MAUI, HAWAII – For most of her career as a pediatric rheumatologist and immunologist, Anne M. Stevens, MD, PhD, didn’t find neutrophils terribly interesting.
“I’m more of a T-cell person. T cells are very precise, they’re regulated, they’re very sophisticated cells. Neutrophils are like these bumbling idiots that just come in and hit everything in sight and cause all sorts of damage,” she observed at the 2018 Rheumatology Winter Clinical Symposium.
Recently, however, she’s changed her mind. Research in the past few years demonstrates that there’s a lot more to neutrophils than previously known. Neutrophils are not only the first-responder immune cells to acutely inflamed tissue, as has long been recognized, but they also play a huge role in initiating and perpetuating chronic inflammation. Indeed, neutrophils figure prominently in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus (SLE), antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, and perhaps in major nonautoimmune diseases as well, including atherosclerosis, type 1 diabetes, thrombosis, and some forms of kidney disease, explained Dr. Stevens, chief of pediatric rheumatology at the University of Washington, Seattle.
Bruce Jancin/Frontline Medical News
Dr. Anne M. Stevens
Indeed, it’s now clear that neutrophils can either die quietly or become activated in death by creating neutrophil extracellular traps, or NETs, in a process called NETosis. Even though the activated neutrophil is dead, its exteriorized NETs continue to function, grabbing and killing bacterial pathogens. But the NETs also attract immune cells. These NETs are long strands of sticky DNA containing chromatin, histones, elastase, myeloperoxidase, hypercitrullinated proteins, and other autoantigens. NETosis exposes these autoantigens to the immune system, with resultant generation of autoimmune responses in predisposed individuals.
Much detail has been learned about this process. For example, one type of neutrophil death results from lymphokine-activated killer cells releasing perforin, which pokes holes in the neutrophil cell membrane, allowing an influx of calcium. The inflow of calcium triggers activation of peptidyl arginine deiminases, and these enzymes in turn cause hypercitrullination of autoantigens, leading to formation of anti–citrullinated peptide autoantibodies (ACPAs). These ACPAs cause inflammation by inducing complement activation and binding to Fc gamma receptors on phagocytes.
Investigators at the Systemic Autoimmunity Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and several other research centers have shown that mixing RA synovial fibroblasts with NETs induces production of interleukin-6 and ACPAs. In a mouse model of RA, this leads to cartilage loss in joints, providing a plausible mechanistic explanation for joint damage in RA (Sci Immunol. 2017 Apr;2[10]:eaag3358).
Potential therapeutic strategies targeting NETosis
The various treatment approaches under study aim to either inhibit NET release, curb recruitment of neutrophils for activation, promote migration of neutrophils away from sites of inflammation, or foster efferocytosis.
Among the therapeutic possibilities are calcineurin inhibitors as a means of preventing the influx of calcium into neutrophils, peptidyl arginine deiminase inhibitors such as Cl-amidine to prevent hypercitrullination, complement component 5a-receptor antagonists to decrease NET formation, the myeloperoxidase inhibitor known for now as PF-1355, and N-acetyl cysteine to scavenge proinflammatory reactive oxygen species and thereby reduce NET release.
The key will be to develop highly selective agents that encourage well-behaved neutrophils; across-the-board blockade of neutrophil activity would be terribly immunosuppressive and likely dangerous.
“What if we could block neutrophil recruitment just to the organ we’re worried about? If I’m worried about nephritis, let’s just block neutrophil infiltration into the kidneys. There are drugs being developed that will block the specific types of integrins involved,” Dr. Stevens said.
She reported having no financial conflicts regarding her presentation.