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• W2085104879 abstract "human T-cell lymphotropic virus type 1/type 2 mycosis fungoides Sézary syndrome TO THE EDITOR The association between infection by the human T-cell lymphotropic virus types 1 (HTLV-1) and 2 (HTLV-2) and the most common form of cutaneous T-cell lymphoma called mycosis fungoides (MF), along with its leukemic variant called Sézary syndrome (SS), is unclear. In both MF and SS, antibodies against HTLV-1 structural proteins and HTLV-1/-2 DNA sequences have been detected in peripheral blood mononuclear cells (PBMCs), cutaneous biopsies (Hall et al., 1991Hall W. Liu C. Schneewind O. Takahashi H. Kaplan M. Roüpe G. et al.Deleted HTLV-I provirus in blood and cutaneous lesions of patients with mycosis fungoides.Science. 1991; 253: 317-320Crossref PubMed Scopus (161) Google Scholar; Whittaker and Luzzatto, 1993Whittaker S.J. Luzzatto L. HTLV-1 provirus and mycosis fungoides.Science. 1993; 259: 1470Crossref PubMed Google Scholar; Zucker-Franklin, 2001Zucker-Franklin D. The role of human T cell lymphotropic virus type I tax in the development of cutaneous T cell lymphoma.Ann NY Acad Sci. 2001; 941: 86-96Crossref PubMed Scopus (27) Google Scholar), and saliva (Morozov et al., 2005Morozov V.A. Syrtsev A.V. Ellerbrok H. Nikolaeva E.V. Bavykin A.S. Pauli G. Mycosis fungoides in European Russia: no antibodies to human T cell leukemia virus type I structural proteins, but virus-like sequences in blood and saliva.Intervirology. 2005; 48: 362-371Crossref PubMed Scopus (12) Google Scholar). HTLV-1 tax sequences have also been detected in PBMCs of healthy donors (Zucker-Franklin and Pancake, 1998Zucker-Franklin D. Pancake B.A. Human T-cell lymphotropic virus type 1 tax among American blood donors.Clin Diagn Lab Immunol. 1998; 5: 831-835PubMed Google Scholar). However, these original observations need to be confirmed; furthermore, the relationship between the presence of HTLV sequences and clinical outcome for the MF/SS patients is not known. This study was performed on Italian patients affected by cutaneous T-cell lymphoma (CTCL) (n=66) in the forms of large-plaque parapsoriasis (n=8), MF (n=45), and SS (n=13) for DNA sequences associated with HTLV-1/-2. Large-plaque parapsoriasis is generally considered a common initial form of MF (Cerroni et al., 2005Cerroni L. Gatter K. Kerl H. Mycosis fungoides.in: Cerroni L. Gatter K. Kerl H. An illustrated guide to skin lymphoma. Blackwell Publishing, Oxford2005: 9-44Google Scholar), whereas it is unclear whether SS is a separate disease or, as others claim, the “leukemic form” of MF. This lack of clarity stems from the fact that SS diagnosis is sometimes preceded by cutaneous lesions that resemble large-plaque parapsoriasis or, in turn, MF patches (Cerroni et al., 2005Cerroni L. Gatter K. Kerl H. Mycosis fungoides.in: Cerroni L. Gatter K. Kerl H. An illustrated guide to skin lymphoma. Blackwell Publishing, Oxford2005: 9-44Google Scholar). Patient records and outcomes for this study are summarized in Table S1 (see Supplementary Material). The study was conducted with institutional approval of the experiments, patient consent, and adherence to the Declaration of Helsinki principles. Download .pdf (.04 MB) Help with pdf files Table S1Clinical characteristics of patients with LPP, MF and SS Serological analyses, which were performed according to the The HTLV European Research Network, 1996The HTLV European Research Network Seroepidemiology of the human T-cell leukaemia/lymphoma viruses in Europe.J Acquir Immune Defic Syndr Hum Retrovirol. 1996; 13: 68-77PubMed Google Scholar, yielded negative results for HTLV-1/-2 antibodies in both patients and controls (data not shown). HTLV-1/-2 gag, env, and pol sequences were undetectable in both PBMCs and cutaneous biopsies from all patients when tested by PCR/Southern blot (data not shown). Control PBMCs of 35 healthy blood donors, and cutaneous biopsies from 13 patients affected by benign inflammatory cutaneous disorders were also negative. PCR analysis of tax sequences performed on MF cutaneous biopsies yielded a positive result in one patient, who presented with a granulomatous form (no. 11MF, Table S1). All samples were tested by SB, using the SK45 probe specific for an HTLV-1/2-tax common region. An SK45-positive signal was evident in 2/45 MF patients (5.3%) (nos. 11MF and 18MF), whereas no HTLV sequences were detected in large-plaque parapsoriasis patients (Figure 1a). Interestingly, patient no. 11MF was the only case, in our cohort of eight cases of granulomatous MF, who showed disease progression. Similarly, patient no. 18MF, diagnosed with a classical form of MF, evolved from stage IB to III in a few months and then to death, in spite of stage-related treatments (photo-chemotherapy, interferon-α, and chemotherapy). The copy number of the HTLV-tax sequence present in the cutaneous biopsy of patient no. 11MF was further evaluated by Syber green real-time PCR (for methods, see Lee et al., 2004Lee T.H. Chafets D.M. Busch M.P. Murphy E.L. Quantitation of HTLV-I and II proviral load using real-time quantitative PCR with SYBR Green chemistry.J Clin Virol. 