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Article ; Online: Two women with primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder during pregnancy.

Gambichler, Thilo / Scheel, Christina H / Kock, Katharina / Klapper, Wolfram / Doerler, Martin / Boms, Stefanie

2023 Volume 48, Issue 5, Page(s) 533–535

MeSH term(s)	Humans ; Female ; Pregnancy ; Skin Diseases ; Skin ; CD4-Positive T-Lymphocytes ; Lymphoproliferative Disorders ; Lymphoma, T-Cell, Cutaneous ; Skin Neoplasms
Language	English
Publishing date	2023-02-10
Publishing country	England
Document type	Letter
ZDB-ID	195504-4
ISSN	1365-2230 ; 0307-6938
ISSN (online)	1365-2230
ISSN	0307-6938
DOI	10.1093/ced/llad004
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Article: Phenotypic plasticity of malignant T cells in blood and skin of a Sézary syndrome patient revealed by single cell transcriptomics.

Peiffer, Lukas / Gambichler, Thilo / Buus, Terkild B / Horny, Kai / Gravemeyer, Jan / Furtmann, Frauke / Spassova, Ivelina / Kubat, Linda / Susok, Laura / Stranzenbach, René / Srinivas, Nalini / Ødum, Niels / Becker, Jürgen C

Frontiers in oncology

2023 Volume 13, Page(s) 1090592

Abstract: Background: Sézary Syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas ... CTCL). In SS patients, malignant T cells are circulating through the blood and cause erythroderma ... with advanced SS.: Methods: We utilized combined single cell RNA and T-cell receptor (TCR) sequencing (scRNA ...

Abstract	Background: Sézary Syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL). In SS patients, malignant T cells are circulating through the blood and cause erythroderma. Objective: To compare the transcriptome of single cells in blood and skin samples from a patient with advanced SS. Methods: We utilized combined single cell RNA and T-cell receptor (TCR) sequencing (scRNA-seq). Results: We scrutinized the malignant T cells in blood and skin in an unbiased manner without pre-sorting of cells. We observed different phenotypes of the same monoclonal malignant T-cell population, confirmed by TCR sequencing and inferred copy number variation analysis. Malignant T cells present in the circulating blood expressed genes resembling central memory T cells such as Conclusions: Using scRNA-seq we detected a high degree of functional heterogeneity within the malignant T-cell population in SS and highlighted crucial differences between SS cells in blood and skin.
Language	English
Publishing date	2023-01-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1090592
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Article ; Online: T regulatory cells in polymorphic light eruption.

Gambichler, T

The British journal of dermatology

2015 Volume 173, Issue 2, Page(s) 330–331

MeSH term(s)	Female ; Humans ; Male ; Photosensitivity Disorders/immunology ; T-Lymphocytes, Regulatory/physiology ; Ultraviolet Therapy/methods
Language	English
Publishing date	2015-08
Publishing country	England
Document type	Comment ; Journal Article
ZDB-ID	80076-4
ISSN	1365-2133 ; 0007-0963
ISSN (online)	1365-2133
ISSN	0007-0963
DOI	10.1111/bjd.13996
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Article ; Online: Frequency of circulating subpopulations of T-regulatory cells in patients with hidradenitis suppurativa.

Hessam, S / Gambichler, T / Höxtermann, S / Skrygan, M / Sand, M / Garcovich, S / Meyer, T / Stockfleth, E / Bechara, F G

Journal of the European Academy of Dermatology and Venereology : JEADV

2019 Volume 34, Issue 4, Page(s) 834–838

Abstract: Background: Decreased number of T-regulatory cells (Tregs) and/or their loss of function ... of natural Tregs among CD4+ T lymphocytes were significantly reduced in the HS group compared to the healthy ...

