Neutrophil NETworking in ENL: Potential as a Putative Biomarker: Future Insights

Abstract

Erythema nodosum leprosum (ENL), also known as type 2 reaction (T2R) is an immune complex mediated (type III hypersensitivity) reactional state encountered in patients with borderline lepromatous and lepromatous leprosy (BL and LL) either before, during, or after the institution of anti-leprosy treatment (ALT). The consequences of ENL may be serious, leading to permanent nerve damage and deformities, constituting a major cause of leprosy-related morbidity. The incidence of ENL is increasing with the increasing number of multibacillary cases. Although the diagnosis of ENL is not difficult to make for physicians involved in the care of leprosy patients, its management continues to be a most challenging aspect of the leprosy eradication program: the chronic and recurrent painful skin lesions, neuritis, and organ involvement necessitates prolonged treatment with prednisolone, thalidomide, and anti-inflammatory and immunosuppressive drugs, which further adds to the existing morbidity. In addition, the use of immunosuppressants like methotrexate, azathioprine, cyclosporine, or biologics carries a risk of reactivation of persisters (Mycobacterium leprae), apart from their own end-organ toxicities. Most ENL therapeutic guidelines are primarily designed for acute episodes and there is scarcity of literature on management of patients with chronic and recurrent ENL. It is difficult to predict which patients will develop chronic or recurrent ENL and plan the treatment accordingly. We need simple point-of-care or ELISA-based tests from blood or skin biopsy samples, which can help us in identifying patients who are likely to require prolonged treatment and also inform us about the prognosis of reactions so that appropriate therapy may be started and continued for better ENL control in such patients. There is a significant unmet need for research for better understanding the immunopathogenesis of, and biomarkers for, ENL to improve clinical stratification and therapeutics. In this review we will discuss the potential of neutrophils (polymorphonuclear granulocytes) as putative diagnostic and prognostic biomarkers by virtue of their universal abundance in human blood, functional versatility, phenotypic heterogeneity, metabolic plasticity, differential hierarchical cytoplasmic granule mobilization, and their ability to form NETs (neutrophil extracellular traps). We will touch upon the various aspects of neutrophil biology relevant to ENL pathophysiology in a step-wise manner. We also hypothesize about an element of metabolic reprogramming of neutrophils by M. leprae that could be investigated and exploited for biomarker discovery. In the end, a potential role for neutrophil derived exosomes as a novel biomarker for ENL will also be explored.

Diagnostic Value of Neutrophil-to-Lymphocyte Ratio, Lymphocyte-to-Monocyte Ratio, and Platelet-to-Lymphocyte Ratio in the Diagnosis of Erythema Nodosum Leprosum: A Retrospective Study

“…Macrophages, which are tissue monocytes, are the main resident cells activated by M. leprae infection [ 6 , 16 ]. Earlier studies indicated that ENL patients experienced a greater release of TNF-α from monocytes upon contact with M. leprae [ 12 , 17 ].…”

“…Histological studies showed an intense perivascular infiltrate of neutrophils throughout the dermis and subcutis, especially within 72 h of ENL onset [ 11 , 12 ]. The circulating neutrophils appeared to contain M. leprae bacilli, albeit in the absence of systemic inflammation [ 16 ]. Neutrophilic degranulation was observed in ENL, with a subsequent high production of low-density neutrophils [ 6 ].…”

“…Neutrophilic degranulation was observed in ENL, with a subsequent high production of low-density neutrophils [ 6 ]. The released granules acted as mediators of innate and adaptive immunity that inflicted collateral tissue damage in ENL [ 16 ].…”

Antimicrobial Activity of Neutrophils Against Mycobacteria

“…This data is suggestive of NETs contributing towards more severe leprosy disease. A recent review discusses the potential for NETs as a putative prognostic tool in ENL to direct medical treatment ( 177 ).…”

Whole blood transcriptomics reveals the enrichment of neutrophil activation pathways during erythema nodosum leprosum reaction

“…Although the mechanisms that trigger the reaction and the crucial pathways linked to the inflammatory response are still elusive, neutrophils are recognized as key players during ENL ( 13 , 14 ). Early histological studies revealed a rich neutrophilic infiltrate in cutaneous ENL lesions ( 15 , 16 ).…”