Elise Ferrand

Bio: Elise Ferrand is an academic researcher. The author has contributed to research in topics: Primary central nervous system lymphoma & STAT6. The author has an hindex of 2, co-authored 4 publications receiving 7 citations.

STAT6: A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology.

Abstract: Signal Transducer and Activator of Transcription 6 (STAT6), belonging to a family of seven similar members is primarily stimulated by interleukin(IL)-4 and IL-13, and acts as a T helper type 2 (Th2)-inducing factor. Thus, it is implicated in the pathophysiology of various allergic conditions, such as asthma, atopic dermatitis, eosinophilic esophagitis and food allergies, but also in tumor microenvironment regulation. Furthermore, certain forms of lymphomas, notably the Hodgkin lymphoma group, the primary mediastinal and primary central nervous system lymphoma, as well as some follicular and T cell lymphomas are associated with dysregulation of the STAT6 pathway. STAT6 immunohistochemical expression also serves as a surrogate marker in the diagnosis of solitary fibrous tumor, despite not directly responsible for the tumorigenic effect. These pathophysiological implications of the STAT6 pathway, its diagnostic or prognostic role in pathology, as well its immunohistochemical detection with different antibodies will be discussed in this review.

Expression of STAT6 and Phosphorylated STAT6 in Primary Central Nervous System Lymphomas.

Abstract: The signal transducer and activator of transcription 6 (STAT6) is implicated in the pathogenesis of some lymphomas including primary central nervous system lymphomas (PCNSLs). The aim of this study was to investigate STAT6 expression and clinicopathologic features in 25 PCNSLs using immunohistochemistry with 2 different anti-STAT6 antibodies. One (YE361) recognizes the C-terminus domain of the STAT6 protein and the other (Y641) recognizes the phosphorylated form of the protein. The phosphorylated STAT6 form was not expressed in any of the cases studied whereas the YE361 STAT6 showed only cytoplasmic expression in 14 (56%) cases. This expression did not correlate with age, prognostic score, multiplicity, invasion of deep structures, response to treatment, disease recurrence, overall survival, or BCL6, BCL2, PD-L1, and CD8 expression. A STAT6 expression score showed a trend for correlating with clinical performance status. It also showed a positive correlation with MYC expression. Thus, the phosphorylated form of STAT6 was not found in the current series, while the YE361 STAT6 showed only cytoplasmic expression and was associated with expression of MYC.

Primary central nervous system lymphomas express immunohistochemical factors of autophagy.

Abstract: Primary central nervous system lymphoma (PCNSL) is an aggressive and rare disease. Autophagy is a catabolic mechanism boosting various tumors, including lymphomas; its inhibition is thus a promising therapeutic target. Its presence has never been studied in PCNSLs. We conducted a retrospective immunohistochemical study of 25 PCNSLs for LC3B, p62, and M6PR, comparing it with clinicopathological characteristics. Fourteen (56%) and eleven (44%) PCNSLs were of low and high LC3B expression, respectively. p62 expression was present in most tumors (n = 21, 84%). M6PR was present in all tumors, with 14 (56%) and 11 (44%) cases being of low and high M6PR expression, respectively. LC3B expression was correlated with the performance status (PS) (p = 0.04). No association was found with other clinical parameters, such as deep structure invasion, multiple lesions, complete response, and recurrence after response. p62 showed a strong positive association with MUM1 expression (p = 0.0005). M6PR expression showed a positive correlation (p = 0.04) with PD-L1 expression. No association was found with p53, Ki67, CD8, BCL2, BCL6, or double MYC/BLC2 co-expressors. No association of LC3B, p62, and M6PR expression with survival was found. Our findings provide evidence for the possible presence of autophagic markers in PCNSLs and, thus, for possible treatment targets.

STAT6 and phosphorylated STAT6 are differentially expressed in lymphomas.

Abstract: BACKGROUND The STAT6 pathway is implicated in the pathogenesis of various lymphomas; however, its immunohistochemical expression has not been fully investigated. Thus, the aim of this study was to investigate the immunohistochemical expression of the two forms of STAT6, phosphorylated or not, in a series of systemic lymphomas. MATERIALS AND METHODS Immunohistochemical expression of two antibodies, STAT6 (clone YE361) and pSTAT6 (clone Y641), which recognise the phosphorylated form of the molecule was studied in 60 lymphomas. RESULTS STAT6YE361 expression was cytoplasmic, with 23.3% of the cases showing high expression. pSTAT6Y641 expression was mostly nuclear and found in 45% of the cases. pSTAT6Y641 nuclear expression was associated with the lymphoma type (p < 0.0001), as it was seen mostly in follicular, Hodgkin and angioimmunoblastic T cell lymphomas. STAT6YE361 cytoplasmic expression was also associated with lymphoma type (p = 0.001), as it was mostly found in diffuse large B cell and marginal B cell lymphomas. No association with PD-L1 expression, other clinicopathological data or prognosis was found. CONCLUSION The two STAT6 clones are differentially expressed between lymphoma types.

The JAK/STAT Pathway and Its Selective Inhibition in the Treatment of Atopic Dermatitis: A Systematic Review

Abstract: In recent years, the broadening understanding of the pathogenesis of atopic dermatitis (AD) has led to the development of novel therapeutic molecules, that target core inflammatory components of the disease. The Janus kinase (JAK)/signal transducer and activation of transcription (STAT) pathway constitutes the principal signaling cascade for a large number of cytokines and growth factors and is involved in intracellular signal transduction and subsequent regulation of gene transcription. Current knowledge suggests that the robust activation of the T-helper (Th)-2 [interleukin (IL)-4, IL-5, IL-13, IL-31] and Th22 (IL-22) immune responses in both skin and serum plays a pivotal role in the immunopathogenesis of AD especially at the acute stage, followed by a variable degree of Th1 (interferon-γ, tumor necrosis factor alpha) and Th17 (IL-17) activation in chronic disease. Of note, most of the aforementioned inflammatory cytokines utilize the JAK/STAT pathway for downstream signal transduction, explaining the emerging role of JAK inhibitors in the therapeutic armamentarium of AD. The present systematic review aims to discuss the involvement of JAK/STAT pathway in the pathogenesis of AD and summarize the clinical data available on the efficacy and safety of JAK inhibitors which have been used in the treatment of AD thus far.

