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Mucosal Immunology

Matthew T Sorbara, Eric G Pamer
The communities of bacteria that reside in the intestinal tract are in constant competition within this dynamic and densely colonized environment. At homeostasis, the equilibrium that exists between these species and strains is shaped by their metabolism and also by pathways of active antagonism, which drive competition with related and unrelated strains. Importantly, these normal activities contribute to colonization resistance by the healthy microbiota, which includes the ability to prevent the expansion of potential pathogens...
July 9, 2018: Mucosal Immunology
J Wu, A H Pendegraft, M Byrne-Steele, Q Yang, C Wang, W Pan, T Lucious, T Seay, X Cui, C O Elson, J Han, P J Mannon
We aimed to determine whether the TCR repertoires of Crohn's disease (CD) patients contain highly prevalent disease-specific T-cell clonotypes reflective of the characteristic and highly shared aberrant serum antibody reactivity to gut commensal flagellin antigens. The CD4 TCRβ CDR3 sequence repertoires from active CD (n = 20) and ulcerative colitis (UC) (n = 10) patients were significantly more diverse, and individual sequences over-represented, compared to healthy controls (HC) (n = 97). While a very small number of expanded public CDR3 sequences are highly shared between active CD and UC, the majority of significantly expanded TCRβ CDR3 clonotypes are private to CD and UC patients with equivalent prevalence among IBD patients...
July 9, 2018: Mucosal Immunology
Noam Jacob, Jonathan P Jacobs, Kotaro Kumagai, Connie W Y Ha, Yoshitake Kanazawa, Venu Lagishetty, Katherine Altmayer, Ariel M Hamill, Aimee Von Arx, R Balfour Sartor, Suzanne Devkota, Jonathan Braun, Kathrin S Michelsen, Stephan R Targan, David Q Shih
Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease (IBD), modulating the location and severity of intestinal inflammation and fibrosis. TL1A expression is increased in inflamed gut mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice lead to spontaneous ileitis, and exacerbated induced proximal colitis and fibrosis. IBD is associated with shifts in the gut microbiome, but the effect of differing microbial populations and their interaction with TL1A on fibrosis has not been investigated...
July 9, 2018: Mucosal Immunology
A M Overstreet, D L LaTorre, L Abernathy-Close, S F Murphy, L Rhee, A M Boger, K R Adlaka, A M Iverson, D S Bakke, C R Weber, D L Boone
Innate immunity contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms of IBD mediated by innate immunity are incompletely understood and there are limited models of spontaneous innate immune colitis to address this question. Here we describe a new robust model of colitis occurring in the absence of adaptive immunity. RAG1-deficient mice expressing TNFAIP3 in intestinal epithelial cells (TRAG mice) spontaneously developed 100% penetrant, early-onset colitis that was limited to the colon and dependent on intestinal microbes but was not transmissible to co-housed littermates...
July 9, 2018: Mucosal Immunology
Holly A Schroeder, Kenetta L Nunn, Alison Schaefer, Christine E Henry, Felix Lam, Michael H Pauly, Kevin J Whaley, Larry Zeitlin, Mike S Humphrys, Jacques Ravel, Samuel K Lai
IgG possesses an important yet little recognized effector function in mucus. IgG bound to viral surface can immobilize otherwise readily diffusive viruses to the mucin matrix, excluding them from contacting target cells and facilitating their elimination by natural mucus clearance mechanisms. Cervicovaginal mucus (CVM) is populated by a microbial community, and its viscoelastic and barrier properties can vary substantially not only across the menstrual cycle, but also in women with distinct microbiota. How these variations impact the "muco-trapping" effector function of IgGs remains poorly understood...
July 9, 2018: Mucosal Immunology
Yunxia Xue, Jingxin He, Chengju Xiao, Yonglong Guo, Ting Fu, Jun Liu, Cuipei Lin, Mingjuan Wu, Yabing Yang, Dong Dong, Hongwei Pan, Chaoyong Xia, Li Ren, Zhijie Li
Inflammation and reepithelialization after corneal abrasion are critical for the rapid restoration of vision and the prevention of microbial infections. However, the endogenous regulatory mechanisms are not completely understood. Here we report that the manipulation of autonomic nervous system (ANS) regulates the inflammation and healing processes. The activation of sympathetic nerves inhibited reepithelialization after corneal abrasion but increased the influx of neutrophils and the release of inflammatory cytokines...
July 9, 2018: Mucosal Immunology
Chelsea Marie, Asad Ali, Kanta Chandwe, William A Petri, Paul Kelly
Environmental enteric dysfunction (EED) refers to a subclinical disorder of intestinal function common in tropical countries and in settings of poverty and economic disadvantage. The enteropathy that underlies this syndrome is characterized by mucosal inflammation and villus blunting mediated by T cell activation. Epithelial cell disruption and microbial translocation drive systemic inflammation. EED in young children is associated geographically with growth failure, malnutrition, and greatly impaired responses to oral vaccines, notably rotavirus and poliovirus vaccines...
