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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
Nicholas A Gherardin, Liyen Loh, Lorenztino Admojo, Alexander J Davenport, Kelden Richardson, Amy Rogers, Phillip K Darcy, Misty R Jenkins, H Miles Prince, Simon J Harrison, Hang Quach, David P Fairlie, Katherine Kedzierska, James McCluskey, Adam P Uldrich, Paul J Neeson, David S Ritchie, Dale I Godfrey
Mucosal-associated invariant T (MAIT) cells are T cells that recognise vitamin-B derivative Ag presented by the MHC-related-protein 1 (MR1) antigen-presenting molecule. While MAIT cells are highly abundant in humans, their role in tumour immunity remains unknown. Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors. Furthermore, there was no evidence that MAIT cells accumulated at the disease site (bone marrow) of these patients...
March 7, 2018: Scientific Reports
Seung Geun Yeo, Yong Sung Won, Sang Hoon Kim, Dong Choon Park
Endometriosis, although not malignant, has clinically demonstrated properties of invasiveness and metastasis. The pathogenesis of endometriosis, however, has not yet been elucidated. The immunological differences between endometriosis and malignant gynecologic tumors were analyzed by assessing C-type lectin receptors, which are associated with innate immunity, and immunoglobulin secretion, which is associated with B cell adaptive immunity, in the peritoneal fluid of these patients. Peritoneal fluid samples were obtained from 42 patients with benign masses (control group), 38 with endometriosis, and 43 with gynecologic (ovarian, uterine, and cervical) cancers...
2018: International Journal of Medical Sciences
Eric Jesteadt, Irma Zhang, Huifeng Yu, Anda Meierovics, Wei-Jen Chua Yankelevich, Siobhan Cowley
Mucosa-associated invariant T (MAIT) cells are an innate T cell subset that expresses a semi-invariant Vα chain paired with limited Vβ chains. MAIT cells are activated by riboflavin metabolite derivatives presented by MR1. The precise mechanisms required to activate MAIT cells are an area of intense interest. Here we used two closely related intracellular pathogens with distinct inflammasome activation phenotypes to probe the role of innate cytokines in MAIT cell activation. Using an in vitro assay containing transgenic murine MAIT cells, we show that macrophages infected with Francisella novicida , a strong inflammasome activator, released high levels of IL-18 and stimulated high levels of MAIT cell IFN-γ through a partially MR1-independent pathway...
March 5, 2018: Infection and Immunity
S M Mansour Haeryfar, Christopher R Shaler, Patrick T Rudak
Mucosa-associated invariant T (MAIT) cells are a subset of innate-like T lymphocytes known for their ability to respond to MHC-related protein 1 (MR1)-restricted stimuli and select cytokine signals. They are abundant in humans and especially enriched in mucosal layers, common sites of neoplastic transformation. MAIT cells have been found within primary and metastatic tumors. However, whether they promote malignancy or contribute to anticancer immunity is unclear. On the one hand, MAIT cells produce IL-17A in certain locations and under certain circumstances, which could in turn facilitate neoangiogenesis, intratumoral accumulation of immunosuppressive cell populations, and cancer progression...
February 22, 2018: Cancer Immunology, Immunotherapy: CII
Erin W Meermeier, Melanie J Harriff, Elham Karamooz, David M Lewinsohn
Mucosal-associated invariant T (MAIT) cells, the most abundant T cell subset in humans, are increasingly being recognized for their importance in microbial immunity. MAIT cells accumulate in almost every mucosal tissue examined, including the lung, liver, and intestinal tract, where they can be activated through T cell receptor (TCR) triggering as well as cytokine stimulation in response to a host of microbial products. In this review, we specifically discuss MAIT cell responses to bacterial and fungal infections, with a focus on responses that are both MR1-dependent and -independent, the evidence for diversity in MAIT TCR usage in response to discrete microbial products, protective immunity induced by MAIT cells, and MAIT cell antimicrobial functions in the context of these infections...
February 16, 2018: Immunology and Cell Biology
Nicholas A Gherardin, Michael N T Souter, Hui-Fern Koay, Kirstie M Mangas, Torsten Seemann, Timothy P Stinear, Sidonia B G Eckle, Stuart P Berzins, Yves d'Udekem, Igor E Konstantinov, David P Fairlie, David S Ritchie, Paul J Neeson, Daniel G Pellicci, Adam P Uldrich, James McCluskey, Dale I Godfrey
Mucosal-associated invariant T (MAIT) cells represent up to 10% of circulating human T-cells. They are usually defined using combinations of non-lineage-specific (surrogate) markers such as anti-TRAV1-2, CD161, IL-18Rα and CD26. The development of MR1-Ag tetramers now permits the specific identification of MAIT cells based on TCR specificity. Here, we compare these approaches for identifying MAIT cells and show that surrogate markers are not always accurate in identifying these cells, particularly the CD4 + fraction...
