients, including transfer RNA, melanoma differentiation-associated protein 5 (MDA5), transcription intermediary factor 1 (TIF1) or signal recognition particle, giving rise to distinct disease subtypes. In certain subtypes of IIM, particularly dermatomyositis, there is an association with dysregulation of the type I interferon pathway, similarly to SLE.
Recently, neutrophils have been implicated in the pathogenesis of several types of myositis. Increased levels of various neutrophil-specific molecules, such as neutrophil elastase, PRTN3 and serine proteases, have been detected in both circulation and muscle tissue of patients with IIM. NETs from patients with IIM can directly interfere with myoblast and myotube biology, impairing the function of these cells in striated muscle. Overall, experimental observations suggest that dysregulated neutrophil pathways may have pathogenic roles in myositis, including the induction of autoimmune responses and tissue damage.
Neutrophils in systemic autoinflammation
Inflammatory responses primarily involve innate immune cells, such as neutrophils, which are the leading cause of autoinflammatory disorders. Recent studies suggest that accurately distinguishing between autoinflammation and autoimmunity can be challenging. Instead of two separate events, these processes can be the extremes of an inflammatory spectrum.
Adenosine deaminase 2 deficiency
Adenosine deaminase 2 (ADA2) is a protein responsible for the breakdown of extracellular adenosine and is primarily expressed by myeloid cells. Adenosine deaminase deficiency (DADA2) is characterized by monogenic vasculitis driven by a biallelic mutation in the ADA2 gene. DADA2 has a diverse range of clinical manifestations, including vasculitis and autoinflammation. In addition, as a result of the ADA2 mutation’s lower protein activity, extracellular adenosine levels rise, which can cause NETs to develop by binding to neutrophil A1 and A3 adenosine receptors. People suffering from DADA2 also have higher levels of circulating LDGs, which can form NETs. Compared to NETs obtained from healthy controls, these NETs cause macrophages to create more inflammatory chemicals, such as tumor necrosis factor (TNF), which may be due to variations in NET molecular composition.
Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome can manifest in several ways, including arthritis involving the sterile joint buildup of neutrophils. This condition is commonly diagnosed in children. Several studies have noted increased NET production and reduced NET clearance in neutrophils from PAPA syndrome patients. NET remnants that have infiltrated the skin and are linked to inflammatory cytokines and increased neutrophil transcriptional responses have been found in skin biopsies from PAPA syndrome patients. Additionally, compared to neutrophil levels in healthy controls, neutrophils in PAPA syndrome patients respond more robustly to interleukin-1 (IL-1). Incubating these neutrophils with the IL-1 receptor antagonist Anakinra, can suppress NET formation. Overall, a connection between IL-1 with dysregulated neutrophil responses in the PAPA syndrome pathogenesis has been reported.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Wigerblad G, Kaplan MJ. Nat Rev Immunol 2022 Oct 18:1-15.
J Immunol. 2022 Jul 20:ji2200154.
Mutua V, Gershwin LJ. Clin Rev Allergy Immunol. 2021; 61:194.
PNAS USA. 2020 Jul; 117(28):16481-16491.
Dott. Gianfrancesco Cormaci
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