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Mehdi Torabizadeh, Mohammad Nabavi, Masoud Zadkarami, Mohammad Shahrooei
Hyper IgM (HIGM) syndromes are a complex of primary immunodeficiency disorders. A 4-years-old boy with recurrent fever and chills, dyspnea, sort throat for a month was admitted to emergency department. In the current case, whole exome sequencing followed by Sanger sequencing were employed in order to screen probable functional mutations. Molecular analysis revealed a functional mutation across the CD40L gene (NM_000074: exon5: c.T464C) resulted in amino acid change p.L155P attributed to X-linked hyper IgM syndrome...
March 7, 2018: Current Research in Translational Medicine
Mario P Colombo, Elena Jachetti, Valeria Cancila, Alice Rigoni, Lucia Bongiovanni, Barbara Cappetti, Beatrice Belmonte, Claudia Enriquez, Patrizia Casalini, Paola Ostano, Barbara Frossi, Sabina Sangaletti, Claudia Chiodoni, Giovanna Chiorino, Carlo E Pucillo, Claudio Tripodo
Immunotherapy, including the use of checkpoint inhibitors, is a potent therapeutic approach for some cancers, but has limited success with prostate tumors, in which immune suppression is instigated by the tumor. The immunosuppressive capacity of mast cells, which promote adenocarcinoma development in the prostate, prompted our investigation on whether mast cells promote tolerance to SV40 Large-T antigen, the transforming oncogene in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. The incidence of adenocarcinoma was reduced in the offspring of a cross between TRAMP mice and mast cell-deficient KitWsh mice...
March 9, 2018: Cancer Immunology Research
Susanne Roser-Page, Tatyana Vikulina, Kanglun Yu, Meghan E McGee-Lawrence, M Neale Weitzmann
Objective: Immunosuppressive biologics are used in the management of RA and additional immunomodulators are under investigation including modulators of the CD40/CD40 ligand (CD40L) costimulation pathway. Tampering with immune function can have unanticipated skeletal consequences due to disruption of the immuno-skeletal interface, a nexus of shared cells and cytokine effectors serving discrete functions in both immune and skeletal systems. In this study, we examined the effect of MR1, a CD40L neutralizing antibody, on physiological bone remodelling in healthy mice...
March 7, 2018: Rheumatology
Pascal J H Kusters, Tom T P Seijkens, Linda Beckers, Dirk Lievens, Holger Winkels, Vivian de Waard, Adriaan Duijvestijn, Moritz Lindquist Liljeqvist, Joy Roy, Alan Daugherty, Andrew Newby, Norbert Gerdes, Esther Lutgens
OBJECTIVE: The mechanisms underlying formation of arterial aneurysms remain incompletely understood. Because inflammation is a common feature during the progressive degeneration of the aortic wall, we studied the role of the costimulatory molecule CD40L, a major driver of inflammation, in aneurysm formation. APPROACH AND RESULTS: Transcriptomics data obtained from human abdominal aortic aneurysms and normal aortas revealed increased abundance of both CD40L and CD40 in media of thrombus-free and thrombus-covered human abdominal aortic aneurysms samples...
March 8, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Otavio Cabral-Marques, Tabata Takahashi França, Ashraf Al-Sbiei, Lena Friederike Schimke, Taj Ali Khan, Claudia Feriotti, Tania Alves da Costa, Osvaldo Reis Junior, Cristina Worm Weber, Janaíra Fernandes Ferreira, Fabiola Scancetti Tavares, Claudia Valente, Regina Sumiko Watanabe Di Gesu, Asif Iqbal, Gabriela Riemekasten, Gustavo Pessini Amarante-Mendes, José Alexandre Marzagão Barbuto, Beatriz Tavares Costa-Carvalho, Paulo Vitor Soeiro Pereira, Maria J Fernandez-Cabezudo, Vera Lucia Garcia Calich, Luigi D Notarangelo, Troy R Torgerson, Basel K Al-Ramadi, Hans D Ochs, Antonio Condino-Neto
BACKGROUND: Patients with X-linked Hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) deficiency often present episodic, cyclic or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin (Ig) replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired function of phagocytes and the need of novel therapeutic approaches...
March 5, 2018: Journal of Allergy and Clinical Immunology
Chien-Chia Chen, Alice Koenig, Carole Saison, Suzan Dahdal, Guillaume Rigault, Thomas Barba, Morgan Taillardet, Dimitri Chartoire, Michel Ovize, Emmanuel Morelon, Thierry Defrance, Olivier Thaunat
Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)-producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression...
