Les lymphomes T épidermotropes comme modèles de progression tumorale

Les lymphomes T cutanés sont liés à l’accumulation, dans la peau, de lymphocytes T matures mémoires à tropisme cutané. La forme la plus fréquente est le mycosis fongoïde, le syndrome de Sézary représentant la forme disséminée avec cellules tumorales circulantes. La physiopathologie et la progression tumorale restent mal comprises, mais plusieurs découvertes récentes suggèrent le développement possible de nouvelles possibilités thérapeutiques : mise en évidence de plusieurs antigènes exprimés par les lymphocytes T tumoraux, voies de signalisation impliquées dans la résistance à l’apoptose, possibilités de stimulation de l’immunité innée. La mise en évidence récente de signatures moléculaires devrait également permettre de mettre au point de nouveaux marqueurs diagnostiques et pronostiques.Primary cutaneous T cell lymphomas (CTCL) represent the most frequently occurring group of extra-nodal T cell lymphomas, originating from skin-homing memory T cells. Sezary syndrome (SS) is a leukemic variant of CTCL that presents with erythroderma, lymphadenopathies and presence of malignant T cells in peripheral blood. SS has an unfavourable prognosis, and is refractory to current treatments. Progress in understanding the pathogenesis and tumor progression of SS is limited. In the past few years, we have identified and reported several CTCL-associated antigens, CD158k/KIR3DL2, CD85j/ILT2, and SC5/vimentin. KIR3DL2 is the first phenotypic marker of Sezary cells that can be used for the diagnostic and follow-up of Sezary syndrome. The SC5 antibody is the only monoclonal antibody reacting with vimentin on the surface of viable Sezary cells. CTCL are characterized by a predominance of Th2 cytokines. The recent suggestion that CTCL cells could be regulatory T (Tr) cells remains controversial. Gene expression studies suggest that in the future we may develop new diagnostic and prognostic tools, and identify subsets of patients who would benefit from more appropriate treatment protocols. Future challenges are to render tumor cells sensitive to apoptosis by inhibiting specific signalling pathways such as the constitutively activated NF-KB pathway, to identify specific surface kinase receptors and to develop specific inhibitors, to develop humanized monoclonal antibodies directed against tumor specific antigens, able to kill tumor cells via complement-dependent and antibody-dependent cytotoxicity, and to stimulate innate immunity

Extranodal NK/T-Cell Lymphoma: Toward the Identification of Clinical Molecular Targets

Extranodal natural killer (NK)/T-cell lymphoma of nasal type (NKTCL) is a malignant disorder of cytotoxic lymphocytes of NK or more rarely T cells associated with clonal Epstein-Barr virus infection. Extranodal NKTCL is rare in Western countries, but in Asia and Central and South America it can account for up to 10% of non-Hodgkin's lymphomas. It is an aggressive neoplasm with very poor prognosis. Although the pathogenesis of extranodal NKTCL remains poorly understood, some insights have been gained in the recent years, especially from genome-wide studies. Based on our own experience and knowledge of the literature, we here review some of the genomic and functional pathway alterations observed in NKTCL that could provide a rationale for the development of innovative therapeutic strategies

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

New Microbicidal Functions of Tracheal Glands: Defective Anti-Infectious Response to Pseudomonas aeruginosa in Cystic Fibrosis

Tracheal glands (TG) may play a specific role in the pathogenesis of cystic fibrosis (CF), a disease due to mutations in the cftr gene and characterized by airway inflammation and Pseudomonas aeruginosa infection. We compared the gene expression of wild-type TG cells and TG cells with the cftr ΔF508 mutation (CF-TG cells) using microarrays covering the whole human genome. In the absence of infection, CF-TG cells constitutively exhibited an inflammatory signature, including genes that encode molecules such as IL-1α, IL-β, IL-32, TNFSF14, LIF, CXCL1 and PLAU. In response to P. aeruginosa, genes associated with IFN-γ response to infection (CXCL10, IL-24, IFNγR2) and other mediators of anti-infectious responses (CSF2, MMP1, MMP3, TLR2, S100 calcium-binding proteins A) were markedly up-regulated in wild-type TG cells. This microbicidal signature was silent in CF-TG cells. The deficiency of genes associated with IFN-γ response was accompanied by the defective membrane expression of IFNγR2 and altered response of CF-TG cells to exogenous IFN-γ. In addition, CF-TG cells were unable to secrete CXCL10, IL-24 and S100A8/S100A9 in response to P. aeruginosa. The differences between wild-type TG and CF-TG cells were due to the cftr mutation since gene expression was similar in wild-type TG cells and CF-TG cells transfected with a plasmid containing a functional cftr gene. Finally, we reported an altered sphingolipid metabolism in CF-TG cells, which may account for their inflammatory signature. This first comprehensive analysis of gene expression in TG cells proposes a protective role of wild-type TG against airborne pathogens and reveals an original program in which anti-infectious response was deficient in TG cells with a cftr mutation. This defective response may explain why host response does not contribute to protection against P. aeruginosa in CF

Identification of a Novel CD160+CD4+ T-Lymphocyte Subset in the Skin: A Possible Role for CD160 in Skin Inflammation