Abstract	Background: Decreased number of T-regulatory cells (Tregs) and/or their loss of function potentially lead to uncontrolled immune-mediated inflammatory responses. There are only few data available on Tregs in hidradenitis suppurativa (HS) - a disease in which it has been suggested that host immune factors and an overactive immune system of the follicular epithelium play a pathogenetic role. Objectives: To analyse frequencies of Tregs subpopulations in blood of HS patients in comparison with a healthy control group. Materials & methods: Blood samples obtained from HS patients and healthy controls were evaluated by flow cytometry and enzyme-linked immunosorbent assay. Results: The frequency of natural Tregs among CD4+ T lymphocytes were significantly reduced in the HS group compared to the healthy controls. The proportion of activated Tregs, non-suppressive Tregs and proliferating Tregs showed no significant difference when compared to controls. Regarding Tregs frequencies, there was no significant difference between the three Hurley stages. Serum concentrations of IL-10, TGF-ß1 and IL-17A did not show significant differences between the HS and control group. Conclusion: The reduction of natural Tregs observed in blood of HS patients could be the result of Tregs homing to sites of inflammatory hot spots in HS skin. Further studies are justified evaluating the role of circulating Tregs during the evolution of HS lesions and as a biomarker for treatment response.
MeSH term(s)	Adult ; Case-Control Studies ; Female ; Hidradenitis Suppurativa/immunology ; Humans ; Male ; Middle Aged ; T-Lymphocytes, Regulatory/immunology
Language	English
Publishing date	2019-12-09
Publishing country	England
Document type	Journal Article
ZDB-ID	1128828-0
ISSN	1468-3083 ; 0926-9959
ISSN (online)	1468-3083
ISSN	0926-9959
DOI	10.1111/jdv.16071
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Article ; Online: Bullous pemphigoid after SARS-CoV-2 vaccination: spike-protein-directed immunofluorescence confocal microscopy and T-cell-receptor studies.

Gambichler, T / Hamdani, N / Budde, H / Sieme, M / Skrygan, M / Scholl, L / Dickel, H / Behle, B / Ganjuur, N / Scheel, C / Abu Rached, N / Ocker, L / Stranzenbach, R / Doerler, M / Pfeiffer, L / Becker, J C

The British journal of dermatology

2022 Volume 186, Issue 4, Page(s) 728–731

MeSH term(s)	COVID-19/prevention & control ; COVID-19 Vaccines/adverse effects ; Fluorescent Antibody Technique ; Humans ; Microscopy, Confocal ; Pemphigoid, Bullous/etiology ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; T-Lymphocytes ; Vaccination
Chemical Substances	COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-01-20
Publishing country	England
Document type	Letter
ZDB-ID	80076-4
ISSN	1365-2133 ; 0007-0963
ISSN (online)	1365-2133
ISSN	0007-0963
DOI	10.1111/bjd.20890
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Article: Primary Cutaneous CD30+ Anaplastic Large T Cell Lymphoma in a Patient Treated with Cyclosporine for Actinic Reticuloid.

Gambichler, T / Patsinakidis, N / Susok, L / Segert, M H / Doerler, M

Case reports in dermatological medicine

2020 Volume 2020, Page(s) 9435242

Abstract: ... T cell lymphoma (CTCL) who developed severe broadband photosensitivity. Clinical evaluation ...

Abstract	Actinic reticuloid (AR)-a subtype of chronic actinic dermatitis-clinically and histopathologically shows lymphoma-like features. We report a male patient initially diagnosed with erythrodermic cutaneous T cell lymphoma (CTCL) who developed severe broadband photosensitivity. Clinical evaluation, histopathology, and phototesting were consistent with AR. The patient was treated with cyclosporine 150-300 mg/d. Under this therapy, he developed several times primary cutaneous anaplastic large cell lymphomas (C-ALCL) which in part tended to regress spontaneously under cyclosporine reduction. The association between cyclosporine treatment and development of C-ALCL and other CD30+ lymphoproliferative disorders has previously been reported in patients with atopic dermatitis, psoriasis, and transplant patients. In conclusion, the present case highlights the difficulties arising in the distinction between AR and CTCL and shows that long-term cyclosporine treatment may cause C-ALCL development in AR as well.
Language	English
Publishing date	2020-03-25
Publishing country	United States
Document type	Case Reports
ZDB-ID	2684644-5
ISSN	2090-6471 ; 2090-6463
ISSN (online)	2090-6471
ISSN	2090-6463
DOI	10.1155/2020/9435242
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Article ; Online: T regulatory cells and other lymphocyte subsets in patients with bullous pemphigoid.

