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

Abstract

Type 2 reaction (T2R) or erythema nodosum leprosum (ENL), a sudden episode of acute inflammation predominantly affecting lepromatous leprosy patients (LL), characterized by a reduced cellular immune response. This possibly indicates a close relationship between the onset of T2R and the altered frequency, and functional activity of T lymphocytes, particularly of memory subsets. This study performed ex vivo and in vitro characterizations of T cell blood subpopulations from LL patients with or without T2R. In addition, the evaluation of activity of these subpopulations was performed by analyzing the frequency of these cells producing IFN-γ, TNF, and IL-10 by flow cytometry. Furthermore, the expression of transcription factors, for the differentiation of T cells, were analyzed by quantitative real-time polymerase chain reaction. Our results showed an increased frequency of CD8 + /TNF + effector memory T cells (T EM ) among T2Rs. Moreover, there was evidence of a reduced frequency of CD4 and CD8 + IFN-γ-producing cells in T2R, and a reduced expression of STAT4 and TBX21. Finally, a significant and positive correlation between bacteriological index (BI) of T2R patients and CD4 + /TNF + and CD4 + /IFN-γ + T cells was observed. Thus, negative correlation between BI and the frequency of CD4 + /IL-10 + T cells was noted. These results suggest that CD8 + /TNF + T EM are primarily responsible for the transient alteration in the immune response to Mycobacterium leprae in ENL patients. Thus, our study improves our understanding of pathogenic mechanisms and might suggest new therapeutic approaches for leprosy.Note: Supplemental table and figure appear at www.ajtmh.org.

Downmodulation of Regulatory T Cells Producing TGF-β Participates in Pathogenesis of Leprosy Reactions

“…Previous work by our group had already shown a high frequency of TBX21 as well as an increase in IFN-γ producing CD4 + T cells in the genesis of T1R in borderline lepromatous patients ( 17 ). On the other hand, in T2R we found an increased in CD8 + TNF producing cells ( 18 ). Thus, after apoptosis of TGF-β + Treg an increase in CD4 + IFN-γ + and CD8 + TNF + cells could occur, triggering T1R and T2R, respectively.…”

“…Several studies aim to investigate immunological mechanisms of susceptibility and identify biomarkers, which can explain, predict and control T1R and T2R reactions (11)(12)(13)(14)(15). Activation of T helper 1 (Th1) cells and production of proinflammatory cytokines, such as IFN-γ and TNF, are described by several studies to explain the pathogenesis of T1R and T2R (16)(17)(18). Although multibacillary patients are hyporesponsive to M. leprae, during onset of reactions they develop a sudden exacerbated immune response against the pathogen (15).…”

Presence of Senescent and Memory CD8+ Leukocytes as Immunocenescence Markers in Skin Lesions of Elderly Leprosy Patients

“…CD8 + T cell frequency is similar between the leprosy clinical forms, although functional features such as higher IL-10 levels in MB compared to PB patients in this T cell subset has been observed ( 12 ). Moreover, TNF-producing CD8 + T cells are essential in the pathogenesis of the type 2 leprosy reaction in MB patients, these reactions are episodes of acute hypersensitivity presenting as aggravation of the previous symptoms and skin lesions ( 13 ).…”

In search of biomarkers for leprosy by unraveling the host immune response to Mycobacterium leprae

“…Moreover, the frequencies of these memory cells correlated with the bacterial load and the number of skin lesions observed in these individuals. Central and effector memory T‐cells have also been identified as possible inducers of the immune alteration in T2R 137,138 . These studies thus indicate that the presence of memory T‐cells is not beneficial for leprosy patients, as they are associated with poor treatment outcome (relapse) or nerve‐damaging episodes (T2R).…”