scholarly journals Longitudinal Pathogenic Properties and N-Glycosylation Profile of Antibodies from Patients with Pemphigus after Corticosteroid Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1411
Author(s):  
Marie Petit ◽  
Marie-Laure Walet-Balieu ◽  
Damien Schapman ◽  
Marie-Laure Golinski ◽  
Carole Burel ◽  
...  
Keyword(s):  
Clinical Remission ◽  
Pemphigus Vulgaris ◽  
Corticosteroid Treatment ◽  
Glycan Structure ◽  
Clinical Activity ◽  
Glycosylation Profile ◽  
Serum Igg ◽  
Systemic Corticosteroids ◽  
Pathogenic Activity

Pemphigus vulgaris is an autoimmune disease that occurs due to pathogenic autoantibodies that recognize the following epidermal adhesion proteins: desmogleins. Systemic corticosteroids usually decrease the titers of anti-desmoglein autoantibodies and improve patients’ conditions. Since modifications of IgG N-glycosylation have been described in some autoimmune diseases, we hypothesized that changes in the pathogenic activity of pemphigus IgG could be related to changes in their N-glycosylation profile. The purpose of this study was to assess, longitudinally, the pathogenicity of pemphigus serum IgG and their N-glycosylation profile during phases of disease activity and clinical remission. The pathogenic activity of serum IgG was measured in vitro on immortalized keratinocytes, by immunofluorescence and dissociation assays, and IgG N-glycans were analyzed by mass spectrometry. We showed (i) a correlation between pemphigus clinical activity and the pathogenicity of serum IgG at baseline and at month 6, while the persistence of the in vitro pathogenic activity of IgG during its evolution, even in patients in clinical remission, seemed to be predictive of relapse; (ii) that modifications of the N-glycan structure were altered the in vitro pathogenicity of patients’ autoantibodies; (iii) that the pathogenic properties of pemphigus IgG did not appear to be related to the disparity in IgG N-glycans during the course of pemphigus.

mTOR pathway regulates the differentiation of peripheral blood Th2/Treg cell subsets in patients with pemphigus vulgaris

2021 ◽  
Author(s):  
Kuan Lai ◽  
Wenjing Zhang ◽  
Songshan Li ◽  
Zhiwen Zhang ◽  
Shuangde Xie ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Pemphigus Vulgaris ◽  
Treg Cells ◽  
Mtor Pathway ◽  
Cd4 T Cell ◽  
Cell Ratio ◽  
Loss Of Balance

Abstract Pemphigus vulgaris (PV) is a chronic and potentially life-threatening autoimmune blistering disease. Aberrant mTOR pathway activity is involved in many autoimmune diseases. This study investigated the correlation of mTOR pathway (PI3K/AKT/mTOR/p70S6K) activity with the loss of balance in T helper 2/regulatory T (Th2/Treg) cells in the peripheral blood of PV patients. CD4+ T cells were isolated from 15 PV patients and 15 healthy controls (HCs), the ratios of Th2/CD4+ T cells and Treg/CD4+ T cells, the activity of the mTOR pathway (PI3K/AKT/mTOR/p70S6K), the transcription factors and cytokines of Th2 and Treg cells were detected. Primary CD4+ T cells from PV patients were cultured under Th2- or Treg-polarizing conditions with or without rapamycin in vitro. We found that PV patients showed significantly elevated serum IL-4 when compared with HCs, and serum IL-4 level was positively correlated with the titer of anti-Dsg1/3 antibody and disease severity, while the serum TGF-β level was negatively correlated with the titer of anti-Dsg3 antibody and disease severity. Meanwhile, PV patients showed increased Th2/CD4+ T cell ratio; decreased Treg/CD4+ T cell ratio; elevated mRNA of PI3K, AKT, mTOR and protein of PI3K (P85), AKT, p-AKT (Ser473), mTOR, p-mTOR (Ser2448), p-p70S6K (Thr389), GATA3; reduced protein of forkhead box protein 3. Rapamycin inhibited Th2 cell differentiation and promoted Treg cell differentiation in vitro. These data suggest a close association between mTOR pathway activation and the loss of balance in Th2/Treg cells in peripheral blood of PV patients. Inhibiting mTORC1 can help restore the Th2/Treg balance.