Association between barrier impairment and skin microbiota in atopic dermatitis from a global perspective: Unmet needs and open questions.

Abstract: Atopic diathesis encompassing atopic dermatitis (AD), allergic rhinoconjunctivitis, food allergy, eosinophilic esophagitis, and asthma is a widely prevalent condition with a broad heterogeneity in clinical course, age of onset, and lifespan persistence. A primary event in AD is the commonly inherited epidermal barrier dysfunction. Together with the host-microbiome interactions, barrier defect and allergen exposure modulate both innate and adaptive immunity, thus triggering and maintaining the inflammatory response. Microbiome diversity, together with the host's contact with nonpathogenic microbes in childhood, is a prerequisite for functional maturation of the immune system, which is in part mediated by microbiome-induced epigenetic changes. Yet, whether microbiome alterations are the result or the reason for barrier impairment and inflammatory response of the host is unclear. Exposure to locally prevalent microbial species could contribute to further modification of the disease course. The objective of this review is to reveal the link between changes in the skin microbiota, barrier dysfunction, and inflammation in AD. Addressing unmet needs includes determining the genetic background of AD susceptibility; the epigenetic modifications induced by the microbiota and other environmental factors; the role of globally diverse provoking factors; and the implementation of personalized, phenotype-specific therapies such as a epidermal barrier restoration in infancy and microbiota modulation via systemic or topical interventions, all of which open gaps for future research.

Type 2 Inflammation in Eosinophilic Esophagitis: From Pathophysiology to Therapeutic Targets

Abstract: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation, whose incidence is rising. It significantly affects patients’ quality of life and, if left untreated, results in fibrotic complications. Although broad consensus has been achieved on first-line therapy, a subset of patients remains non-responder to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This review provides a comprehensive description of the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins and transcription factors) that could represent present and future therapeutic targets, while summarizing previous therapeutic approaches in literature.

Treadmill Exercise Attenuates Cerebral Ischemia-Reperfusion Injury by Promoting Activation of M2 Microglia via Upregulation of Interleukin-4

Abstract: Background: Exercise has been proven to be an effective therapy for stroke by reducing the microglia-initiated proinflammatory response. Few studies, however, have focused on the phenotypic changes in microglia cells caused by exercise training. The present study was designed to evaluate the influence of treadmill exercise on microglia polarization and the molecular mechanisms involved. Methods: Male Sprague-Dawley rats were randomly assigned into 3 groups: sham, MCAO and exercise. The middle cerebral artery occlusion (MCAO) and exercise groups received MCAO surgery and the sham group a sham operation. The exercise group also underwent treadmill exercise after the surgery. These groups were studied after 4 and 7 days to evaluate behavioral performance using a modified neurological severity score (mNSS), and infarct conditions using 2,3,5-triphenyl tetrazolium chloride. Quantitative real-time polymerase chain reaction (qRT-PCR) and Luminex was employed to determine the expressions of markers of microglia phenotypes. Western blotting was employed to identify the phosphorylation levels of Janus kinase1 (JAK1) and signal transducer and activator of transcription 6 (STAT6). Immunofluorescence was conducted to identify microglia phenotypes. Results: Treadmill exercise was found to improve neurobehavioral outcomes, mainly motor and balance functions, reduce infarct volumes and significantly increase interleukin-4 (IL-4) expression. In addition, treadmill exercise inhibited M1 microglia and promoted M2 microglia activation as evidenced by decreased M1 and increased M2 markers. Furthermore, an obvious increase in p-JAK1 and p-STAT6 was observed in the exercise group. Conclusions: Treadmill exercise ameliorates cerebral ischemia-reperfusion injury by enhancing IL-4 expression to promote M2 microglia polarization, possibly via the JAK1-STAT6 pathway.

A germline STAT6 gain-of-function variant is associated with early-onset allergies.

Abstract: The signal transducer and activator of transcription 6 (STAT6) signaling pathway plays a central role in allergic inflammation. To date, however, there have been no descriptions of STAT6 gain-of-function variants leading to allergies in humans.We report a STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with 3 affected members.Exome sequencing and immunophenotyping of T-helper cell subsets were conducted. The function of the STAT6 protein was analyzed by Western blot, immunofluorescence, electrophoretic mobility shift assays, and luciferase assays. Gastric organoids obtained from the index patient were used to study downstream effector cytokines.We identified a heterozygous missense variant (c.1129G>A;p.Glu377Lys) in the DNA binding domain of STAT6 that was de novo in the index patient's father and was inherited by 2 of his 3 children. Severe atopic dermatitis and food allergy were key presentations. Clinical heterogeneity was observed among the affected individuals. Higher levels of peripheral blood TH2 lymphocytes were detected. The mutant STAT6 displayed a strong preference for nuclear localization, increased DNA binding affinity, and spontaneous transcriptional activity. Moreover, gastric organoids showed constitutive activation of STAT6 downstream signaling molecules.A germline STAT6 gain-of-function variant results in spontaneous activation of the STAT6 signaling pathway and is associated with an early-onset and severe allergic phenotype in humans. These observations enhance our knowledge of the molecular mechanisms underlying allergic diseases and will potentially contribute to novel therapeutic interventions.