"Primary mucosal melanoma arising from the eustachian tube with CTLA-4, IL-17A, IL-17C, and IL-17E upregulation"Wei, Calvin; Sirikanjanapong, Sasis; Lieberman, Seth; Delacure, Mark; Martiniuk, Frank; LEVIS, WILLIAM; Wang, Beverly Y
Primary malignant melanoma arising from the eustachian tube is extremely rare. We report the case of a 63-year-old white man who presented with a 1-month history of left-sided hearing loss and aural fullness. Flexible fiberoptic laryngoscopy detected a blue-purple mass that appeared to arise from the left lateral nasopharynx. Computed tomography demonstrated an enhancing mass arising from an orifice of the left eustachian tube. The tumor was debulked endoscopically and was confirmed to have originated in the left eustachian tube. Histologically, the tumor was made up of heavily pigmented pleomorphic spindle cells with frequent mitoses. The tumor cells were immunohistochemically positive for S-100 protein, HMB-45, Melan-A, and PNL-2. The final diagnosis was a mucosal malignant melanoma. We also performed a nested polymerase chain reaction assay for several genes of interest, including CTLA-4, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, PLZF, Foxp3, RORgammat, CD27, and CD70. These genes have been studied mainly in cutaneous melanomas, especially for the development of immunotherapy, but only very limited studies have been done on mucosal melanomas. Our investigation found upregulation of CTLA-4, IL-17A, IL-17C, and IL-17E. Based on our finding of CTLA-4 upregulation, it may be suggested that our patient might have had low antitumor immunity and that he might have benefited from CTLA-4 blockade. On the other hand, upregulation of IL-17A and IL-17E might reflect increased antitumor immunity, which could suggest that patients with a mucosal melanoma might benefit from immunomodulators associated with the effect of Th17. These genes also have great potential to help melanoma patients obtain tailored treatment, and they can be used as biomarkers for predicting prognosis..
"Ingenol mebutate: potential for further development of cancer immunotherapy"Doan, Hung Q; Gulati, Nicholas; LEVIS, WILLIAM R
GRANTS:GM07739/GM/NIGMS NIH HHS/United States
Ingenol mebutate is a diterpene ester derived from the plant Euphorbia peplus and is FDA approved for the topical treatment of actinic keratoses (AK). Shown to be efficacious with as little as a 3-day trial, this compound is being further tested for the topical treatment of other nonmelanoma skin cancers with promising preclinical data. In an effort to elucidate the molecular mechanism of this novel drug, Stahlhut et al. (2012) suggest a role for calcium and apoptosis. Further studies are needed to evaluate the intracellular mechanisms of ingenol mebutate-mediated cytotoxicity. Additionally, studies such as this not only shed light on the mechanism of ingenol mebutate and its derivatives, but also pave the way for evaluating the involvement of the immune system in eliminating drug-treated cells and tissues. This has important implications for the development of novel topical immune modulatory products and the field of topical immunotherapy..
"Pseudoepitheliomatous hyperplasia and transepidermal elimination in lepromatous leprosy: does T-cell plasticity play a role?" [Case Report]Fischer, Max K; Myer, Kaley A; Que, Syril Keena T; Harris, Jonathan A; Martiniuk, Frank T; Meehan, Shane A; LEVIS, WILLIAM R
GRANTS:UL1 RR029893/RR/NCRR NIH HHS/United States;UL1RR029893/RR/NCRR NIH HHS/United States
BACKGROUND: The longstanding concept of a Th1-Th2 dichotomy in leprosy, with Th1-predominant tuberculoid leprosy and Th2-predominant lepromatous leprosy (LL), has recently been challenged, and Cbl-b overexpression may emerge as an important factor in anergy and progression of LL. Moreover, Th17 and Th22 subsets have been identified as Th1-Th2 modulators in inflammatory skin diseases, most notably psoriasis, but their roles in leprosy have not yet been elucidated. The occurrence of pseudoepitheliomatous hyperplasia (PEH) with transepidermal elimination of mycobacteria in LL patients, which could theoretically be a portal for contact transmission, thus raises important immunological questions: Do Th17 and/or Th22 subsets mediate epidermal proliferation akin to Th1-driven psoriasis in supposedly Th2-predominant LL disease, and is the Th1-Th2 immunostat set systemically or locally? Furthermore, which microRNAs (miRs), signal transducers, and activators of transcription (STAT) proteins regulate this transition in leprosy, if any, and does differential Cb1-b expression play a role? OBSERVATION: A 71-year-old man presented with an infiltrative dermopathy characteristic of LL, as well as several hyperkeratotic plaques. Microscopic examination of the hyperkeratotic lesions demonstrated PEH with loss of the grenz zone and transepidermal elimination of acid-fast bacilli, whereas classic histopathologic features of LL were present at other sites. HYPOTHESES: We hypothesize that: Th17 and Th22 T-cell subsets act locally to induce T-cell plasticity in LL lesions, manifesting PEH; miR-181a is normal or increased in LL lesions with PEH compared to its expressional loss in classic LL lesions; miR-21 and STAT3 are increased in LL lesions with PEH, given their association with epithelial hyperproliferation; and Cbl-b is diminished in LL lesions with PEH compared to classic LL lesions. CONCLUSION: By understanding the factors that regulate T-cell and cytokine responses in leprosy, it should be possible to recognize these dynamic immunologic processes clinically and histopathologically and devise specific immunologic interventions..