2004; 31: 275-282Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Using quantified DNA from C10 and C344Mo HTLV cell lines as standard, we estimated about 25 copies of tax per 105 cells (data not shown). However, tax sequences were not detected in PBMCs, clinically unaffected skin, or a reactive lymph node from the same patient. Positive results were found only in the affected tissue. In SS patients, an SK45-positive signal was detected in skin (8/11), and in PBMC (2/6) (Figure 1a). According to the histopathological features of cutaneous lymphomas, SS patients showed a relatively poor dermo-epidermic atypical lymphocyte infiltrate with respect to MF cases. This may reflect the lower PCR-SB signal intensity obtained in SS biopsies compared with MF specimens. To define more precisely the size of the tax sequence detected in our samples, external primers to SK43 (nt 6798–6819; AY818420) and SK44 (nt 7591–7571; AY818420) were used to amplify a 790-bp DNA fragment (Morozov et al., 2005Morozov V.A. Syrtsev A.V. Ellerbrok H. Nikolaeva E.V. Bavykin A.S. Pauli G. Mycosis fungoides in European Russia: no antibodies to human T cell leukemia virus type I structural proteins, but virus-like sequences in blood and saliva.Intervirology. 2005; 48: 362-371Crossref PubMed Scopus (12) Google Scholar). The failure to detect tax with the external primers suggests that the tax-like sequences present in our CTCL patients have a length between 159 and 790 bp. When 159-bp amplimers of patients 11MF and 18 MF were sequenced and aligned using the BLAST database, the two MF amplimers were found to share 100% homology with a portion of the tax gene of HTLV-2 isolates and 85% homology with the tax gene of HTLV-1 isolates (Figure 1b). The sequence that is detected in the patients is localized in the functional domain of the tax gene that controls the subcellular localization of the tax protein (Turci et al., 2006Turci M. Pilotti E. Ronzi P. Magnani G. Boschini A. Parisi S.G. et al.Coinfection with HIV-1 and human T-cell lymphotropic virus type II in intravenous drug users is associated with delayed progression to AIDS.J Acquir Immune Defic Syndr. 2006; 41: 100-106Crossref PubMed Scopus (39) Google Scholar), and is important for cellular gene transactivation through cyclic-AMP response element binding protein (CREB)/activating transcription factor (ATF) CREB/ATF or nuclear factor-kappa B (NF-κB) signaling pathways (Feuer and Green, 2005Feuer G. Green P.L. Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2.Oncogene. 2005; 24: 5996-6004Crossref PubMed Scopus (128) Google Scholar). The amplimers of SS patients could not be sequenced because of the low quantity of DNA obtained from biopsies, and the patient's death during follow-up. The presence of infiltrating T cells in CTCL and the possible involvement of tax-like sequences in disease progression points to the possibility that altered production of cytokines may influence tumor phenotype and growth. We have determined the plasma expression levels of 15 cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFN-γ, tumor necrosis factor-α, IL-1β, IL-5, IL-7, IL-12, IL-13, IL-17, G-CSF) in seven tax2-like positive and seven tax2-like negative CTCL subjects, as well as in healthy donors. Fourteen of the 15 cytokines were upregulated in tax-positive versus tax-negative groups and in tax-positive versus donors groups (P-value <0.05). IL-7 was the single downregulated cytokine. A lower difference in cytokine expression patterns was observed in tax-negative, when compared to healthy subjects, with the exception of IL-17 and IL-7 (Figure 1c). The two tax2-like positive MF cases presented the same cytokine pattern as did the SS cases. The data suggest that the two different cytokine patterns occurring in CTCL appeared to be characterized by the presence or absence of tax2-like sequences. As this sequence was absent in almost all MF cases, but present in nearly all SS cases, presence of the tax2-like sequence could be a marker for disease status. However, since IL-7 and IL-17, both tax-inducible cytokines (Dodon et al., 2004Dodon M.D. Li Z. Hamaia S. Gazzolo L. Tax protein of human T-cell lekaemia virus type 1 induces interleukin 17 gene expression in T cells.J Gen Virol. 