In Vitro Antibiotic Testing and Its Relationship to Clinical Activity

1997 ◽  
Vol 9 (sup1) ◽  
pp. 93-99
Author(s):  
Y. Mouton ◽  
L. Dubreuil
Keyword(s):  
Clinical Activity

scholarly journals Diphenylhydantoin-induced pure red cell aplasia

Blood ◽  
1985 ◽  
Vol 65 (4) ◽  
pp. 789-794 ◽  
Author(s):  
EN Dessypris ◽  
S Redline ◽  
JW Harris ◽  
SB Krantz
Keyword(s):  
Colony Formation ◽  
Cytotoxic Effect ◽  
Autologous Blood ◽  
Pure Red Cell Aplasia ◽  
Red Cell ◽  
Erythroid Progenitors ◽  
Red Cell Aplasia ◽  
Serum Igg ◽  
Allogeneic Marrow

Abstract The pathogenesis of diphenylhydantoin-induced pure red cell aplasia was investigated in the case of a 32-year-old man who developed pure red cell aplasia while he was under treatment with diphenylhydantoin. The patient's serum IgG purified from serum drawn at the time of diagnosis suppressed normal allogeneic marrow colony-forming (CFU-E) and burst- forming (BFU-E) and autologous blood BFU-E growth in vitro only in the presence of diphenylhydantoin. This IgG-diphenylhydantoin complex had no effect on CFU-GM growth in vitro. Normal IgG or patient's IgG purified from serum drawn after the remission of red cell aplasia had no effect on erythroid colony formation in vitro in the presence of diphenylhydantoin. The IgG-diphenylhydantoin complex exerted no direct cytotoxic effect on normal marrow erythroblasts, CFU-E, and BFU-E, nor did it interfere with the action of erythropoietin on marrow erythroblasts. These studies suggest that diphenylhydantoin-induced red cell aplasia is immunologically mediated through an IgG inhibitor, which requires the presence of the drug to suppress erythroid colony formation in vitro. This inhibitor seems to exert its effect on erythroid progenitors at or beyond the stage of differentiation of CFU- E, but not on erythroblasts.

scholarly journals The antiseptic Miramistin: a review of its comparative in vitro and clinical activity

2020 ◽  
Vol 44 (4) ◽  
pp. 399-417 ◽  
Author(s):  
Ali Osmanov ◽  
Zara Farooq ◽  
Malcolm D Richardson ◽  
David W Denning
Keyword(s):  
Soviet Union ◽  
Negative Impact ◽  
English Literature ◽  
Soviet Bloc ◽  
Clinical Activity ◽  
Good Tolerability ◽  
The Soviet Union ◽  
Potential Benefits ◽  
Low Toxicity

ABSTRACT Miramistin is a topical antiseptic with broad antimicrobial action, including activity against biofilms and a clinical profile showing good tolerability. Miramistin was developed within a framework of the Soviet Union Cold War Space Program. It is available for clinical use in several prior Soviet bloc countries, but barely known outside of these countries and there is almost no mention of miramistin in the English literature. However, considering emerging antimicrobial resistance, the significant potential of miramistin justifies its re-evaluation for use in other geographical areas and conditions. The review consists of two parts: (i) a review of the existing literature on miramistin in English, Russian and Ukrainian languages; (ii) a summary of most commonly used antiseptics as comparators of miramistin. The oral LD50 was 1200 mg/kg, 1000 mg/kg and 100 g/L in rats, mice and fish, respectively. Based on the results of the review, we suggest possible applications of miramistin and potential benefits over currently used agents. Miramistin offers a novel, low toxicity antiseptic with many potential clinical uses that need better study which could address some of the negative impact of antimicrobial, antiseptic and disinfectant resistance.

scholarly journals A Central Role for the Armadillo Protein Plakoglobin in the Autoimmune Disease Pemphigus Vulgaris

2001 ◽  
Vol 153 (4) ◽  
pp. 823-834 ◽  
Author(s):  
Reto Caldelari ◽  
Alain de Bruin ◽  
Dominique Baumann ◽  
Maja M. Suter ◽  
Christiane Bierkamp ◽  
...  
Keyword(s):  
Steric Hindrance ◽  
In Vitro Model ◽  
Molecular Mechanisms ◽  
Pemphigus Vulgaris ◽  
Cell Types ◽  
Linear Distribution ◽  
Igg Binding ◽  
Vitro Model ◽  
First Time