Gambichler, T / Tsitlakidon, A / Skrygan, M / Höxtermann, S / Susok, L / Hessam, S

Clinical and experimental dermatology

2017 Volume 42, Issue 6, Page(s) 632–637

Abstract: ... to investigate the significance of T regulatory cells and other lymphocyte subsets in patients with BP ... cytotoxic T lymphocytes, B lymphocytes, natural killer cells, CD4+CD25++CD127- cells were assessed ...

Abstract	Background: Bullous pemphigoid (BP) is the most common autoimmune blistering disease, and is associated with autoantibodies to the hemidesmosomal BP autoantigens BPAG1 and BPAG2. Aim: We aimed to investigate the significance of T regulatory cells and other lymphocyte subsets in patients with BP. Methods: In total, 31 inpatients with BP were treated with systemic prednisolone in a tapered dose regimen, while 28 healthy individuals matched for age and sex served as the healthy control (HC) group., Blood samples were taken at baseline and after treatment, and levels of inducer/helper and suppressor/cytotoxic T lymphocytes, B lymphocytes, natural killer cells, CD4+CD25++CD127- cells were assessed by flow cytometry, while CD4, CD8, and FOXP3 positivity were assessed by immunohistochemistry, and FOXP3 mRNA was assessed by reverse transcription (RT)-PCR. Results: Flow cytometry showed that numbers of CD8+ and CD4+CD25++CD127- cells were significantly increased, while the number of CD4+ cells and the CD4/CD8 ratio were significantly decreased at baseline and after therapy in patients with BP compared with HCs. Immunohistology revealed that CD4+, CD8+ and FOXP3+ cells were significantly increased at baseline and post-treatment in patients with BP compared with HCs. FOXP3 mRNA levels were significantly increased in the blood of patients with BP compared with HCs. Conclusion: These results indicate that increased numbers of CD8+, CD4+CD25++CD127- cells and FOXP3+ cells may play a pathogenetic role during the course of BP.
Language	English
Publishing date	2017-08
Publishing country	England
Document type	Journal Article
ZDB-ID	195504-4
ISSN	1365-2230 ; 0307-6938
ISSN (online)	1365-2230
ISSN	0307-6938
DOI	10.1111/ced.13135
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Zs.A 1278: Show issues

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Article ; Online: Low Drosha protein expression in cutaneous T-cell lymphoma is associated with worse disease outcome.

Gambichler, T / Salveridou, K / Schmitz, L / Käfferlein, H U / Brüning, T / Stockfleth, E / Sand, M / Lang, K

Journal of the European Academy of Dermatology and Venereology : JEADV

2019 Volume 33, Issue 9, Page(s) 1695–1699

Abstract: ... cancer types.: Objectives: We aimed to evaluate Drosha and Dicer protein expression in cutaneous T ...