July 9, 2018: Mucosal Immunology
Sudarshan Paramsothy, Adam K Rosenstein, Saurabh Mehandru, Jean-Frederic Colombel
The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium...
June 15, 2018: Mucosal Immunology
Jennifer K Mulligan, Kunal Patel, Tucker Williamson, Nicholas Reaves, William Carroll, Sarah E Stephenson, Peng Gao, Richard R Drake, Benjamin A Neely, Stephen Tomlinson, Rodney J Schlosser, Carl Atkinson
Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease with an unknown etiology. Recent studies have implicated the complement system as a potential modulator of disease immunopathology. We performed proteomic pathway enrichment analysis of differentially increased proteins, and found an enrichment of complement cascade pathways in the nasal mucus of individuals with CRSwNP as compared to control subjects. Sinonasal mucus levels of complement 3 (C3) correlated with worse subjective disease severity, whereas no significant difference in systemic C3 levels could be determined in plasma samples...
June 15, 2018: Mucosal Immunology
Bart Hilvering, Timothy S C Hinks, Linda Stöger, Emanuele Marchi, Maryam Salimi, Rahul Shrimanker, Wei Liu, Wentao Chen, Jian Luo, Simei Go, Timothy Powell, Jennifer Cane, Samantha Thulborn, Ayako Kurioka, Tianqi Leng, Jamie Matthews, Clare Connolly, Catherine Borg, Mona Bafadhel, Christian B Willberg, Adaikalavan Ramasamy, Ratko Djukanović, Graham Ogg, Ian D Pavord, Paul Klenerman, Luzheng Xue
Human type-2 CD8+ T cells are a cell population with potentially important roles in allergic disease. We investigated this in the context of severe asthma with persistent airway eosinophilia-a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+ CRTH2+ (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D2 (PGD2 ) and cysteinyl leukotriene E4 (LTE4 ) are also increased in the airways of the same group of patients...
June 15, 2018: Mucosal Immunology
Yash A Choksi, Vishruth K Reddy, Kshipra Singh, Caitlyn W Barrett, Sarah P Short, Bobak Parang, Cody E Keating, Joshua J Thompson, Thomas G Verriere, Rachel E Brown, M Blanca Piazuelo, David M Bader, M Kay Washington, Mukul K Mittal, Thomas Brand, Alain P Gobert, Lori A Coburn, Keith T Wilson, Christopher S Williams
Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves -/- mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity...
June 15, 2018: Mucosal Immunology
Antoine Ménoret, James A Buturla, Maria M Xu, Julia Svedova, Sanjeev Kumar, Vijay A K Rathinam, Anthony T Vella
Immune-mediated lung is considered the result of an exacerbated innate injury immune response, although a role for adaptive lymphocytes is emerging. αβ T cells specific for S. aureus enterotoxin A orchestrate a Tγδ17 response during lung injury. However, the mechanism driving IL-17 production is unclear. Here, we show a role for IL-2 triggering IL-17 production by lung granular γδ T cells as IL-17 synthesis and neutrophil recruitment was reduced by IL-2 blocking mAbs in vitro and in vivo. Mass cytometry analysis revealed that lung γδ T cells responded directly to IL-2 as evident from STAT5 phosphorylation and RoRγt expression...
June 15, 2018: Mucosal Immunology
Kristen M Reeder, Chad W Dunaway, Jonathan P Blackburn, Zhihong Yu, Sadis Matalon, Annette T Hastie, Elizabeth J Ampleford, Deborah A Meyers, Chad Steele
Asthmatics sensitized to fungi are reported to have more severe asthma, yet the immunopathogenic pathways contributing to this severity have not been identified. In a pilot assessment of human asthmatics, those subjects sensitized to fungi demonstrated elevated levels of the common γ-chain cytokine IL-7 in lung lavage fluid, which negatively correlated with the lung function measurement PC20. Subsequently, we show that IL-7 administration during experimental fungal asthma worsened lung function and increased the levels of type 2 cytokines (IL-4, IL-5, IL-13), proallergic chemokines (CCL17, CCL22) and proinflammatory cytokines (IL-1α, IL-1β)...
June 15, 2018: Mucosal Immunology
Tiffany Hensley-McBain, Alicia R Berard, Jennifer A Manuzak, Charlene J Miller, Alexander S Zevin, Patricia Polacino, Jillian Gile, Brian Agricola, Mark Cameron, Shiu-Lok Hu, Jacob D Estes, R Keith Reeves, Jeremy Smedley, Brandon F Keele, Adam D Burgener, Nichole R Klatt
HIV and pathogenic SIV infection are characterized by mucosal dysfunction including epithelial barrier damage, loss of Th17 cells, neutrophil infiltration, and microbial translocation with accompanying inflammation. However, it is unclear how and when these contributing factors occur relative to one another. In order to determine whether any of these features initiates the cycle of damage, we longitudinally evaluated the kinetics of mucosal and systemic T-cell activation, microbial translocation, and Th17 cell and neutrophil frequencies following intrarectal SIV infection of rhesus macaques...
