The immunopathology of erythema nodosum leprosum

Leprosy is a disease caused by Mycobacterium leprae, an acid-fast bacillus whose clinical spectrum correlates with the host immune response. Erythema nodosum leprosum (ENL) is an immune-mediated inflammatory complication causing high morbidity in affected leprosy patients. A case-control follow-up study was conducted in Ethiopia to test the hypothesis that ENL is associated with impaired immune regulation. In 46 patients with ENL and 31 lepromatous leprosy (LL) matched controls, the frequency of regulatory T-cells, memory T-cells and B-cells were analysed by flow cytometry. The in vitro pro-inflammatory cytokines production by peripheral blood mononuclear cells (PBMCs) to the response of M. leprae whole cell sonicate stimulation was determined by Enzyme-linked immunosorbent assay. The gene expression of these cytokines in the blood and skin biopsies was determined by quantitative polymerase chain reaction (qPCR) before and after treatment. Patients with ENL had lower percentage of CD4+ regulatory T-cells than LL controls at recruitment. The percentage of CD3+, CD4+ and CD8+ T-cells expressing activated T-cells were significantly higher in the PBMCs of patients with ENL than in LL controls before treatment. The in vitro production and gene expression of the cytokines: TNF-α, IFN-γ, IL-1β, IL-6, IL-8 and IL-17A were significantly increased in untreated patients with ENL. ENL patients had a higher median percentage of tissue-like memory (TLM) and activated memory (AM) B-cells than LL controls before treatment while the median percentage of total B-cells and resting memory (RM) B-cells did not significantly different in both groups before treatment. The level of anti-PGL-1, LAM and Ag85 antibodies were not significantly different in patients with ENL before treatment. Patients with ENL had significantly lower circulating C1q than LL controls before treatment. However, after treatment, the amount of circulating C1q was not significantly different in both groups. Our findings suggest that ENL is associated with reduced percentage of regulatory T-cells and increased CD4+/CD8+ T-cell ratio and this immune imbalance may lead to the initiation of ENL reactions in either permitting productions of antibodies critical to an immune-complex formation or as a cell-mediated immune response in patients with leprosy. Consequently, this study illuminates the role of T-cell activation in the pathogenesis of ENL reaction and challenges the long-standing dogma of immune-complexes as the sole aetiology of ENL reactions.