Abstract	Background: Dysregulation of microRNAs (miRNAs) key regulators may contribute to the pathogenesis of malignancies. miRNA machinery genes such Dicer and Drosha have been reported to be biomarkers in different cancer types. Objectives: We aimed to evaluate Drosha and Dicer protein expression in cutaneous T-cell lymphoma (CTCL). Methods: We performed Drosha and Dicer immunohistochemistry in 45 patients with mycosis fungoides and subtypes. Drosha and Dicer expression scores were correlated with clinical parameters including disease-specific death (DSD), stage of disease and different laboratory data. Uni- and multivariate statistics were performed. Results: On univariate analysis, elevated serum LDH and low Drosha expression were significantly associated with advanced stage (P = 0.032 and 0.0062, respectively) and lymphoma-specific death (LSD; P = 0.017 and P = 0.005, respectively). Moreover, elevated circulating CD4+/CD26- lymphocytes were significantly associated with advanced stage (P = 0.032) and DSD (P = 0.0098). On multivariate analysis, low Drosha expression remained in the logistic regression model as significant independent predictor for advanced disease stages [P = 0.013; odds ratio: 5 (confidence interval) CI 1.3-19.3]. Moreover, low Drosha expression (P = 0.026) and elevated LDH (P = 0.025) remained as significant independent predictors for DSD with odds ratios of 13.5 (CI 1.3-134.4 and 8.7 CI 1.3-57.2, respectively). Conclusions: Low Drosha expression is an independent predictor for advanced stage as well as LSD in CTCL patients indicating a tumour suppressor gene function of Drosha in this disorder.
MeSH term(s)	Aged ; Biomarkers, Tumor/blood ; DEAD-box RNA Helicases/blood ; Female ; Humans ; Lymphoma, T-Cell, Cutaneous/blood ; Lymphoma, T-Cell, Cutaneous/mortality ; Lymphoma, T-Cell, Cutaneous/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Ribonuclease III/blood
Chemical Substances	Biomarkers, Tumor ; DICER1 protein, human (EC 3.1.26.3) ; DROSHA protein, human (EC 3.1.26.3) ; Ribonuclease III (EC 3.1.26.3) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2019-06-06
Publishing country	England
Document type	Journal Article
ZDB-ID	1128828-0
ISSN	1468-3083 ; 0926-9959
ISSN (online)	1468-3083
ISSN	0926-9959
DOI	10.1111/jdv.15652
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Article ; Online: A Brief Communication on Circulating PD-1-positive T-Regulatory Lymphocytes in Melanoma Patients Undergoing Adjuvant Immunotherapy With Nivolumab.

Gambichler, Thilo / Schröter, Ulrike / Höxtermann, Stefan / Susok, Laura / Stockfleth, Eggert / Becker, Jürgen C

Journal of immunotherapy (Hagerstown, Md. : 1997)

2019 Volume 42, Issue 7, Page(s) 265–268

Abstract: Upregulation of T-regulatory lymphocytes (Tregs) is one of numerous immune escape mechanisms ...

Abstract	Upregulation of T-regulatory lymphocytes (Tregs) is one of numerous immune escape mechanisms of malignancies. In the present pilot study we aimed to study the effect of adjuvant nivolumab during the initiation of treatment on circulating Tregs subpopulations in patients with stage III melanoma. We subsequently recruited patients with stage III melanoma who had the indication for adjuvant anti-programmed death 1 (PD-1) treatment with nivolumab. Blood collections were performed before the initiation of nivolumab and before every 2-week therapy cycle. Flow cytometry was performed for the determination of circulating CD4CD25highCD127PD-1(PD-1Tregs) and CD4CD25highCD127CTLA-4 (CTLA-4Tregs) Treg populations. Circulating PD-1Tregs [18.1% (range, 2.9%-41.7%) vs. 4.2% (0.4%-9.8%), P=0.0001] significantly decreased after the first cycle of immunotherapy and maintained decreased during a 3-month course of treatment. By contrast, CTLA-4Tregs significantly increased after the first nivolumab dose when compared with CTLA-4Tregs before the second treatment [0.75 (0-45.5) vs. 2.1 (0.1-90.8), P=0.0002]. Blood levels of PD-1Tregs and CTLA-4Tregs remained more or less decreased and increased during a 3-month therapy with nivolumab, respectively. Data of PD-1Tregs as well as CTLA-4Tregs was not significantly associated with frequencies of immune-related adverse events (P<0.05). In conclusion, we have demonstrated that circulating PD-1Tregs of melanoma patients in stage III rapidly and continuously decline after the initiation of adjuvant treatment with the PD-1 blocking antibody nivolumab. By contrast, this decline is paralleled with an increase of CTLA-4Tregs. The expression of PD-1 and CTLA-4 on Tregs might be a potential biomarker for the efficacy of immune checkpoint blockade in melanoma.
MeSH term(s)	Aged ; Antineoplastic Agents, Immunological/therapeutic use ; Female ; Humans ; Immunophenotyping ; Lymphocyte Count ; Male ; Melanoma/blood ; Melanoma/diagnosis ; Melanoma/drug therapy ; Melanoma/metabolism ; Middle Aged ; Molecular Targeted Therapy ; Neoplasm Staging ; Nivolumab/therapeutic use ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/metabolism ; T-Lymphocytes, Regulatory/metabolism ; Treatment Outcome
Chemical Substances	Antineoplastic Agents, Immunological ; Programmed Cell Death 1 Receptor ; Nivolumab (31YO63LBSN)
Language	English
Publishing date	2019-05-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1064067-8
ISSN	1537-4513 ; 1053-8550 ; 1524-9557
ISSN (online)	1537-4513
ISSN	1053-8550 ; 1524-9557
DOI	10.1097/CJI.0000000000000277
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Article ; Online: MCPyV Large T Antigen-Induced Atonal Homolog 1 Is a Lineage-Dependency Oncogene in Merkel Cell Carcinoma.