February 13, 2018: Immunology and Cell Biology
Pierre Baillet, Guillaume Cadiot, Marion Goutte, Felix Goutorbe, Hedia Brixi, Christine Hoeffel, Christophe Allimant, Maud Reymond, Hélène Obritin-Guilhen, Benoit Magnin, Gilles Bommelaer, Bruno Pereira, Constance Hordonneau, Anthony Buisson
AIM: To assess magnetic resonance imaging (MRI) and faecal calprotectin to detect endoscopic postoperative recurrence in patients with Crohn's disease (CD). METHODS: From two tertiary centers, all patients with CD who underwent ileocolonic resection were consecutively and prospectively included. All the patients underwent MRI and endoscopy within the first year after surgery or after the restoration of intestinal continuity [median = 6 mo (5.0-9.3)]. The stools were collected the day before the colonoscopy to evaluate faecal calprotectin level...
February 7, 2018: World Journal of Gastroenterology: WJG
Madeleine E Zinser, Andrew J Highton, Ayako Kurioka, Barbara Kronsteiner, Joachim Hagel, Tianqi Leng, Emanuele Marchi, Chansavath Phetsouphanh, Chris B Willberg, Susanna J Dunachie, Paul Klenerman
Mucosal-associated invariant T (MAIT) cells are a well-characterized innate-like T cell population abundant in the human liver, peripheral tissues and blood. MAIT cells serve in the first line of defense against infections, through engagement of their T cell receptor, which recognizes microbial metabolites presented on MR1, and through cytokine-mediated triggering. Typically, they show a quiescent memory phenotype but can undergo rapid up-regulation of effector functions including cytolysis upon stimulation...
February 9, 2018: Immunology and Cell Biology
Ophélie Rouxel, Agnès Lehuen
Autoimmune and inflammatory diseases have complex etiologies not fully understood. Both innate and adaptive immune cells are involved in the pathogenesis of these diseases. Mucosal-associated invariant (MAI)T cells express an invariant TCRα chain (Vα7.2-Jα33 in humans and Vα19-Jα33 in mice) and recognize the conserved MHC-I related molecule MR1 presenting bacterial metabolites derived from the synthesis of vitamin B. MAIT cells harbor tissue homing properties and produce inflammatory cytokines suggesting that MAIT cells may play a key role in autoimmune and inflammatory diseases...
February 6, 2018: Immunology and Cell Biology
Kelin Li, Charles K Vorkas, Ashutosh Chaudhry, Donielle L Bell, Richard A Willis, Alexander Rudensky, John D Altman, Michael S Glickman, Jeffrey Aubé
Mucosal-associated invariant T (MAIT) cells are an abundant class of innate T cells restricted by the MHC I-related molecule MR1. MAIT cells can recognize bacterially-derived metabolic intermediates from the riboflavin pathway presented by MR1 and are postulated to play a role in innate antibacterial immunity through production of cytokines and direct bacterial killing. MR1 tetramers, typically stabilized by the adduct of 5-amino-6-D-ribitylaminouracil (5-A-RU) and methylglyoxal (MeG), are important tools for the study of MAIT cells...
2018: PloS One
Wael Awad, Jérôme Le Nours, Lars Kjer-Nielsen, James McCluskey, Jamie Rossjohn
The major histocompatibility complex (MHC) class-I related molecule MR1 is a monomorphic and evolutionary conserved antigen (Ag)-presenting molecule that shares the overall architecture of MHC-I and CD1 proteins. However, in contrast to MHC-I and the CD1 family that present peptides and lipids, respectively, MR1 specifically presents small organic molecules. During microbial infection of mammalian cells, MR1 captures and presents vitamin B precursors, derived from the microbial biosynthesis of riboflavin, on the surface of antigen presenting cells (APCs)...
February 2, 2018: Immunology and Cell Biology
Criselle D'Souza, Troi Pediongco, Huimeng Wang, Jean-Pierre Y Scheerlinck, Lyudmila Kostenko, Robyn Esterbauer, Andrew W Stent, Sidonia B G Eckle, Bronwyn S Meehan, Richard A Strugnell, Hanwei Cao, Ligong Liu, Jeffrey Y W Mak, George Lovrecz, Louis Lu, David P Fairlie, Jamie Rossjohn, James McCluskey, Alison L Every, Zhenjun Chen, Alexandra J Corbett
Mucosal-associated invariant T (MAIT) cells produce inflammatory cytokines and cytotoxic granzymes in response to by-products of microbial riboflavin synthesis. Although MAIT cells are protective against some pathogens, we reasoned that they might contribute to pathology in chronic bacterial infection. We observed MAIT cells in proximity to Helicobacter pylori bacteria in human gastric tissue, and so, using MR1-tetramers, we examined whether MAIT cells contribute to chronic gastritis in a mouse H. pylori SS1 infection model...
