BACKGROUND Although Mycobacterium leprae (ML) is well characterised as the causative agent of leprosy, the pathophysiological mechanisms underlying peripheral nerve damage still need further understanding. In vitro and in vivo studies have yielded insights into molecular mechanisms of ML interaction with Schwann cells (SC), indicating the regulation of genes and proteins crucial to neural plasticity. OBJECTIVES We aimed to investigate the effect of ML on neurotrophins expression in human SC (hSC) and mice sciatic nerves to better understand their role in leprosy neuropathy, and aiming to contribute to future therapeutic approaches. METHODS We evaluated mRNA and protein expression of BDNF, NGF, NT-3, NT-4 in hSC from amputation nerve fragments, as well as in athymic nude mice, infected by ML for eight months. FINDINGS and MAIN CONCLUSIONS Our in vitro results showed a trend to decline in NGF and BDNF mRNA in ML-treated hSC, compared to controls. The immunodetection of BDNF and NT-4 was significantly downregulated in ML-treated hSC. Conversely, ML-infected mice demonstrated upregulation of NT-3, compared to non-infected animals. Our findings indicate that ML may be involved in neurotrophins regulation, suggesting that a pathogen-related imbalance of these growth factors may have a role in the neural impairment of leprosy.

ABSTRACT The inflammatory cytokines involved in the immune response to chronic periodontal disease (CPD) in the context of leprosy reactions (LR) were analyzed in 57 new cases of multibacillary leprosy (MBL). They were stratified by the presence of CPD and LR. Messenger RNA (mRNA) expression of inflammatory mediators was determined by qRT-PCR using skin biopsy and by ELISA using serum samples, maintaining 5% of significance level in ANOVA and correlation analyses. Twenty-three (40.4%) patients presented the first LR, whereas 22 (45.0%) patients presented CPD. IL-4 and IL-6 serum levels were significantly lower in patients with CPD and LR than in patients without CPD but with LR; IFN-γ serum levels were higher in patients with CPD and LR than in patients with no CPD and no LR; IL-4 serum levels were negatively correlated with TNF-α gene expression, while IL-6 serum levels were positively correlated with IFN-γ gene expression, in the skin of subjects with CPD and LR. The presence of DPC in individuals with LR immunoregulated IL-6, IFN-γ, and IL-4 concentrations. The presence of DPC decreased serum levels of IL-6 and IL-4 in reactional individuals. CPD concomitant to LR resulted in increased IFN-γ serum levels.

Leprosy is a chronic infectious disease that requires better understanding since it continues to be a significant health problem in many parts of the world. Leprosy reactions are acute inflammatory episodes regarded as the central etiology of nerve damage in the disease. The activation of endothelium is a relevant phenomenon to be investigated in leprosy reactions. The present study evaluated the expression of endothelial factors in skin lesions and serum samples of leprosy patients. Immunohistochemical analysis of skin samples and serum measurements of VCAM-1, VEGF, tissue factor and thrombomodulin were performed in 77 leprosy patients and 12 controls. We observed significant increase of VCAM-1 circulating levels in non-reactional leprosy (p = 0.0009). The immunostaining of VEGF and tissue factor was higher in endothelium of non-reactional leprosy (p = 0.02 for both) than healthy controls. Patients with type 1 reaction presented increased thrombomodulin serum levels, compared with non-reactional leprosy (p = 0.02). In type 2 reaction, no significant modifications were observed for the endothelial factors investigated. The anti-inflammatory and antimicrobial activities of the endotfhelial factors may play key-roles in the pathogenesis of leprosy and should be enrolled in studies focusing on alternative targets to improve the management of leprosy and its reactions.