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Mucosal Immunology

Yolanda Guillén, Marc Noguera-Julian, Javier Rivera, Maria Casadellà, Alexander S Zevin, Muntsa Rocafort, Mariona Parera, Cristina Rodríguez, Marçal Arumí, Jorge Carrillo, Beatriz Mothe, Carla Estany, Josep Coll, Isabel Bravo, Cristina Herrero, Jorge Saz, Guillem Sirera, Ariadna Torrella, Jordi Navarro, Manuel Crespo, Eugènia Negredo, Christian Brander, Julià Blanco, Maria Luz Calle, Nichole R Klatt, Bonaventura Clotet, Roger Paredes
Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but its effects on the gut microbiome remain unclear. Previous shotgun metagenomic studies in HIV-negative subjects linked low-microbial gene counts (LGC) to gut dysbiosis in diseases featuring intestinal inflammation. Using a similar approach in 156 subjects with different HIV-1 phenotypes, we found a strong, independent, dose-effect association between nadir CD4+ T-cell counts and LGC. As in other diseases involving intestinal inflammation, the gut microbiomes of subjects with LGC were enriched in gram-negative Bacteroides, acetogenic bacteria and Proteobacteria, which are able to metabolize reactive oxygen and nitrogen species; and were depleted in oxygen-sensitive methanogenic archaea and sulfate-reducing bacteria...
August 31, 2018: Mucosal Immunology
Aideen C Allen, Mieszko M Wilk, Alicja Misiak, Lisa Borkner, Dearbhla Murphy, Kingston H G Mills
Current acellular pertussis (aP) vaccines induce strong antibody and Th2 responses but fail to protect against nasal colonization and transmission of Bordetella pertussis. Furthermore, immunity wanes rapidly after immunization. We have developed a novel adjuvant combination (called LP-GMP), comprising c-di-GMP, an intracellular receptor stimulator of interferon genes (STING) agonist, and LP1569, a TLR2 agonist from B. pertussis, which synergistically induces production of IFN-β, IL-12 and IL-23, and maturation of dendritic cells...
August 20, 2018: Mucosal Immunology
Maria E Joosse, Celia L Menckeberg, Lilian F de Ruiter, H Rolien C Raatgeep, Lisette A van Berkel, Ytje Simons-Oosterhuis, Irma Tindemans, A Femke M Muskens, Rudi W Hendriks, Remco M Hoogenboezem, Tom Cupedo, Lissy de Ridder, Johanna C Escher, Sharon Veenbergen, Janneke N Samsom
Disease heterogeneity hampers achieving long-term disease remission in inflammatory bowel disease (IBD). Monitoring ongoing tissue-localized regulatory and inflammatory T-cell responses in peripheral blood would empower disease classification. We determined whether regulatory and inflammatory phenotypes of circulating CD38+ effector (CD62Lneg CD4+ ) T cells, a population enriched for cells with mucosal antigen specificity, classify disease course in pediatric IBD patients. In healthy individuals, circulating CD38+ effector T cells had a predominant regulatory component with lower frequencies of IFNγ-secreting T cells, higher frequencies of IL-10-secreting T cells and higher frequencies of inhibitory molecule T-cell immunoglobulin and ITIM domain+ (TIGIT) cells than CD38neg effector T cells...
August 20, 2018: Mucosal Immunology
Takanori Asakura, Makoto Ishii, Ho Namkoong, Shoji Suzuki, Shizuko Kagawa, Kazuma Yagi, Takaki Komiya, Takafumi Hashimoto, Satoshi Okamori, Hirofumi Kamata, Sadatomo Tasaka, Akio Kihara, Ahmed E Hegab, Naoki Hasegawa, Tomoko Betsuyaku
Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+ Gr-1+ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b+ Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells...
August 16, 2018: Mucosal Immunology
Gopinath Kasetty, Praveen Papareddy, Ravi K V Bhongir, Mohamad N Ali, Michiko Mori, Malgorzata Wygrecka, Jonas S Erjefält, Anna Hultgårdh-Nilsson, Lena Palmberg, Heiko Herwald, Arne Egesten
Extracellular histones are present in the airways because of cell death occurring during inflammation. They promote inflammation and cause tissue damage due to their cationic nature. The anionic phosphoglycoprotein osteopontin (OPN) is expressed at high levels during airway inflammation and has been ascribed both pro- and anti-inflammatory roles. In this study, it was hypothesized that OPN may neutralize the harmful activities of extracellular histones at the airway mucosal surface. In a model of histone-induced acute lung injury, OPN-/- mice showed increased inflammation and tissue injury, and succumbed within 24 h, whereas wild-type mice showed lower degrees of inflammation and no mortality...