In pemphigus vulgaris (PV), autoantibody binding to desmoglein (Dsg) 3 induces loss of intercellular adhesion in skin and mucous membranes. Two hypotheses are currently favored to explain the underlying molecular mechanisms: (a) disruption of adhesion through steric hindrance, and (b) interference of desmosomal cadherin-bound antibody with intracellular events, which we speculated to involve plakoglobin. To investigate the second hypothesis we established keratinocyte cultures from plakoglobin knockout (PG−/−) embryos and PG+/+ control mice. Although both cell types exhibited desmosomal cadherin-mediated adhesion during calcium-induced differentiation and bound PV immunoglobin (IgG) at their cell surface, only PG+/+ keratinocytes responded with keratin retraction and loss of adhesion. When full-length plakoglobin was reintroduced into PG−/− cells, responsiveness to PV IgG was restored. Moreover, in these cells like in PG+/+ keratinocytes, PV IgG binding severely affected the linear distribution of plakoglobin at the plasma membrane. Taken together, the establishment of an in vitro model using PG+/+ and PG−/− keratinocytes allowed us (a) to exclude the steric hindrance only hypothesis, and (b) to demonstrate for the first time that plakoglobin plays a central role in PV, a finding that will provide a novel direction for investigations of the molecular mechanisms leading to PV, and on the function of plakoglobin in differentiating keratinocytes.

scholarly journals Oxygen-Dependent Changes in the N-Glycome of Murine Pulmonary Endothelial Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1947
Author(s):  
Akos Tiboldi ◽  
Johannes Führer ◽  
Wolfgang Schaubmayr ◽  
Eva Hunyadi-Gulyas ◽  
Marie Louise Zach ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Lectin Binding ◽  
Supplemental Oxygen ◽  
Redox Status ◽  
Blood Oxygenation ◽  
Glycan Structure ◽  
Pulmonary Endothelium ◽  
Proteomic Approach ◽  
Oxygen Conditions

Supplemental oxygen is frequently used together with mechanical ventilation to achieve sufficient blood oxygenation. Despite the undoubted benefits, it is vigorously debated whether too much oxygen can also have unpredicted side-effects. Uncertainty is also due to the fact that the molecular mechanisms are still insufficiently understood. The lung endothelium is covered with an exceptionally broad glycocalyx, carrying N- and O-glycans, proteoglycans, glycolipids and glycosaminoglycans. Glycan structures are not genetically determined but depend on the metabolic state and the expression level and activity of biosynthetic and glycan remodeling enzymes, which can be influenced by oxygen and the redox status of the cell. Altered glycan structures can affect cell interactions and signaling. In this study, we investigated the effect of different oxygen conditions on aspects of the glycobiology of the pulmonary endothelium with an emphasis on N-glycans and terminal sialylation using an in vitro cell culture system. We combined a proteomic approach with N-glycan structure analysis by LC-MS, qRT-PCR, sialic acid analysis and lectin binding to show that constant and intermittent hyperoxia induced time dependent changes in global and surface glycosylation. An siRNA approach identified St6gal1 as being primarily responsible for the early transient increase of α2-6 sialylated structures in response to hyperoxia.

scholarly journals Citrobacter freundii sepsis in an immunosuppressed patient with pemphigus vulgaris

2018 ◽  
Vol 11 (1) ◽  
pp. e227091 ◽  
Author(s):  
Martina Ferranti ◽  
Giulia Tadiotto Cicogna ◽  
Andrea Sattin ◽  
Mauro Alaibac
Keyword(s):  
Immunosuppressive Agents ◽  
Pemphigus Vulgaris ◽  
Immunosuppressed Patient ◽  
Citrobacter Freundii ◽  
Bullous Disease ◽  
Autoimmune Bullous Disease ◽  
Systemic Corticosteroids ◽  
Mucous Membranes ◽  
Current Therapies ◽  
Anti Cd20

Pemphigus vulgaris is an autoimmune bullous disease that involves the skin and mucous membranes. Current therapies aim to decrease antibody production by means of the use of systemic corticosteroids, immunosuppressive agents and, recently, rituximab, an anti-CD20 monoclonal antibody. However, the chronic immune suppression could entail complications, like infections and secondary malignancies. We describe a case of a patient with pemphigus who developed a sepsis due to Citrobacter freundii infection.

scholarly journals Pre-clinical activity of combined LSD1 and mTORC1 inhibition in MLL-translocated acute myeloid leukaemia

Leukemia ◽  
2019 ◽  
Vol 34 (5) ◽  
pp. 1266-1277 ◽  
Author(s):  
Gauri Deb ◽  
Bettina Wingelhofer ◽  
Fabio M. R. Amaral ◽  
Alba Maiques-Diaz ◽  
John A. Chadwick ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Residual Disease ◽  
Molecular Subtype ◽  
Clinical Activity ◽  
Lineage Differentiation ◽  
A Genome ◽  
Acute Myeloid