2018: Frontiers in Immunology
Lu Han, Lu Dai, Yuan-Fei Zhao, Hai-Yang Li, Ou Liu, Feng Lan, Wen-Jian Jiang, Hong-Jia Zhang
Acute aortic dissection is one of the most lethal cardiovascular disease. The major histopathological feature of AAD is medial degradation, especially breakdown of elastin and collagen. However, the underlying mechanism remains a mystery. Platelets expressed CD40 Ligand (CD40L) is recently recognised as a key effector of cardiovascular disease development through its pro-inflammatory effect. To clarify the role of CD40L in AAD, we examined level of CD40L in human blood serum samples and found that it is significantly higher in AAD patients compared with healthy subjects (26...
March 4, 2018: Aging
Binghao Li, Yang Zeng, Patrick M Reeves, Chongzhao Ran, Qiuyan Liu, Xiying Qu, Yingying Liang, Zhao Liu, Jianping Yuan, Pierre R Leblanc, Zhaoming Ye, Ann E Sluder, Jeffrey A Gelfand, Timothy A Brauns, Huabiao Chen, Mark C Poznansky
AMD3100 (plerixafor), a CXCR4 antagonist, has been demonstrated to suppress tumor growth and modulate intratumoral T-cell trafficking. However, the effect of AMD3100 on immunomodulation remains elusive. Here, we explored immunomodulation and antitumor efficacy of AMD3100 in combination with a previously developed mesothelin-targeted, immune-activating fusion protein, VIC-008, in two syngeneic, orthotopic models of malignant mesothelioma (MM) in immunocompetent mice. We showed that combination therapy significantly suppressed tumor growth and prolonged animal survival in two mouse models...
March 6, 2018: Cancer Immunology Research
Kyung-Ho Roh, Hannah W Song, Pallab Pradhan, Kevin Bai, Caitlin D Bohannon, Gordon Dale, Jardin Leleux, Joshy Jacob, Krishnendu Roy
B cells play a major role in the adaptive immune response by producing antigen-specific antibodies against pathogens and imparting immunological memory. Following infection or vaccination, antibody-secreting B cells and memory B cells are generated in specialized regions of lymph nodes and spleens, called germinal centers. Here, we report a fully synthetic ex-vivo system that recapitulates the generation of antigen-specific germinal-center (GC) like B cells using material-surface driven polyvalent signaling...
February 21, 2018: Biomaterials
Carole Le Coz, Melissa Trofa, Camille M Syrett, Anna Martin, Harumi Jyonouchi, Soma Jyonouchi, Montserrat C Anguera, Neil Romberg
An inherited syndrome of autoimmunity associated with CD40LG duplication is silenced by non-random X-chromosome inactivation and is treatable with CD40L directed therapy.
February 27, 2018: Journal of Allergy and Clinical Immunology
Jooeun Bae, Teru Hideshima, Yu-Tzu Tai, Yan Song, Paul Richardson, Noopur Raje, Nikhil C Munshi, Kenneth C Anderson
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138+ MM cells, CD4+ CD25+ FoxP3+ regulatory T cells, and HLA-DRLow/- CD11b+ CD33+ myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8+ T cells and of immune checkpoints in bone marrow cells from myeloma patients...
February 22, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Riccardo Barrile, Andries D van der Meer, Hyoungshin Park, Jacob P Fraser, Damir Simic, Fang Teng, David Conegliano, Justin Nguyen, Abhishek Jain, Mimi Zhou, Katia Karalis, Donald E Ingber, Geraldine A Hamilton, Monicah A Otieno
Clinical development of Hu5c8, a monoclonal antibody against CD40L intended for treatment of autoimmune disorders, was terminated due to unexpected thrombotic complications. These life-threatening side-effects were not discovered during preclinical testing due to the lack of predictive models. In the present study, we describe the development of a microengineered system lined by human endothelium perfused with human whole blood, a 'Vessel-Chip'. The Vessel-Chip allowed us to evaluate key parameters in thrombosis, such as endothelial activation, platelet adhesion, platelet aggregation, fibrin clot formation, and thrombin anti-thrombin (TAT) complexes in the Chip-effluent in response to Hu5c8 in the presence of soluble CD40L...
February 27, 2018: Clinical Pharmacology and Therapeutics
Ahmed Y Ali, Xun Wu, Nour Eissa, Sen Hou, Jean-Eric Ghia, Thomas T Murooka, Versha Banerji, James B Johnston, Francis Lin, Spencer B Gibson, Aaron J Marshall
The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kδ-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kγ has not been extensively studied in B cells. Here, we assess whether PI3Kγ has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kγ inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kδ/γ inhibitor duvelisib had a greater impact than single isoform-selective inhibitors...
