Lessons of Leprosy: The Emergence of TH17 Cytokines During Type II Reactions (ENL) Is Teaching Us About T-cell Plasticity
May 2012 | Volume 11 | Issue 5 | Original Article | 626 | Copyright © 2012
Background: Leprosy was the first disease classified according to the thymus derived T-cell in the 1960s and the first disease classified by the cytokine profile as intact interferon-γ(IFN-γ) and interleukin-2 (IL2) or TH1 (tuberculoid) and deficient IFN-γ and IL2 or TH2
(lepromatous), in the 1980s.
Objective: In the present study, we set out to explore the T helper 17 (TH17) lymphocyte subset, the hallmark of T-cell plasticity, in skin biopsies from patients with erythema nodosum leprosum (ENL) who were treated with thalidomide.
Method: RNA was extracted from paraffin embedded tissue before and after thalidomide treatment of ENL and RT-PCR was performed.
Results: IL17A, the hallmark of TH17, was consistently seen before and after thalidomide treatment, confirming the TH17 subset to be involved in ENL and potentially up-regulated by thalidomide.
Conclusion: A reduction in CD70, GARP, IDO, IL17B (IL-20), and IL17E (IL-25) , coupled with increases in RORγT, ARNT, FoxP3, and IL17C (IL-21) following thalidomide treatment, opens the door to understanding the complexity of the immunomodulatory drug thalidomide, which can operate as an anti-inflammatory while simultaneously stimulating cell-mediated immunity (CMI). We conclude that TH17 is involved in the immunopathogenesis of ENL and that thalidomide suppresses inflammatory components of TH17, while enhancing other components of TH17 that are potentially involved in CMI.
J Drugs Dermatol. 2012;11(5):626-630.
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Frank Macfarlane Burnet won the Nobel Prize for the clonal selection theory of immunity in 1960. 1 In 1961, Miller published evidence that these lymphocyte "clones" were educated in the thymus. 2 In 1962, the British classified leprosy according to the thymus with intact cell mediated immunity labeled as "tuberculoid" and the anergic form as "lepromatous." 3,4 In the 1980s, the concept of tuberculoid with intact IFN-γ and IL-2 5 and lepromatous with deficient IFN-γ, IL-2 and increased IL-4 and IL-106 led to the concept of the TH1-TH2 paradigm based on cytokine profiles. 7 This binary concept of the immune system was dominant for 20 years.8 In 2000, Oppmann and coworkers discovered through bio-informatics the third submit of IL-12, p19 and designated the p40p19 cytokine as IL-23. 9 In 2005, Steinman discovered the TH17 lymphocyte subset in the autoimmune disorder EAE and provided a major revision of the TH1-TH2 paradigm.10 This discovery has led to multiple review articles and further use of the term T-cell plasticity, where TH17 is in ying-yang with suppressor T-cell (Tregs), including hybrid T-cells with both RORγT and FoxP3.11 Surprisingly, these findings may explain the recent reports that have shown that Tregs, as measured by CD4CD25-FoxP3 functions, occur throughout the leprosy spectrum rather than being dominant at the TH2 or anergic lepromatous form of the disease.12,13 Despite the fact that leprosy is the first disease classified according to T-cells, TH17 has not yet been thoroughly studied in the leprosy spectrum. As PMNs are a hallmark of the TH17 subset and type II (ENL) leprosy reactions, we theorized this T-cell subset would be involved in type II (ENL) leprosy reactions.