CD160 is a glycosylphosphatidylinositol-anchored cell surface molecule expressed by human circulating cytotoxic lymphocytes that correspond to the majority of natural killer cell (NK) expressing CD56dim, TCRγδ lymphocytes, and to a minor CD8 T-cell subset. CD160 engagement by major histocompatibility complex class I molecules triggers by itself both cytotoxic function and cytokine production in NK lymphocytes, whereas it provides co-activating signals to TCR-induced proliferation in T CD8+ lymphocytes. In this study, we analyzed by immunohistochemistry the phenotype of lymphocytes infiltrating normal skin and inflammatory skin lesions of atopic dermatitis, contact dermatitis, and psoriasis. We identified a minor original subset of CD4+CD160+ T cells infiltrating inflammatory lesions. We found that this lymphocyte subset localization is not restricted to the skin, as we demonstrated that CD160 transcripts could be induced in IL-2 or IL-15-activated CD4+ peripheral blood lymphocytes. Finally, we report that CD160 acts as a co-activator receptor for CD3-induced proliferation of CD4+CD160+ T cells isolated from inflammatory skin lesions. Thus, we hypothesize that the unique CD4+CD160+ lymphocyte subset plays a role in the pathogenesis of skin inflammation

Functional Characterization of Neurotensin Receptors in Human Cutaneous T Cell Lymphoma Malignant Lymphocytes

Cutaneous T cell lymphomas are a clonal proliferation of CD4+ T lymphocytes primarily involving the skin. Mycosis fungoides is an epidermotropic CD4+ cutaneous T cell lymphoma, and a more aggressive form, Sezary syndrome, occurs when the malignant cells become nonepidermotropic. The role of neuropeptides in the growth and chemotaxis capacity of cutaneous T cell lymphoma cells remains unknown. In this report, we found that cutaneous T cell lymphoma cells, similarly to normal resting or activated peripheral lymphocytes, were able to bind neurotensin. We used an interleukin-2-dependent cutaneous T cell lymphoma malignant T cell line derived from cutaneous T cell lymphoma lesions in order to study the role of neurotensin in the proliferation and migration of these malignant cells. First, we determined that the malignant cells expressed neurotensin receptors on their cell membrane. Functional results indicated that neurotensin did not stimulate the growth of the cell line. In contrast, this neuropeptide inhibited the proliferation of the tumor cells in response to exogenous interleukin-2. Furthermore, we found that neurotensin enhanced both spontaneous and chemoattractant-induced migration of the malignant cells. This suggests that neurotensin in skin can play a role in the disease by locally limiting the growth of the cutaneous T cell lymphoma tumor cells in response to cytokines and by enhancing their chemotaxis capacity

Hospital-acquired sinusitis is a common cause of fever of unknown origin in orotracheally intubated critically ill patients

INTRODUCTION: Sinusitis is a well recognised but insufficiently understood complication of critical illness. It has been linked to nasotracheal intubation, but its occurrence after orotracheal intubation is less clear. We studied the incidence of sinusitis in patients with fever of unknown origin (FUO) in our intensive care unit with the aim of establishing a protocol that would be applicable in everyday clinical practice. METHODS: Sinus X-rays (SXRs) were performed in all patients with fever for which an initial screening (physical examination, microbiological cultures and chest X-ray) revealed no obvious cause. All patients were followed with a predefined protocol, including antral drainage in all patients with abnormal or equivocal results on their SXR. RESULTS: Initial screening revealed probable causes of fever in 153 of 351 patients (43.6%). SXRs were taken in the other 198 patients (56.4%); 129 had obvious or equivocal abnormalities. Sinus drainage revealed purulent material and positive cultures (predominantly Pseudomonas and Klebsiella species) in 84 patients. Final diagnosis for the cause of fever in all 351 patients based on X-ray results, microbiological cultures, and clinical response to sinus drainage indicated sinusitis as the sole cause of fever in 57 (16.2%) and as contributing factor in 48 (13.8%) patients with FUO. This will underestimate the actual incidence because SXR and drainage were not performed in all patients. CONCLUSION: Physicians treating critically ill patients should be aware of the high risk of sinusitis and take appropriate preventive measures, including the removal of nasogastric tubes in patients requiring long-term mechanical ventilation. Routine investigation of FUO should include computed tomography scan, SXR or sinus ultrasonography, and drainage should be performed if any abnormalities are found

Les réseaux sociaux numériques de chercheurs en SHS

Que ce soit Research gate, academia.edu ou des sites avec une fonction sociale  (Mendeley, Zotero), les outils se diversifient. Sont-ils nécessaires ? Utiles ? Qui est vraiment demandeur ? Prennent-ils en compte les besoins des chercheurs en SHS ? Quelles fonctions seraient les plus indispensables à la communauté des SHS

Epidermal IL-33 drives inflammation in necroptosis-induced skin inflammation by recruiting TNF-producing immune cells.

Caspase-8 deficiency in the epidermis (caspase-8 EKO) results in cutaneous inflammation resembling pustular psoriasis, triggered by necroptotic cell death of keratinocytes. Necroptosis is a highly proinflammatory form of programmed necrosis due to the release of intracellular molecules called alarmins, which can act as inflammatory mediators. However, their role in necroptosis-induced skin inflammation remains unexplored. Here, we demonstrate that alarmin IL-33 and its receptor ST2 are essential early mediators of necroptosis-induced skin inflammation. Genetic ablation of Il-33 or St2 dramatically delays lesion development and improves survival of caspase-8 EKO animals. IL-33 is highly expressed in necroptotic epidermis of caspase-8 EKO mice and induces immune cell recruitment in the skin upon keratinocyte necroptosis. Impairment of the IL33-ST2 axis does not affect epidermal necroptosis but reduces the recruitment of TNF-producing infiltrating immune cells and subsequent amplification of cutaneous inflammation. Collectively, our findings highlight a pivotal role for IL-33 and ST2 in necroptosis-induced skin inflammation