Clearing the traps: how decreased degradation of NETs affects Lupus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with patients displaying a variety of symptoms from fatigue and skin rashes to joint pain and swelling. It is characterized by numerous anti-nuclear antibodies and organ damage and is hypothesised to have evolved from the inefficient or improper clearance of apoptotic and necrotic cells. In 2004, one of the most ingenious systems for host defence was discovered, termed neutrophil extracellular traps (NETs). These consist of chromatin and antimicrobial enzymes that are released from neutrophils, by a process called NETosis, as a ‘last resort’ defence to trap and kill pathogens. It has been shown previously that the ability to break down NETs is reduced in a subpopulation of SLE patients with severe disease.

In a recent study published in Arthritis Research & Therapy, Anna Blom and colleagues from Lund University, Sweden address the important question of how defective degradation of NETs in SLE patients impacts the clinical phenotype of the disease. Sixty-nine SLE patients with a median age of 39 years were recruited to this prospective study and followed for approximately five years. Recordings of disease activity, infections and other clinically relevant information, as well as serum samples, were taken every two months. Sera from 77 healthy volunteers were used to determine the normal range of ability to degrade NETs.

Significantly, 41 percent of patients exhibited a decreased ability to degrade NETs at least once, with a median of 20 percent of patients when analysing all time points. Decreased degradation was associated with symptoms of glomerulonephritis, low complement levels and increased levels of antibodies against histones and DNA. Patients were also more likely to develop alopecia and fever after an episode of impaired NETs degradation.

This large, well-designed study provides an important insight into disease pathogenesis and highlights a novel correlation between defective clearance of NETs and SLE disease manifestations, though degradation ability may vary for each patient over time. During the course of the study disease activity improved for the majority of patients, and interestingly although no direct efforts were made to restore the ability to degrade NETs, this also improved.

Collectively, the findings  highlight the importance of regular follow-ups with patients to reduce SLE flares, the potential use of NETs as a diagnostic biomarker for disease activity and indicate that therapeutics targeting NET clearance may be of benefit.