AbstractThe histone demethylase lysine-specific demethylase 1 (LSD1 or KDM1A) has emerged as a candidate therapeutic target in acute myeloid leukaemia (AML); tranylcypromine-derivative inhibitors induce loss of clonogenic activity and promote differentiation, in particular in the MLL-translocated molecular subtype of AML. In AML, the use of drugs in combination often delivers superior clinical activity. To identify genes and cellular pathways that collaborate with LSD1 to maintain the leukaemic phenotype, and which could be targeted by combination therapies, we performed a genome-wide CRISPR-Cas9 dropout screen. We identified multiple components of the amino acid sensing arm of mTORC1 signalling—RRAGA, MLST8, WDR24 and LAMTOR2—as cellular sensitizers to LSD1 inhibition. Knockdown of mTORC1 components, or mTORC1 pharmacologic inhibition, in combination with LSD1 inhibition enhanced differentiation in both cell line and primary cell settings, in vitro and in vivo, and substantially reduced the frequency of clonogenic primary human AML cells in a modelled minimal residual disease setting. Synergistic upregulation of a set of transcription factor genes associated with terminal monocytic lineage differentiation was observed. Thus, dual mTORC1 and LSD1 inhibition represents a candidate combination approach for enhanced differentiation in MLL-translocated AML which could be evaluated in early phase clinical trials.

scholarly journals Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 559-569 ◽  
Author(s):  
Aldo M. Roccaro ◽  
Antonio Sacco ◽  
Emanuel N. Husu ◽  
Costas Pitsillides ◽  
Steven Vesole ◽  
...  
Keyword(s):  
Significant Inhibition ◽  
Mtor Pathway ◽  
Clinical Activity ◽  
Independent Manner ◽  
Waldenström Macroglobulinemia ◽  
Constitutive Activation ◽  
Dual Targeting ◽  
Waldenstrom Macroglobulinemia

Abstract We have previously shown clinical activity of a mammalian target of rapamycin (mTOR) complex 1 inhibitor in Waldenstrom macroglobulinemia (WM). However, 50% of patients did not respond to therapy. We therefore examined mechanisms of activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR in WM, and mechanisms of overcoming resistance to therapy. We first demonstrated that primary WM cells show constitutive activation of the PI3K/Akt pathway, supported by decreased expression of phosphate and tensin homolog tumor suppressor gene (PTEN) at the gene and protein levels, together with constitutive activation of Akt and mTOR. We illustrated that dual targeting of the PI3K/mTOR pathway by the novel inhibitor NVP-BEZ235 showed higher cytotoxicity on WM cells compared with inhibition of the PI3K or mTOR pathways alone. In addition, NVP-BEZ235 inhibited both rictor and raptor, thus abrogating the rictor-induced Akt phosphorylation. NVP-BEZ235 also induced significant cytotoxicity in WM cells in a caspase-dependent and -independent manner, through targeting the Forkhead box transcription factors. In addition, NVP-BEZ235 targeted WM cells in the context of bone marrow microenvironment, leading to significant inhibition of migration, adhesion in vitro, and homing in vivo. These studies therefore show that dual targeting of the PI3K/mTOR pathway is a better modality of targeted therapy for tumors that harbor activation of the PI3K/mTOR signaling cascade, such as WM.

scholarly journals Serum Concentration of Interleukin-6 Is Increased Both in Active and Remission Stages of Pemphigus Vulgaris

2008 ◽  
Vol 2008 ◽  
pp. 1-5 ◽  
Author(s):  
Joanna Narbutt ◽  
Jolanta Lukamowicz ◽  
Jarosław Bogaczewicz ◽  
Anna Sysa-Jedrzejowska ◽  
Jolanta Dorota Torzecka ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Negative Correlation ◽  
Interleukin 6 ◽  
Clinical Remission ◽  
Healthy Subjects ◽  
Pemphigus Vulgaris ◽  
Study Group ◽  
Active Stage

As most studies on pemphigus vulgaris (PV) pathogenesis concern its active stage, we aimed to evaluate the serum concentration of TNF-α, IL-1, and IL-6 in PV patients in clinical remission. The study group consisted of sera from 19 PV patients in active stage and from 24 patients in clinical remission. 19 sera taken from healthy subjects served as the controls. Serum IL-6 concentrations in PV active and PV remission group were significantly higher when compared to the controls(P<.05). In patients in active stage of PV, a significant correlation between serum IL-1 and IL-6 concentrations was found (rP=0.46;P<.05). We also found a negative correlation between TNF-αlevel andpemphigusantibodies titer in the patients from the remission group (rS=−0.47303;P<.02). Our data suggest that IL-6 and TNF-αmay be involved in maintaining immunological disturbances in remission stage of PV.

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