2004; 85: 1921-1932Crossref PubMed Scopus (36) Google Scholar), are secreted similarly in both MF and SS patients (Cirée et al., 2004Cirée A. Michel L. Camilleri-Broët S. Jean Louis F. Oster M. Flageul B. et al.Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sézary syndrome).Int J Cancer. 2004; 112: 113-120Crossref PubMed Scopus (91) Google Scholar), the presence of tax2-like sequence is not required for the modulation of their expression. MF skin contains high levels of IL-6, which is another tax-inducible cytokine (Galli et al., 2004Galli G. Chantry D. Annunziato F. Romagnani P. Cosmi L. Lazzeri E. et al.Macrophage-derived chemokine production by activated human T cells in vitro and in vivo: preferential association with the production of type 2 cytokines.Eur J Immunol. 2004; 30: 204-210Crossref Scopus (105) Google Scholar). In our tax2-negative patients, IL-6 levels were in the normal range, but significantly elevated in the tax2-positive group. IL-6 appears to be involved in the recruitment of lymphocytes into non-lymphoid tissues, including the skin (Watson et al., 1996Watson C. Whittaker S. Smith N. Vora A.J. Dumonde D.C. Brown K.A. IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes.Clin Exp Immunol. 1996; 105: 112-119Crossref PubMed Scopus (130) Google Scholar). Therefore, its role could be cellular recruitment in MF, but it has a significant systemic function in SS patients. Of note is the finding that SS patients have a cytokine production profile typical of the effector CD4+Th-17 lineage (Weawer et al., 2006Weawer C.T. Harrington L.E. Mangan P.R. Gavrieli M. Murphy K.M. Th17: An effector CD4 T cell lineage with regulatory T cell ties.Immunity. 2006; 24: 677-688Abstract Full Text Full Text PDF PubMed Scopus (1114) Google Scholar). Studies are in progress to understand the role of IL-7 as a growth factor for Sézary cells. In this study, we have explored the presence of HTLV tax-like sequences in CTCL and hypothesized a possible role as a negative prognostic marker for disease progression in MF/SS. The basis of the hypothesis is its absence in large-plaque parapsoriasis patients, its sporadic detection in MF patients with disease progression, and its high frequency in blood and skin of SS patients. Our results show unambiguously that MF and SS patients are harboring an HTLV-2, rather than HTLV-1, tax-like sequence. These data are consistent with the report that HTLV-2, but not HTLV-1, is prevalent in southern Europe (Salemi et al., 1996Salemi M. Vandamme A.M. Guano F. Gradozzi C. Cattaneo E. Casoli C. et al.Complete nucleotide sequence of the Italian human T-cell lymphotropic virus type II isolate Gu and phylogenetic identification of a possibile origin of South European epidemics.J Gen Virol. 1996; 77: 1193-1201Crossref PubMed Scopus (26) Google Scholar; Toro et al., 2005Toro C. Rodes B. Bassani S. Jimenez V. Tuset C. Brugal M.T. On behalf of the HTLV Spanish Study Group et al.Molecular epidemiology of HTLV-2 infection among intravenous drug users in Spain.J Clin Virol. 2005; 33: 65-70Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). A unique case of HTLV-2-related MF has been described (Zucker-Franklin et al., 1992Zucker-Franklin D. Hooper W.C. Evatt B.L. Human lymphotropic retroviruses associated with mycosis fungoides: evidence that human T-cell lymphotropic virus type II (HTLV-II) as well as HTLV-I may play a role in the disease.Blood. 1992; 80: 1537-1545PubMed Google Scholar), but it was reported as an HTLV-2 infection, rather than as a patient who was carrying an endogenous sequence. Our findings are against a previous HTLV-2 infection and a defective provirus, in tissues and PBMC of CTCL patients. The authors state no conflict of interest. We thank Professor Lucy Rasmussen (Stanford University, CA) and Professor Umberto Bertazzoni (University of Verona, Italy) for critically reviewing the manuscript and for English revision. This work was supported by Cariparma Banking Foundation (Grant 2004.0190) (C.C.) Table S1. Clinical characteristics of patients with LPP, MF, and SS." @default.
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• W2085104879 title "The HTLV tax-Like Sequences in Cutaneous T-Cell Lymphoma Patients" @default.
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