"Lessons of leprosy: the emergence of TH17 cytokines during type II reactions (ENL) is teaching us about T-cell plasticity"Martiniuk, Frank; Giovinazzo, Jerome; Tan, Ainah U; Shahidullah, Rozana; Haslett, Patrick; Kaplan, Gilla; LEVIS, WILLIAM R
GRANTS:1UL1RR029893/RR/NCRR NIH HHS/United States;UL1 RR029893/RR/NCRR NIH HHS/United States
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-gamma (IFN-gamma) and interleukin-2 (IL2) or TH1 (tuberculoid) and deficient IFN-gamma 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 RORgammaT, 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..
"Letter to the Editor-Atrial fibrillation: An inflammatory and autoimmune disorder" [Letter]Schairer, David O.; LEVIS, WILLIAM R.
"MicroRNA 150 in Humans and Murine Contact Sensitivity" [Letter]Wolf, Joel; LEVIS, WILLIAM
"The study of simple chemicals in animals and man: mechanisms of contact sensitivity"Wolf, Joel; LEVIS, WILLIAM R
When simple chemical are applied to the skin, a series of events ensues that under some conditions ultimately results in contact sensitivity (CS), a proven cell-mediated immune response (CMI). Since the discovery of CMI using picryl-Cl (PCl) in 1942, we have learned a great deal on the cellular mechanisms involved in CS, including the potential to treat warts, skin cancer, autoimmune disorders, and allergies. In this review we summarize some of the basic mechanisms of both the innate and acquired immune systems involved in CS..
"CD70 and Th17 are involved in human contact sensitivity"Lee, David S; Gulati, Nicholas; Martiniuk, Frank; LEVIS, WILLIAM R
GRANTS:1UL1RR029893/RR/NCRR NIH HHS/United States;GM07739/GM/NIGMS NIH HHS/United States;T32 GM007739-34/GM/NIGMS NIH HHS/United States;UL1 RR029893-03/RR/NCRR NIH HHS/United States
CD70 (CD27L) has been shown to be preferentially expressed on Th1, but not Th2, CD4+ lymphocytes in murine contact sensitivity. The CD70-CD27 co-stimulatory pathway as well as the Th17 subset of lymphocytes have also been identified in human contact sensitivity reactions. The authors have previously reported increased expression of CD70 and the Th17-specific transcription factor retinoid orphan receptor gamma T in the elicitation phase of allergic contact dermatitis by reverse transcriptase-polymerase chain reaction. The manipulation of these pathways has potential for ameliorating autoimmune and inflammatory disorders such as allergic contact dermatitis, psoriasis and rheumatoid arthritis. Also, upregulation of the CD70-CD27 and Th17 pathways has been associated with the remarkable ability of topical sensitizers to treat warts and skin cancers including melanoma. As natural killer and natural killer T cells are also involved in contact sensitivity, future studies investigating the function of these cells are necessary to elucidate the transition between innate and acquired immune responses in the context of the Th1/Th2/Th17 and regulatory T cell paradigm.
