Involvement of TNF-Producing CD8+ Effector Memory T Cells with Immunopathogenesis of Erythema Nodosum Leprosum in Leprosy Patients

Despite the drastic reduction in the number of leprosy cases since the implementation of multidrug therapy (MDT), in 1980, by the WHO, the disease still appears as a relevant public health concern in endemic countries, including Brazil, which reported more than 10% of new cases detected in 2016 around the world.1 The skin and peripheral nerve lesions, traditionally found in leprosy, are associated with the tropism of Mycobacterium leprae both to macrophages and to Schwann cells, which, in turn, are major reservoirs of both the pathogen and of the immune response from hosts. If untreated, the injuries provoked by such a response usually lead to atrophies, paresis, face disfigurement, and even blindness.2 Given the influence of genetic factors on the disease process and on the clinical course of leprosy, the genes that influence the pattern and intensity of immunological response are natural candidates to determine both the occurrence of the disease and the clinical outcome thereof.3 Leprosy presents several clinical manifestations ranging within a spectrum, and the most acceptable classification in scientific studies was provided by Ridley and Jopling,4 in 1966, with the division of the disease into five forms, two of them being polar and the other three borderline forms. On one side, the tuberculoid pole (TT) is characterized by Th1-mediated immune response and a low number of skin lesions, with the appearance of granulomas, lymphocitic infiltrates, and, in unusual cases, bacilli. At the opposite end of the spectrum, the lepromatous pole (LL) is characterized by absent Th1 cellular immunity and high titers of antibodies against M. leprae, which are not effective in controlling the high load of bacilli. The nodular skin lesions disseminated throughout the body of LL patients present a high number of foamy macrophages and histiocytes containing high numbers of acid-fast bacilli with very few lymphocytes in a completely disorganized manner.5,6 The dynamic nature of the immune response to M. leprae leads to spontaneous fluctuations in the clinical state, which are known as leprosy reactions. As disclosed by a prior study performed by our group, more than half of the multibacillary patients are affected by acute inflammation episodes, known as leprosy reactions, either before, during, or after MDT, and even after healing.7 The type 1 reaction (T1R), also referred to as reversal reactions, mostly affects borderline patients, as a cause of the increased frequency of antigen-specific CD8+/CD45RA+ T cells expressing the cutaneous leukocyte-associated antigen molecule, both in the blood and inside the lesions.8 On the other hand, the type 2 reaction (T2R), also known as erythema nodosum leprosum (ENL), is characterized by a sudden exacerbation of the chronic conditions, with the appearance of additional skin lesions, reactivation of former ones, formation of painful nodules, general malaise, and aggravation of neurological damage. An early diagnosis of T2R, together with a suitable therapeutic management, may contribute to reduce the incapacities resulting from these episodes that are often severe.9,10 Several decades ago, it was thought that the participation of immune complexes and the activation of complement components were associated with the genesis of T2R.11 In addition, one study noted a modification in the proportion of CD4 and CD8+ T cells in the skin lesions and blood from LL patients, either with or without reaction.12 More recently, both pro- and anti-inflammatory mediators were shown to be increased in the plasma of T2R patients.13 Nevertheless, one should still clarify the role of different T lymphocyte subsets in the secretion of these cytokines, as well as the way these antagonistic cytokines act in synergy to characterize the reactional episode and the severity thereof. T lymphocyte subsets perform very heterogeneous functional activities and contribute in distinct forms to the dynamics of infectious diseases. Such subsets present differentiations according to their surface molecules. The identification of CCR7 and CD45RA is crucial for the characterization of T lymphocyte subsets.14 The aforesaid two molecules are commonly used to classify the following T lymphocyte subsets: naive (CCR7+/CD45RA+), central memory (CCR7+/CD45RA−), effector memory (CCR7−/CD45RA−), and effector cells (CCR7−/CD45RA+).15 Therefore, this work intends to identify the cytokine (IFN-γ, TNF and IL-10)-producing T cell subsets, the expression of the transcription factors thereof, as well as to compare the relevant results with the clinical manifestations found in the genesis of T2R patients.