Human and Mouse Mast Cells Express and Secrete the GPI-Anchored Isoform of CD160

CD160 is expressed by human and mouse natural killer (NK) cells and other cytotoxic lymphocyte subpopulations. CD160 is mostly expressed as a trimeric 83kDa glycosylphosphatidylinositol (GPI)-anchored activating NK receptor, cleaved upon IL-15 stimulation in a secreted trimeric soluble form (sCD160) that binds to major histocompatibility complex (MHC) class I molecules, while a transmembrane isoform appears. sCD160 exhibits immunoregulatory function as it inhibits CD8+ T-lymphocyte cytotoxic activity. We show that human mast cells (MCs) express CD160. In human and mouse skin, resident MCs expressed CD160, whereas in C57BL/6-KitW-sh/W-sh mice, CD160+ cells were only identified at the site of reconstitution with syngeneic cultured MCs. In the human mast cell line, HMC-1, we only identified the transcripts of the GPI-anchored CD160 isoform. Furthermore, CD160 was identified in HMC-1 and mouse MC supernatants, suggesting that MCs release sCD160. Supporting this hypothesis, HMC-1 express the GPI-specific phospholipase D variant 2 involved in the NK lymphocyte membrane cleavage of CD160, and morphological studies highlighted a relative loss of CD160 expression in inflammatory skin sites, where MC degranulation is expected to occur. We also demonstrated an inhibition of T-cell cytotoxicity by HMC-1 supernatant that was partially reversed by anti-CD160 mAb. In conclusion, sCD160, produced by MCs, may have a role in T-cell–MC interactions in vivo

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

ABSTRACT Background Advanced-stage mycosis fungoides (MF)/Sezary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. Patients and methods This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). Results Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. Conclusion This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach

Histopathologic diagnosis of lymphomatous versus inflammatory erythroderma: a morphologic and phenotypic study on 47 skin biopsies.: Histopathological diagnosis of erythroderma

International audienceErythroderma may be secondary to a cutaneous T-cell lymphoma (CTCL) and various other erythrodermic inflammatory dermatoses (EID), and their histopathologic distinction is often difficult. The aim of this study was to determine if morphological parameters, namely: the presence of b-catenin, and JunB (previously shown to be expressed by CTCL cells), the epidermal CD8:CD3 ratio, and CD30 expression may help in the histopathologic diagnosis of erythroderma, especially in differentiating CTCL and EID. We retrospectively reviewed a series of 47 skin biopsies from patients with erythroderma (18 CTCL and 29 EID). The diagnosis of each case was established using clinical, biological and histopathologic data. After a blind assessment of the hematoxylin--eosin--safran stained slides, a correct diagnosis of the underlying cause of erythroderma was made only in 31% of cases. A correct differential diagnosis between lymphoma and EID was done with certainty in 57% of cases. Various morphologic and phenotypic parameters were then recorded and we compared their frequency in the CTCL versus the EID group. With the exception of atypical lymphocytes, the moderate to high density of dermal infiltrates and Pautrier microabcesses, only found in CTCL, no morphologic parameter was found to be specific of CTCL, although single lymphocytes epidermotropism, telangiectasias, and slight lymphocytic dermal infiltrate were significantly more frequent in EID. A low (<10%) CD8:CD3 ratio in the epidermal lymphocytic infiltrate and dermal CD30+ lymphocytes were significantly more frequent in CTCL. JunB expression by lymphocytes was specific of CTCL, but was inconstant in our series (17%). We found β-catenin expression in a minority of cases from both the CTCL and EID groups. Among EID, dermal suprapapillary thinning was specific of psoriasis. Neutrophils exocytosis and edema of papillary dermis were significantly more frequent in psoriasis, and spongiosis was more frequent in eczema. In conclusion, few morphological and phenotypical parameters are helpful in making a differential diagnosis between erythrodermic CTCL and EID using paraffin embedded skin biopsies

Involvement of the CD39/CD73/adenosine pathway in T-cell proliferation and NK cell-mediated antibody-dependent cell cytotoxicity in Sézary syndrome

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Intérêt de la distinction de deux formes cliniques de Mycosis fongoïde folliculotrope : analyse dans deux centres de référence.