August 16, 2018: Mucosal Immunology
Cihan Tastan, Ece Karhan, Wei Zhou, Elizabeth Fleming, Anita Y Voigt, Xudong Yao, Lei Wang, Meghan Horne, Lindsey Placek, Lina Kozhaya, Julia Oh, Derya Unutmaz
Human mucosal-associated invariant T (MAIT) cell receptors (TCRs) recognize bacterial riboflavin pathway metabolites through the MHC class 1-related molecule MR1. However, it is unclear whether MAIT cells discriminate between many species of the human microbiota. To address this, we developed an in vitro functional assay through human T cells engineered for MAIT-TCRs (eMAIT-TCRs) stimulated by MR1-expressing antigen-presenting cells (APCs). We then screened 47 microbiota-associated bacterial species from different phyla for their eMAIT-TCR stimulatory capacities...
August 16, 2018: Mucosal Immunology
Micah D Dunlap, Nicole Howard, Shibali Das, Ninecia Scott, Mushtaq Ahmed, Oliver Prince, Javier Rangel-Moreno, Bruce A Rosa, John Martin, Deepak Kaushal, Gilla Kaplan, Makedonka Mitreva, Ki-Wook Kim, Gwendalyn J Randolph, Shabaana A Khader
C-C motif chemokine receptor 2 (CCR2) is a major chemokine axis that recruits myeloid cells including monocytes and macrophages. Thus far, CCR2-/- mice have not been found to be susceptible to infection with Mycobacterium tuberculosis (Mtb). Here, using a prototype W-Beijing family lineage 2 Mtb strain, HN878, we show that CCR2-/- mice exhibit increased susceptibility to tuberculosis (TB). Following exposure to Mtb HN878, alveolar macrophages (AMs) are amongst the earliest cells infected. We show that AMs accumulate early in the airways following infection and express CCR2...
August 16, 2018: Mucosal Immunology
Manuela Flórido, Heni Muflihah, Leon C W Lin, Yingju Xia, Frederic Sierro, Mainthan Palendira, Carl G Feng, Patrick Bertolino, John Stambas, James A Triccas, Warwick J Britton
The lung is the primary site of infection with the major human pathogen, Mycobacterium tuberculosis. Effective vaccines against M. tuberculosis must stimulate memory T cells to provide early protection in the lung. Recently, tissue-resident memory T cells (TRM ) were found to be phenotypically and transcriptional distinct from circulating memory T cells. Here, we identified M. tuberculosis-specific CD4+ T cells induced by recombinant influenza A viruses (rIAV) vaccines expressing M. tuberculosis peptides that persisted in the lung parenchyma with the phenotypic and transcriptional characteristics of TRMs ...
August 16, 2018: Mucosal Immunology
Annika Gross, Lotta A P Pack, Gabriel M Schacht, Sebastian Kant, Hanna Ungewiss, Michael Meir, Nicolas Schlegel, Christian Preisinger, Peter Boor, Nurdan Guldiken, Claudia A Krusche, Gernot Sellge, Christian Trautwein, Jens Waschke, Arnd Heuser, Rudolf E Leube, Pavel Strnad
Desmosomes are the least understood intercellular junctions in the intestinal epithelia and provide cell-cell adhesion via the cadherins desmoglein (Dsg)2 and desmocollin (Dsc)2. We studied these cadherins in Crohn's disease (CD) patients and in newly generated conditional villin-Cre DSG2 and DSC2 knockout mice (DSG2ΔIEC ; DSC2ΔIEC ). CD patients exhibited altered desmosomes and reduced Dsg2/Dsc2 levels. The intestines of both transgenic animal lines were histopathologically inconspicuous. However, DSG2ΔIEC , but not DSC2ΔIEC mice displayed an increased intestinal permeability, a wider desmosomal space as well as alterations in desmosomal and tight junction components...