Fan, Kaiji / Gravemeyer, Jan / Ritter, Cathrin / Rasheed, Kashif / Gambichler, Thilo / Moens, Ugo / Shuda, Masahiro / Schrama, David / Becker, Jürgen C

The Journal of investigative dermatology

2019 Volume 140, Issue 1, Page(s) 56–65.e3

Abstract: ... of different Merkel cell polyomavirus (MCPyV)-derived truncated large T antigens induced ATOH1 expression ...

Abstract	Despite the fact that the transcription factor ATOH1 is a master regulator of Merkel cell development, its role in Merkel cell carcinoma (MCC) carcinogenesis remains controversial. Here, we provide several lines of evidence that ATOH1 is a lineage-dependent oncogene in MCC. Luciferase assays revealed binding of ATOH1 and subsequent activation to the promoter of miR-375, which is one of the most abundant microRNAs in MCCs. Overexpression of ATOH1 in variant MCC cell lines and fibroblasts induced miR-375 expression, whereas ATOH1 knockdown in classical MCC cell lines reduced miR-375 expression. Moreover, ATOH1 overexpression in these cells changed their growth characteristics from adherent to suspension and/orspheroidal growth, that is, resembling the neuroendocrine growth pattern of classical MCC cell lines. Notably, ectopic expression of different Merkel cell polyomavirus (MCPyV)-derived truncated large T antigens induced ATOH1 expression in fibroblasts, which was paralleled by miR-375 expression and similar morphologic changes. In summary, MCPyV-associated carcinogenesis is likely to induce the characteristic neuroendocrine features of MCC via induction of ATOH1; thus, ATOH1 can be regarded as a lineage-dependent oncogene in MCC.
MeSH term(s)	Antigens, Viral, Tumor/genetics ; Antigens, Viral, Tumor/metabolism ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Carcinogenesis ; Carcinoma, Merkel Cell/genetics ; Cell Differentiation ; Cell Line, Tumor ; Cell Lineage ; Gene Expression Regulation, Neoplastic ; Humans ; Merkel cell polyomavirus/physiology ; MicroRNAs/genetics ; Oncogenes/genetics ; Polyomavirus Infections ; Skin Neoplasms/genetics ; Tumor Virus Infections
Chemical Substances	ATOH1 protein, human ; Antigens, Viral, Tumor ; Basic Helix-Loop-Helix Transcription Factors ; MIRN375 microRNA, human ; MicroRNAs
Language	English
Publishing date	2019-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2019.06.135
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