January 29, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Olivier Lantz, François Legoux
In humans, MAIT cells represent the most abundant T-cell subset reacting against bacteria. MAIT cells belong to the evolutionarily conserved family of "preset" T cells that includes also NKT cells. Both subsets are selected by double positive thymocytes leading to common features such as PLZF expression. Preset T cells correspond to subsets prepositioned in specific tissue locations with preprogrammed versatile effector functions such as antimicrobial functions and possibly also metabolic control and tissue repair activity...
December 27, 2017: Immunology and Cell Biology
Yun-Wei Dong, Ming-Ling Liao, Xian-Liang Meng, George N Somero
Orthologous proteins of species adapted to different temperatures exhibit differences in stability and function that are interpreted to reflect adaptive variation in structural "flexibility." However, quantifying flexibility and comparing flexibility across proteins has remained a challenge. To address this issue, we examined temperature effects on cytosolic malate dehydrogenase (cMDH) orthologs from differently thermally adapted congeners of five genera of marine molluscs whose field body temperatures span a range of ∼60 °C...
January 22, 2018: Proceedings of the National Academy of Sciences of the United States of America
Dominic Paquin-Proulx, Vivian Lida Avelino-Silva, Bianca A N Santos, Nathália Silveira Barsotti, Fabiana Siroma, Jessica Fernandes Ramos, Adriana Coracini Tonacio, Alice Song, Alvino Maestri, Natalia Barros Cerqueira, Alvina Clara Felix, José Eduardo Levi, Benjamin C Greenspun, Miguel de Mulder Rougvie, Michael G Rosenberg, Douglas F Nixon, Esper G Kallas
Dengue virus (DENV) and Zika virus (ZIKV) are members of the Flaviviridae and are predominantly transmitted via mosquito bites. Both viruses are responsible for a growing number of infections in tropical and subtropical regions. DENV infection can cause lethargy with severe morbidity and dengue shock syndrome leading to death in some cases. ZIKV is now linked with Guillain-Barré syndrome and fetal malformations including microcephaly and developmental disorders (congenital Zika syndrome). The protective and pathogenic roles played by the immune response in these infections is unknown...
January 22, 2018: PLoS Neglected Tropical Diseases
James E Ussher, Christian B Willberg, Paul Klenerman
Mucosal associated invariant T cells (MAIT cells) bear a T cell receptor (TCR) that specifically targets microbially-derived metabolites. Functionally they respond to bacteria and yeasts, which possess the riboflavin pathway, essential for production of such metabolites and which are presented on MR1. Viruses cannot generate these ligands, so a priori, they should not be recognized by MAIT cells and indeed this is true when considering recognition through the TCR. However, MAIT cells are distinctive in another respect, since they respond quite sensitively to non-TCR signals, especially in the form of inflammatory cytokines...
January 19, 2018: Immunology and Cell Biology
Yongjuan Luo, Yanbo Zhu, Xin Guan, Yunjia Lin
AIM: To study the changes of mitral valve (MV) in patients with nonvalvular atrial fibrillation (NVAF)-related mitral regurgitation (MR) and the relationship between MV parameters and the enlarged left atrium (LA). MATERIALS AND METHODS: A total of 43 patients with NVAF were divided into two groups: (1) the MR1 group with mild MR and (2) the MR2 group with moderate-to-severe MR. Real time 3D transesophageal echocardiography (TEE) was performed to detect the structure of MV...
January 19, 2018: Echocardiography
Lauren J Howson, Giorgio Napolitani, Dawn Shepherd, Hemza Ghadbane, Prathiba Kurupati, Lorena Preciado-Llanes, Margarida Rei, Hazel C Dobinson, Malick M Gibani, Karen Wei Weng Teng, Evan W Newell, Natacha Veerapen, Gurdyal S Besra, Andrew J Pollard, Vincenzo Cerundolo
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)β clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRβ clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes...
January 17, 2018: Nature Communications
Ghada Ben Youssef, Marie Tourret, Marion Salou, Liana Ghazarian, Véronique Houdouin, Stanislas Mondot, Yvonne Mburu, Marion Lambert, Saba Azarnoush, Jean-Sébastien Diana, Anne-Laure Virlouvet, Michel Peuchmaur, Thomas Schmitz, Jean-Hugues Dalle, Olivier Lantz, Valérie Biran, Sophie Caillat-Zucman
Mucosal-associated invariant T (MAIT) cells are semi-invariant Vα7.2+ CD161highCD4- T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied Vα7.2+ CD161high T cell and related subset levels in infancy and after cord blood transplantation. We show that Vα7.2+ and Vα7.2- CD161high T cells are generated early during gestation and likely share a common prenatal developmental program...
January 16, 2018: Journal of Experimental Medicine
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