August 16, 2018: Mucosal Immunology
Jonathon E Himes, Ria Goswami, Riley J Mangan, Amit Kumar, Thomas L Jeffries, Joshua A Eudailey, Holly Heimsath, Quang N Nguyen, Justin Pollara, Celia LaBranche, Meng Chen, Nathan A Vandergrift, James W Peacock, Faith Schiro, Cecily Midkiff, Guido Ferrari, David C Montefiori, Xavier Alvarez Hernandez, Pyone Pyone Aye, Sallie R Permar
Breast milk HIV-1 transmission is currently the predominant contributor to pediatric HIV infections. Yet, only ~10% of breastfeeding infants born to untreated HIV-infected mothers become infected. This study assessed the protective capacity of natural HIV envelope-specific antibodies isolated from the milk of HIV-infected women in an infant rhesus monkey (RM), tier 2 SHIV oral challenge model. To mimic placental and milk maternal antibody transfer, infant RMs were i.v. infused and orally treated at the time of challenge with a single weakly neutralizing milk monoclonal antibody (mAb), a tri-mAb cocktail with weakly neutralizing and ADCC functionalities, or an anti-influenza control mAb...
August 16, 2018: Mucosal Immunology
N L Berntsen, B Fosby, C Tan, H M Reims, J Ogaard, X Jiang, E Schrumpf, L Valestrand, T H Karlsen, P-D Line, R S Blumberg, E Melum
Cholangiocytes function as antigen-presenting cells with CD1d-dependent activation of natural killer T (NKT) cells in vitro. NKT cells may act both pro- and anti-inflammatory in liver immunopathology. We explored this immune pathway and the antigen-presenting potential of NKT cells in the bile ducts by challenging wild-type and Cd1d-/- mice with intrabiliary injection of the NKT cell activating agent oxazolone. Pharmacological blocking of CD1d-mediated activation was performed with a monoclonal antibody. Intrabiliary oxazolone injection in wild-type mice caused acute cholangitis with significant weight loss, elevated serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin, increased histologic grade of cholangitis and number of T cells, macrophages, neutrophils and myofibroblasts per portal tract after 7 days...
August 16, 2018: Mucosal Immunology
Luis Solans, Anne-Sophie Debrie, Lisa Borkner, Nacho Aguiló, Anaïs Thiriard, Loic Coutte, Santi Uranga, François Trottein, Carlos Martín, Kingston H G Mills, Camille Locht
BPZE1 is a live attenuated Bordetella pertussis vaccine for nasal administration to mimic the natural route of infection. Here, we studied the mechanism of BPZE1-induced immunity in the murine nasal cavity in contrast to acellular vaccine (aPV), although both vaccines protected against lung colonization. Transfer of splenocytes or serum from BPZE1-vaccinated or aPV-vaccinated mice protected naïve mice against lung colonization but not against nasal colonization. However, transfer of nasal washes from BPZE1-vaccinated mice resulted in protection against nasal colonization, which was lost in IgA-deficient or poly-Ig receptor-deficient mice, indicating that it depends on secretory IgA (SIgA) induction induced in the nose...
August 16, 2018: Mucosal Immunology
Liza Konnikova, Gilles Boschetti, Adeeb Rahman, Vanessa Mitsialis, James Lord, Camilla Richmond, Vesselin T Tomov, Will Gordon, Scott Jelinsky, James Canavan, Andrew Liss, Sarah Wall, Michael Field, Fanny Zhou, Jeffery D Goldsmith, Meenakshi Bewtra, David T Breault, Miriam Merad, Scott B Snapper
Simultaneous analyses of peripheral and mucosal immune compartments can yield insight into the pathogenesis of mucosal-associated diseases. Although methods to preserve peripheral immune cells are well established, studies involving mucosal immune cells have been hampered by lack of simple storage techniques. We provide a cryopreservation protocol allowing for storage of gastrointestinal (GI) tissue with preservation of viability and functionality of both immune and epithelial cells. These methods will facilitate translational studies allowing for batch analysis of mucosal tissue to investigate disease pathogenesis, biomarker discovery and treatment responsiveness...
August 15, 2018: Mucosal Immunology
Barbara Ruder, Vinay Murtadak, Michael Stürzl, Stefan Wirtz, Ute Distler, Stefan Tenzer, Mousumi Mahapatro, Florian R Greten, Yinling Hu, Markus F Neurath, Ethel Cesarman, Gianna Ballon, Claudia Günther, Christoph Becker
Viruses are present in the intestinal microflora and are currently discussed as a potential causative mechanism for the development of inflammatory bowel disease. A number of viruses, such as Human Herpesvirus-8, express homologs to cellular FLIPs, which are major contributors for the regulation of epithelial cell death. In this study we analyzed the consequences of constitutive expression of HHV8-viral FLIP in intestinal epithelial cells (IECs) in mice. Surprisingly, expression of vFlip disrupts tissue homeostasis and induces severe intestinal inflammation...