"Cancer: this war is personal" [Editorial]LEVIS, WILLIAM
"Endemic leprosy in new york city"LEVIS, WILLIAM R; Paraskevas, Lilly-Rose; Jacobson, Mark; Spencer, John; Spencer, Trudy; Martiniuk, Frank
GRANTS:1UL1RR029893-0109/RR/NCRR NIH HHS/United States;UL1 RR029893-01/RR/NCRR NIH HHS/United States
"Erythema nodosum leprosum, Sweet's syndrome, and human immunodeficiency virus may be related through an overlap in immunopathogenesis" [Letter]Elbuluk, Nada; Martiniuk, Frank; LEVIS, WILLIAM R
"Thalidomide and Analogues: Potential for Immunomodulation of Inflammatory and Neoplastic Dermatologic Disorders"Ladizinski, B; Shannon, EJ; Sanchez, MR; LEVIS, WR
Thalidomide and analogues are a class of immunomodulatory drugs or IMiDS Thalidomide was initially approved by the U S Food and Drug Administation for treatment of erythema nodosum in leprosy and is now approved for multiple myeloma as well A second generation IMiD, lenalidomide, is also approved for multiple myeloma and refractory myelodysplastic syndrome Discovery of this class of drugs has been serendipitous and empirical, as the drug targets have been unknown In this review, the authors integrate recent identification of drug targets of IMiDS, which include the inducible form of nitric oxide synthase (iNOS), Rho GTPase and caspase-1, with the developments in the understanding of the molecular biology of human inflammatory, infectious and neoplastic skin disorders Because thalidomide reemerged through leprosy, the original disease classified by the T cell, the authors have also emphasized advances in the understanding of T-cell subsets in human skin disorders.
"The role of complement in dendritic cell (DC) control of T-cell subsets" [Editorial]LEVIS, WILLIAM R; Martiniuk, Frank
This section of the Journal of Drugs in Dermatology (JDD) is dedicated to Dendreon's Provenge (Sipuleucel-T), the first therapeutic DC vaccine proven effective and approved by the United States (U.S.) Food and Drug Administration (FDA) for advanced cancer. This editorial will discuss three articles in this issue, their relationship to Provenge and the recent TH17-Treg subsets that are regulated by CD46.
"TH17 is involved in the remarkable regression of metastatic malignant melanoma to topical diphencyprone"Martiniuk, Frank; Damian, Diona L; Thompson, John F; Scolyer, Richard A; Tchou-Wong, Kam-Meng; LEVIS, WILLIAM R
GRANTS:1UL1RR029893/RR/NCRR NIH HHS/United States;UL1 RR029893-01/RR/NCRR NIH HHS/United States
The authors provide an update on a previously reported patient with in-transit metastatic melanoma of the scalp treated with topical diphencyprone (DPCP). Molecular studies implicate the thymus-derived TH17 lymphocyte subset in a remarkable immunotherapeutic regression. The authors performed RT-PCR of total RNA from paraffin-embedded tissue before and after treatment with DPCP. Before treatment with DPCP, the authors found elevated expression of IL 17C/D/E/F; after treatment there was no detectable expression. Conversely, increased expression of PLZF/CD27 and CTLA4 was seen after treatment with no expression before treatment. No expression of IL17A/B, CD7, RORgTand FoxP3 were before or after treatment. Conclusions are limited to only the time samples were obtained. Remarkable regression of an in-transit metastatic melanoma treated with the immunomodulatory agent DPCP showed gain and loss of gene expression of the TH17 pathway. Further study of this pathway from NK to NK-T to TH7 and TH1 cells both with and without accessory or dendritic cells will improve understanding of contact sensitizers as topical immunomodulators.
"Effect of thalidomide on nitric oxide production in lipopolysaccharide-activated RAW 264.7 cells"Park, Eunkyue; LEVIS, WILLIAM R; Greig, Nigel; Jung, Euisun; Schuller-Levis, Georgia
Thalidomide is anti-inflammatory under some conditions, yet has been reported to up-regulate Th1 (T helper 1) immunity measured by increased IL-2 (Interleukin-2) and gamma interferon. The authors have assessed the effect of thalidomide and analogues, di- and tri-thiothalidomide, on a lipopolysaccharide (LPS) activated macrophage cell line (RAW 246.7 cells). The authors' findings showed that nitric oxide (NO) was significantly inhibited by thalidomide (15%) and its analogues (di-thiothalidomide; 15%, tri-thiothalidomide; 32%). The proinflammatory molecules TNF-alpha (tumor necrosis factor-alpha) and IL-6 were not significantly inhibited. Pretreatment with thalidomide and analogues before activation was not different from simultaneous treatment. Inhibition of inducible nitric oxide synthase (iNOS) may prove to be an important target for the anti-inflammatory and anti-cancer effects of thalidomide and related immunomodulatory drugs (IMiDs).