Introduction: Le mycosis fongoïde folliculotrope (MFF) est une variante fréquente de mycosis fongoïde qui réalise cliniquement des papules folliculaires, des lésions acnéiformes, une alopécie, et des plaques infiltrées, et qui touche préférentiellement la tête et le tronc. Le MFF était classiquement considéré comme plus agressif que le MF. Néanmoins, deux études récentes ont distingué une forme précoce d’évolution indolente et une forme avancée d’évolution plus agressive. Cette étude a pour but d’analyser si la distinction récemment décrite entre ces deux formes est reproductible en vie réelle, en étudiant tous les cas de MFF sans atteinte extra-cutanée recrutés pendant 2 ans dans 2 centres de référence. Matériel et Méthodes: Il s’agit d’une étude rétrospective franco-italienne bi-centrique ayant inclus 43 patients, 17 femmes et 26 hommes, âgés de 21 à 89 ans, dont le diagnostic de MFF a été posé entre janvier 2015 et décembre 2016. Les patients ont été divisés en 2 groupes : groupe A (stade précoce) caractérisé par des papules folliculaires (fig. 1), des kystes et un infiltrat péri-folliculaire; groupe B (stade avancé) caractérisé par des plaques infiltrées (fig. 2) et un infiltrat envahissant massivement le derme. Pour chaque groupe nous avons analysé les données clinico-pathologiques et la réponse aux traitements. Nous avons déterminé le Time to Next Treatment (TtNT), temps entre le début du 1er traitement et le début du 2ème, ou la dernière date du dernier suivi pour ceux qui n’ont pas eu de 2ème traitement. Résultats: 30 patients appartenaient au groupe A et 13 patients au groupe B. Les patients du groupe A étaient plus souvent au stade IA (76% des cas) alors que les patients du groupe B étaient plus souvent au stade IB (54% des cas). Dans les groupes A et B, les patients ont reçu principalement des traitements topiques : dermocorticoïdes (groupe A : 57% vs 30% pour le groupe B), PUVA (17% vs 0%), UVB (20% vs 38%), Chlormethine gel (3% vs 8%), radiothérapie (0% vs 8%). 1 patient (3%) du groupe A a reçu un traitement systemique par bexarotène vs 2 patients (6%) pour le groupe B. 58% des malades du groupe A a présenté une réponse aux dermocorticoïdes vs 25% pour le groupe B. Le TtNT a montré une différence de 4 mois entre le groupe A et B (8.4 vs 4.1 mois)

Cutaneous Involvement in Waldenström's Macroglobulinaemia.

Cutaneous involvement in Waldenström's macroglobulinaemia (WM) has been poorly characterized. To describe this involvement, a retrospective study of 19 patients with WM and cutaneous involvement of tumour B cells was performed. Twelve patients (group 1) had lymphoplasmacytic, non-transformed cutaneous proliferation, while in 7 cases (group 2) cutaneous involvement corresponded to histological transformation. In group 1, skin involvement was inaugural in 6 cases. The lesions were infiltrated plaques (83%), papules (25%) and tumours (42%). Four patients had a similar clinical picture (purplish, bilateral and symmetrical infiltration on the face). MYD88 L265P mutation was detected in the skin biopsy in all 6 cases tested. The 3-year specific survival rate was 88%. In group 2, cutaneous transformation occurred during the follow-up of the WM (71%). Lesions presented as ulcerated tumours (86%) of the trunk (57%) and lower limbs (57%). The 3-year specific survival rate was 22%. Skin involvement in WM has distinctive characteristics (e.g. clinical, histological, immunohistochemical, MYD88 L265P mutation)

CD158k Is a Reliable Marker for Diagnosis of Sézary Syndrome and Reveals an Unprecedented Heterogeneity of Circulating Malignant Cells

The diverse aspects of cutaneous T-cell lymphomas may impede the diagnosis of Sézary syndrome (SS) and mycosis fungoides (MF), in particular, at early stages of the disease. We defined the CD158k/KIR3DL2 molecule as a first positive cell surface marker for Sézary cells (SCs). Here, we designed an optimized flow cytometry gating strategy, allowing the definition of lymphocytes of different sizes and defects of cell surface markers. Quantification by cytomorphology, flow cytometry, or clonal evaluation, gave similar results at initial time points and during the evolution in a prospective study involving 64 consecutive cutaneous T-cell lymphoma or erythrodermic patients. We found that CD158k+ T cells and circulating CD4+ T cells from MF patients exhibited unexpected patterns of cell surface expression with a marked heterogeneity of circulating lymphocytes even at initial diagnosis. Taken together, our results show that a multistep gating of CD158k+ cells is reliable to assess tumor burden in case of SS and suggest that both circulating MF CD4+ T cells and CD158k+ T cells are not homogeneous distinct memory populations. Further phenotypic and functional characterizations of such subsets are needed to better understand the underlying molecular mechanisms leading to the development of these diseases

Large‐cell transformation is an independent poor prognostic factor in Sézary syndrome: analysis of 117 cases

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