August 13, 2018: Mucosal Immunology
Yuan Gao, John Su, Yibing Zhang, Allison Chan, Jun Hyung Sin, Di Wu, Kyungi Min, Karsten Gronert
Recently identified regulatory PMN control immune-driven dry eye disease (DED) in females by producing the arachidonic acid (ω-6)-derived specialized pro-resolving mediator (SPM), LXA4 , in lymph nodes. Dietary ω-3 docosahexaenoic acid (DHA) is protective in DED but mechanisms of action remain elusive. DHA is converted to ω-3 SPMs by PMN via the same lipoxygenases (LOX) that generate LXA4 . We investigated if dietary DHA amplifies SPM formation and affects T effector cell function and/or regulatory PMN in DED...
August 13, 2018: Mucosal Immunology
Naina Gour, Ursula Smole, Hwan-Mee Yong, Ian P Lewkowich, Nu Yao, Anju Singh, Edward Gabrielson, Marsha Wills-Karp, Stephane Lajoie
Aberrant type 2 responses underlie the pathologies in allergic diseases like asthma, yet, our understanding of the mechanisms that drive them remains limited. Recent evidence suggests that dysregulated innate immune factors can perpetuate asthma pathogenesis. In susceptible individuals, allergen exposure triggers the activation of complement, a major arm of innate immunity, leading to the aberrant generation of the C3a anaphylatoxin. C3 and C3a have been shown to be important for the development of Th2 responses, yet remarkably, the mechanisms by which C3a regulates type 2 immunity are relatively unknown...
August 13, 2018: Mucosal Immunology
David P Sullivan, Triet Bui, William A Muller, Veronika Butin-Israeli, Ronen Sumagin
Neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of gastrointestinal inflammation, with significant implications for host defense, injury and repair. However, phenotypic and mechanistic aspects of PMN recruitment in inflamed intestines have not been explored in vivo. Using novel epithelial/PMN fluorescence reporter mice, advanced intravital imaging and 3D reconstruction analysis, we mapped the microvasculature architecture across the intestinal layers and determined that in response to Salmonella/endotoxin-induced inflammation, PMN transendothelial migration (TEM) was restricted to submucosal vessels...
August 13, 2018: Mucosal Immunology
Julie Chesné, Vânia Cardoso, Henrique Veiga-Fernandes
Mucosal barriers constitute major body surfaces that are in constant contact with the external environment. Mucosal sites are densely populated by a myriad of distinct neurons and immune cell types that sense, integrate and respond to multiple environmental cues. In the recent past, neuro-immune interactions have been reported to play central roles in mucosal health and disease, including chronic inflammatory conditions, allergy and infectious diseases. Discrete neuro-immune cell units act as building blocks of this bidirectional multi-tissue cross-talk, ensuring mucosal tissue health and integrity...
August 8, 2018: Mucosal Immunology
Yanxia Lu, Hassen Kared, Shu Wen Tan, Etienne Becht, Evan W Newell, Hugo P S Van Bever, Tze Pin Ng, Anis Larbi
Asthma comprises heterogeneous clinical subtypes driven by diverse pathophysiological mechanisms. We characterized the modulation of the inflammatory environment with the phenotype, gene expression, and function of helper CD4 T cells among acutely exacerbated and stable asthma patients. Systemic Th2 immune deviation (IgE and Th2 cytokines) and inflammation (IL-6, CRP) were associated with increased Th17 cells during acute asthma. Th2/Th17 cell differentiation during acute asthma was regulated by the enhanced expression of transcription factors (c-MAF, IRF-4)...
August 7, 2018: Mucosal Immunology
Siva Karthik Varanasi, Naveen K Rajasagi, Ujjaldeep Jaggi, Barry T Rouse
This report deals with the possible mechanism by which IL-18 can contribute to the control and resolution of inflammatory lesions in the cornea caused by herpes simplex virus infection. Our results demonstrate that the expression of the IL-18R by both regulatory T cells (Treg) and effector T cells was a pivotal event that influenced lesion pathogenesis. The engagement of IL-18R on Treg with its cytokine ligand resulted in Amphiregulin expression a molecule associated with tissue repair. In support of this scheme of events, lesion severity became more severe in animals unable to express the IL-18R because of gene knockout and was reduced in severity when IL-18 was overexpressed in the cornea...
August 7, 2018: Mucosal Immunology
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