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Carlos G Wambier,1 Leandra Naira Z Ramalho,2 Marco Andrey C Frade,1 Norma T Foss1 1Division of Dermatology, Department of Internal Medicine, 2Department of Pathology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil Background: Nuclear factor kappa B (NFκB) transcription factors play a central role in controlling the expression of genes involved in inflammatory reactions, proliferation, and survival of human cells. However, the in situ evaluation of NFκB activity in leprosy has not been completed previously. The aim of this study was to determine whether NFκB activity correlates with susceptibility or resistance to Mycobacterium leprae infection in biopsies from skin lesions of 38 patients with the clinical and laboratory diagnosis of leprosy. Methods: The NFκB activation profile was evaluated in biopsies from skin lesions of 38 patients with the clinical and laboratory diagnosis of leprosy. NFκB activation was evaluated and quantified by Southwestern histochemistry, and its activation index (range, 0–4) was calculated according to the percentage of nuclear positivity by the histochemistry. Activation index >1 was considered representative of activation of NFκB. Results: Fifteen patients (39.5%) demonstrated activated NFκB. Multibacillary leprosy was associated with activated NFκB (54.5%, P=0.028). Borderline leprosy was most strongly associated with NFκB activation (80%), with an odds ratio of 32.7 (P=0.016). These clinical forms are characterized by increased susceptibility to M. leprae and by immunological instability. Activation of NFκB was absent in the granulomas in tuberculoid leprosy, which represents an effective inflammatory reaction pattern against M. leprae. Conclusion: These results indicate that NFκB activation could favor susceptibility and immunological instability to M. leprae infection, potentially by the stimulation of phagocytosis and the regulation of apoptotic mechanisms of infected cells, leading to the proliferation of this intracellular bacillus. Further studies are needed to evaluate if inhibition of NFκB activation in multibacillary leprosy could favor resistance and an effective granulomatous immune response. Keywords: transcription factors, nuclear factor kappa B, immunomodulation, Mycobacterium leprae, leprosy resistance, leprosy susceptibility