June 15, 2018: Mucosal Immunology
Fiona D Barr, Christina Ochsenbauer, Charles R Wira, Marta Rodriguez-Garcia
Women acquire human immunodeficiency virus (HIV) mainly through sexual intercourse. However, low transmission rates per sexual act indicate that local immune mechanisms contribute to HIV prevention. Neutrophils represent 10-20% of the genital immune cells in healthy women. Neutrophils mediate mucosal protection against bacterial and fungal pathogens through different mechanisms, including the release of neutrophil extracellular traps (NETs). NETs are DNA fragments associated with antimicrobial granular proteins...
June 6, 2018: Mucosal Immunology
Fatima Nawaz, Livia R Goes, Jocelyn C Ray, Ronke Olowojesiku, Alia Sajani, Aftab A Ansari, Ian Perrone, Joseph Hiatt, Donald Van Ryk, Danlan Wei, Mia Waliszewski, Marcelo A Soares, Katija Jelicic, Mark Connors, Stephen A Migueles, Elena Martinelli, Francois Villinger, Claudia Cicala, Anthony S Fauci, James Arthos
Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin α4 β7 , expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with α4 β7 ...
June 6, 2018: Mucosal Immunology
Xi Shen, Liping Liu, Richard M Peek, Sari A Acra, Daniel J Moore, Keith T Wilson, Fang He, D Brent Polk, Fang Yan
The beneficial effects of the gut microbiota on growth in early life are well known. However, knowledge about the mechanisms underlying regulating intestinal development by the microbiota is limited. p40, a Lactobacillus rhamnosus GG-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells for protecting the intestinal epithelium against injury and inflammation. Here, we developed p40-containing pectin/zein hydrogels for targeted delivery of p40 to the small intestine and the colon...
June 6, 2018: Mucosal Immunology
Christy A Harrison, Daniel Laubitz, Christina L Ohland, Monica T Midura-Kiela, Karuna Patil, David G Besselsen, Deepa R Jamwal, Christian Jobin, Fayez K Ghishan, Pawel R Kiela
Intestinal epithelial Na+ /H+ exchange facilitated by the apical NHE3 (Slc9a3) is a highly regulated process inhibited by intestinal pathogens and in inflammatory bowel diseases. NHE3-/- mice develop spontaneous, bacterially mediated colitis, and IBD-like dysbiosis. Disruption of epithelial Na+ /H+ exchange in IBD may thus represent a host response contributing to the altered gut microbial ecology, and may play a pivotal role in modulating the severity of inflammation in a microbiome-dependent manner. To test whether microbiome fostered in an NHE3-deficient environment is able to drive mucosal immune responses affecting the onset or severity of colitis, we performed a series of cohousing experiments and fecal microbiome transplants into germ-free Rag-deficient or IL-10-/- mice...
June 6, 2018: Mucosal Immunology
Chengyun Xu, Chaochun Zou, Musaddique Hussain, Wei Shi, Yanan Shao, Ziyan Jiang, Xiling Wu, Meiping Lu, Junsong Wu, Qiangmin Xie, Yuehai Ke, Fanxin Long, Lanfang Tang, Ximei Wu
Sonic hedgehog (SHH) is abundantly expressed and critical for morphogenesis in embryonic lungs; however, SHH expression drops to a much lower level in mice from E17.5 and in humans from the 21st gestational week. We find that SHH expression is robustly upregulated in the airway epithelia of children with asthma or mouse models with allergic airway disease. Specifically, airway-specific SMO loss of function significantly suppresses allergen-induced goblet cell phenotypes, whereas an airway-specific SMO gain of function markedly enhances the goblet cell phenotypes in mouse models with allergic airway disease...
June 4, 2018: Mucosal Immunology
Kathryn A Knoop, Rodney D Newberry
Goblet cells (GCs) are specialized epithelial cells that line multiple mucosal surfaces and have a well-appreciated role in barrier maintenance through the secretion of mucus. Moreover, GCs secrete anti-microbial proteins, chemokines, and cytokines demonstrating functions in innate immunity beyond barrier maintenance. Recently it was appreciated that GCs can form goblet cell-associated antigen passages (GAPs) and deliver luminal substances to underlying lamina propria (LP) antigen-presenting cells (APCs) in a manner capable of inducing adaptive immune responses...
June 4, 2018: Mucosal Immunology
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