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

Abstract

Leprosy reactions are an acute and systemic manifestation, which occurs suddenly, can be severe and lead leprosy patients to disability. Reactional episodes are observed among half of the multibacillary patients, mainly in borderline lepromatous and lepromatous forms. They may begin at any time during multidrug therapy, and even before the treatment. Physical disabilities, which are the source of extreme suffering and pain for patients, occur in progression of the cellular immune response associated with a reaction and are still poorly understood. Thus, this work aimed to phenotypically and functionally characterize CD4+ and CD8+ Treg cells ex vivo and in response to Mycobacterium leprae (ML). We studied 52 individuals, including 18 newly diagnosed and untreated multibacillary leprosy patients, 19 reactional multibacillary patients (Type I or Type II episodes) and 15 healthy volunteers, included as controls, all residents of the city of Rio de Janeiro. The functional activity and frequencies of these cells were evaluated through multiparametric flow cytometry. In addition, the production of cytokines in supernatant from peripheral blood mononuclear cell cultures was also investigated against ML by enzyme-linked immunosorbent assay. Our results showed a decrease in CD4+TGF-β+ Treg and CD8+ TGF-β+ Treg in leprosy multibacillary patients during both types of reactional episodes. Alterations in the cytokine profile was also observed in Type II reactions, along with upregulation of IL-17 and IL-6 in supernatant. Thus, our study suggests that downregulation of Treg cells is related with both classes of reactional episodes, improving our understanding of immune hyporesponsiveness in multibacillary patients and hyperesponsiveness in both reactions.

Th17 Cells and Cytokines in Leprosy: Understanding the Immune Response and Polarization

“…Studies involving reactive patients have identified an increase in TGF-β, INF-γ, and IL-17 levels in patients with RT2 compared with those with RT1 and non-reactive patients 36 . These data differ from those reported by Gomes de Castro et al­ 35 who found lower levels of these cytokines in patients with RT2 than in those with RT1 and LL, suggesting their role in maintaining a hyporesponsive state in the LL polar type, which may lead to the genesis of leprosy reactions. However, these divergent data emphasize the importance of further investigations with regard to TGF-β along with other cytokines responsible for the differentiation of Th17 cells, such as IL-6, IL-21, and IL-1β.…”

“…Quaresma et al 11 identified a higher TGF-β expression in patients with LL and Sadhu et al 12 reported higher IL-10 levels in patients with BL/LL compared with those with the TT form. De Castro et al 35 also showed higher IL-10 levels in BL than in LL. These findings are in accordance with those reported by Attia et al, who showed higher levels of TGF-β in patients compared with controls, although no differences were observed across the leprosy spectrum 16 .…”

“…Through blocking rIL-6 and rIL-23, IL-17A expression decreased and TGF-β expression increased, confirming the roles of these cytokines in leprosy. Castro et al 35 suggested that the upregulation of IL-17 and IL-6 influences the development of RT2. Additionally, Azevedo et al 26 reported higher expression of IL-17F, IL-8, CCL20, and CCL29 in patients with RT2 and lower expression of IL-22, IL-23, TGF-β, and FoxP3.…”

Immunopathogenesis of Type 1 and Type 2 Leprosy Reaction: An Update Review

“…This study offers innovative perspectives on the pathophysiological mechanisms underlying leprosy responses, focusing on the role of CD8 + Tregs. The subset of cellular entities has been subject to inadequate scrutiny in prior investigations, notwithstanding its noteworthy implications for the clinical advancement of leprosy [ 11 ].…”

“…Before de Castro et al (2020) [ 11 ] studied the role of Tregs on T2LR, Negera et al (2017) [ 13 ] conducted a comprehensive investigation of the Treg cells in individuals diagnosed with erythema nodosum leprosum. A cohort research of 46 individuals exhibiting erythema nodosum leprosum reaction and 31 individuals with non-reactional lepromatous leprosy were selected.…”