January 31, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Carlee D Ruediger, Bobby John, Sathesh Kumar, Han S Lim, Geetanjali Rangnekar, Kurt C Roberts-Thomson, Glenn D Young, David Chase, Prashanthan Sanders, Scott R Willoughby
BACKGROUND: It has been suggested that ethnicity can make a significant difference to the likelihood of thromboembolic stroke related to atrial fibrillation. Ethnic differences have been shown to alter inflammatory and haemostatic factors; however, this may all be confounded by differences in cardiovascular risk factors between different ethnicity. The impact of different ethnicities on the thrombogenic profile is not known. The aim of this study was to investigate differences in markers of inflammation, endothelial function and tissue remodelling between Caucasian and Indian populations with supraventricular tachycardia (SVT)...
January 2018: Indian Pacing and Electrophysiology Journal
Rajesh Parmar, Hardik Patel, Naveen Yadav, Ritika Parikh, Khyati Patel, Aditi Mohankrishnan, Vishakha Bhurani, Urja Joshi, Sarat Kumar Dalai
Immunization with radiation-attenuated sporozoites (RAS) shown to confer complete sterile protection against Plasmodia liver-stage (LS) infection that lasts about 6 to 9 months in mice. We have found that the intermittent infectious sporozoite challenge to immune mice following RAS vaccination extends the longevity of sterile protection by maintaining CD8+ T cell memory responses to LS infection. It is reported that CD8α+ dendritic cells (DCs) are involved in the induction of LS-specific CD8+ T cells following RAS or genetically attenuated parasite (GAP) vaccination...
2018: Frontiers in Immunology
Zong-Mei Bian, Matthew G Field, Susan G Elner, J Michelle Kahlenberg, Victor M Elner
CD40L signaling occurs in several diseases with inflammatory components, including ocular and retinal diseases. However, it has never been evaluated as a pathogenic mechanism in age-related macular degeneration (AMD) or as an inducer of inflammasome formation in any cell type. mRNA and protein levels of CD40, IL-1β, NALP1, NALP3, caspase-1, and caspase-5 were determined by RT-PCR, qPCR, and Western blot. CD40L receptor (CD40, α5β1, and CD11b) expression was determined by Western and immunofluorescent staining...
February 15, 2018: Experimental Eye Research
Elena Y Senchenkova, Janice Russell, Shantel A Vital, Alper Yildirim, A Wayne Orr, D Neil Granger, Felicity N E Gavins
Angiotensin II (Ang-II)-induced hypertension is associated with accelerated thrombus formation in arterioles and leukocyte recruitment in venules. The mechanisms that underlie the prothrombotic and proinflammatory responses to chronic Ang-II administration remain poorly understood. We evaluated the role of CD40/CD40 ligand (CD40L) signaling in Ang-II-mediated microvascular responses and assessed whether and how soluble CD40L (sCD40L) contributes to this response. Intravital video microscopy was performed to analyze leukocyte recruitment and dihydrorhodamine-123 oxidation in postcapillary venules...
February 8, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Giovanna Cutrona, Claudio Tripodo, Serena Matis, Anna Grazia Recchia, Carlotta Massucco, Marina Fabbi, Monica Colombo, Laura Emionite, Sabina Sangaletti, Alessandro Gulino, Daniele Reverberi, Rosanna Massara, Simona Boccardo, Daniela de Totero, Sandra Salvi, Michele Cilli, Mariavaleria Pellicanò, Martina Manzoni, Sonia Fabris, Irma Airoldi, Francesca Valdora, Silvano Ferrini, Massimo Gentile, Ernesto Vigna, Sabrina Bossio, Laura De Stefano, Angela Palummo, Giovanni Iaquinta, Martina Cardillo, Simonetta Zupo, Giannamaria Cerruti, Adalberto Ibatici, Antonino Neri, Franco Fais, Manlio Ferrarini, Fortunato Morabito
Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L + cells...
February 14, 2018: Science Translational Medicine
Joanna Cwikiel, Ingebjørg Seljeflot, Eivind Berge, Ida Unhammer Njerve, Hilde Ulsaker, Harald Arnesen, Arnljot Flaa
BACKGROUND: Coronary artery disease (CAD) is considered a low-grade inflammatory disease. We aimed to identify effects of short-term strenuous exercise on mediators of systemic inflammation, endothelial and platelet activation in patients with angiographically verified CAD. We hypothesized that a more pronounced inflammatory response would be present in patients with CAD than in those without CAD. METHODS: In subjects with symptoms indicative of stable CAD, an exercise stress test on a bicycle ergometer was performed...
February 9, 2018: Cytokine
Kegan J Moneghetti, Mehdi Skhiri, Kévin Contrepois, Yukari Kobayashi, Holden Maecker, Mark Davis, Michael Snyder, Francois Haddad, Jose G Montoya
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS. Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling...
February 9, 2018: Scientific Reports
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