A Systematic Review of Immunological Studies of Erythema Nodosum Leprosum

Anastasia Polycarpou, Stephen L Walker, Diana N J Lockwood, Anastasia Polycarpou, Stephen L Walker, Diana N J Lockwood

Abstract

Erythema nodosum leprosum (ENL) is a painful inflammatory complication of leprosy occurring in 50% of lepromatous leprosy patients and 5-10% of borderline lepromatous patients. It is a significant cause of economic hardship, morbidity and mortality in leprosy patients. Our understanding of the causes of ENL is limited. We performed a systematic review of the published literature and critically evaluated the evidence for the role of neutrophils, immune complexes (ICs), T-cells, cytokines, and other immunological factors that could contribute to the development of ENL. Searches of the literature were performed in PubMed. Studies, independent of published date, using samples from patients with ENL were included. The search revealed more than 20,000 articles of which 146 eligible studies were included in this systematic review. The studies demonstrate that ENL may be associated with a neutrophilic infiltrate, but it is not clear whether it is an IC-mediated process or that the presence of ICs is an epiphenomenon. Increased levels of tumor necrosis factor-α and other pro-inflammatory cytokines support the role of this cytokine in the inflammatory phase of ENL but not necessarily the initiation. T-cell subsets appear to be important in ENL since multiple studies report an increased CD4+/CD8+ ratio in both skin and peripheral blood of patients with ENL. Microarray data have identified new molecules and whole pathophysiological pathways associated with ENL and provides new insights into the pathogenesis of ENL. Studies of ENL are often difficult to compare due to a lack of case definitions, treatment status, and timing of sampling as well as the use of different laboratory techniques. A standardized approach to some of these issues would be useful. ENL appears to be a complex interaction of various aspects of the immune system. Rigorous clinical descriptions of well-defined cohorts of patients and a systems biology approach using available technologies such as genomics, epigenomics, transcriptomics, and proteomics could yield greater understanding of the condition.

Keywords: TNF-α; erythema nodosum leprosum; immune complexes; immunology; leprosy; neutrophils; systematic review; type 2 reaction.

Figures

Figure 1
Figure 1
Flowchart. Flowchart of included studies.
Figure 2
Figure 2
Immune mechanisms in erythema nodosum leprosum (ENL). The diagram illustrates the different immune mechanisms which have been described in the literature of ENL. High volume of immune complexes (ICs) are formulated due to the increased antibody formation by the B cells and the increased mycobacterial antigens by fragmentation of the M. leprae bacilli. ICs are deposited in the skin. Neutrophils are drawn to the skin where they help in the IC clearance using their surface Fcγ receptors. An increase of CD4+/CD8+ T cell subset ratio in both peripheral blood and skin characterizes the disorder. Macrophages form the M. leprae intracellular niche and in concert with neutrophils and T-cells secret high levels of tumor necrosis factor (TNF)-α and other pro-inflammatory cytokines to further complicate the phenotype of ENL.

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