Abstract
Erythema Nodosum Leprosum (ENL) is a recurrent acute inflammatory complication of leprosy affecting up to 50% of all Borderline Lepromatous and Lepromatous Leprosy (BL/LL) patients. Although ENL is described as an immune reaction mediated by neutrophils, studies demonstrating the direct role of neutrophils in ENL are still rare. One subpopulation of low-density neutrophils (LDNs), present within the fraction of peripheral blood mononuclear cells (PBMC), has been associated with the pathogenesis and severity of diseases like sepsis, lupus, and tuberculosis. We herein analyzed LDNs and high-density neutrophils (HDNs) in terms of frequency, phenotype, and morphology. Serum levels of MMP-9 (a neutrophilic degranulation marker) were evaluated by ELISA; and LDNs were generated in vitro by stimulating healthy-donor, whole-blood cultures. PBMC layers of ENL patients presented segmented/hypersegmented cells that were morphologically compatible with neutrophils. Immunofluorescence analyses identified LDNs in ENL. Flow cytometry confirmed the elevated frequency of circulating LDNs (CD14−CD15+) in ENL patients compared to healthy donors and nonreactional Borderline Tuberculoid (BT) patients. Moreover, flow cytometry analyses revealed that ENL LDNs had a neutrophilic-activated phenotype. ENL patients under thalidomide treatment presented similar frequency of LDNs as observed before treatment but its activation status was lower. In addition, Mycobacterium leprae induced in vitro generation of LDNs in whole blood in a dose-dependent fashion; and TGF-β, an inhibitor of neutrophilic degranulation, prevented LDNs generation. MMP-9 serum levels of BL/LL patients with or without ENL correlated with LDNs frequency at the same time that ultrastructural observations of ENL LDNs showed suggestive signs of degranulation. Together, our data provide new insights into the knowledge and understanding of the pathogenesis of ENL while enriching the role of neutrophils in leprosy.
Highlights
Leprosy, a chronic infectious disease caused by the intracellular, acid-fast bacillus Mycobacterium leprae, primarily affects the skin and peripheral nerves [1]
Leprosy patients without any reactions were included before starting multidrug therapy (MDT)
The results reported in the present study, aim to provide further insight into several key aspects of low-density neutrophils (LDNs) in leprosy
Summary
A chronic infectious disease caused by the intracellular, acid-fast bacillus Mycobacterium leprae, primarily affects the skin and peripheral nerves [1]. The registered prevalence of leprosy (end of 2018) and new case detection worldwide in 2019 was recorded as 177,175 (WHO 2019). Clinical manifestations of leprosy are categorized in a wide-ranging spectrum according to the intensity of the individual immune response to infection [2]. Within the spectrum of the disease, Tuberculoid Leprosy (TT) is at the far end of the resistant pole and is characterized by few lesions, rare detectable bacilli, and an intense cellular immune response. Lepromatous Leprosy (LL) is diffuse, with intense bacillary multiplication and activation of humoral immunity in detriment of the cellular response. Borderline Tuberculoid (BT), Borderline Borderline (BB), and Borderline Lepromatous (BL), are unstable intermediate forms, classified as such according to their proximity to either end of the spectrum [2]
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