Immuno-surveillance networks operating at barrier sites are tuned by local tissue cues to ensure effective immunity. Site-specific commensal bacteria provide key signals ensuring host defense in the ...skin and gut. However, how the oral microbiome and tissue-specific signals balance immunity and regulation at the gingiva, a key oral barrier, remains minimally explored. In contrast to the skin and gut, we demonstrate that gingiva-resident T helper 17 (Th17) cells developed via a commensal colonization-independent mechanism. Accumulation of Th17 cells at the gingiva was driven in response to the physiological barrier damage that occurs during mastication. Physiological mechanical damage, via induction of interleukin 6 (IL-6) from epithelial cells, tailored effector T cell function, promoting increases in gingival Th17 cell numbers. These data highlight that diverse tissue-specific mechanisms govern education of Th17 cell responses and demonstrate that mechanical damage helps define the immune tone of this important oral barrier.
Display omitted
•Distinct signals shape the Th17 cell network at the oral barrier•Oral barrier Th17 cells develop independently of commensal microbe colonization•Physiologic damage through mastication promotes the generation of oral Th17 cells•Barrier damage triggers oral Th17-cell-mediated protective immunity and inflammation
The signals regulating immunity at the gingiva, a key oral barrier, remain unclear. Dutzan et al. show that oral barrier Th17 cells are induced in response to mastication rather than commensal colonization, identifying physiologic mechanical damage as a unique tissue-specific cue conditioning local immunity and inflammation at the oral barrier.
The requirement to remove apoptotic cells is equally important in homeostasis and inflammatory disease. In particular, during viral infections large quantities of infected cells undergo apoptosis and ...need to be efficiently cleared by phagocytes to prevent secondary necrosis. Although specific roles of several apoptotic cell sensors, such as the TAM (Tyro3, Axl, MerTK) receptor family, have been characterized in mouse models, little is known about their regulation and involvement in apoptotic cell uptake (efferocytosis) by human macrophages under inflammatory conditions. We show that whereas pro‐inflammatory stimuli consistently downregulated MerTK expression in human monocyte‐derived macrophages (MDMs), stimuli indicative of a viral infection, interferon‐α (IFN‐α) and the TLR3 ligand poly(I:C), specifically induced Axl expression and promoted binding of the bridging molecule Gas6. Axl induction by IFN‐α and poly(I:C) was associated with higher MDM efferocytic capacity compared to cells treated with other pro‐inflammatory stimuli, such as LPS and IFN‐γ. While MerTK blocking antibody uniformly suppressed apoptotic cell uptake by MDMs, Axl blocking antibody significantly reduced efferocytosis by poly(I:C)‐stimulated MDMs, but not by resting MDMs. Our observations demonstrate that Axl induction during viral infections contributes to maintaining macrophage capacity to engulf apoptotic cells, which may have important consequences for resolution of anti‐viral immune responses.
Resting human macrophages express high levels of the TAM receptor MerTK and efficiently engulf apoptotic cells. Macrophage stimulation with LPS or IFN‐γ leads to MerTK downregulation and reduction of efferocytosis. In contrast, triggers associated with viral infections, such as IFN‐α or poly(I:C), partly maintain macrophage efferocytic capacity through induction of Axl.
TAM (Tyro3, Axl, MerTK) receptor tyrosine kinases mediate apoptotic cell uptake by phagocytes through the bridging molecules Protein S or growth arrest specific 6 (Gas6), and are critical for lung ...immune homeostasis.4 We and others have shown that Axl is specifically expressed on mouse airway macrophages, is constitutively bound to its ligand Gas6, and is critical for efficient efferocytosis.5,6 Axl-deficient mice develop exaggerated lung inflammation upon influenza infection associated with accumulation of apoptotic cells in the airways,5 indicating a critical role for Axl in apoptotic cell clearance from the inflamed lung. ...we report for the first time that (1) the apoptotic cell recognition receptor Axl is exclusively expressed by human airway/alveolar macrophages, (2) Axl expression depends on the presence of type I/III IFNs, (3) increased shedding of sAxl occurs in sputum from patients with moderate-to-severe asthma, and (4) Axl mRNA expression in airway macrophages isolated from sputum is reduced in patients with moderate-to-severe asthma. Methods Study population and sample collection Paired peripheral blood and sputum samples (spontaneous or induced by using hypertonic saline) were collected from 15 healthy individuals and 46 patients with moderate-to-severe asthma fulfilling the British Thoracic Society criteria (disease steps 3-5).E1 Clinical characteristics of patients are presented in Table E1. Feature Moderate-to-severe asthma (n = 46) Healthy control (n = 15) Sex: male/female 19/27 4/11 Age (y) 55 (45-63) 37.2 (30-46) Smoking history Never 21 11 Ex 18 4 Current 7 0 Asthma severity BTS step 3 8 BTS step 4 12 BTS step 5 26 FEV1 (L) 2.14 (1.63-2.73) NA FEV1 % predicted 77 (64-94) NA FVC (L) 3.10 (2.63-3.69) NA FVC % predicted 93 (83-109) NA FEV1/FVC ratio 0.7 (0.59-0.79) NA 1 R. Fernandez-Boyanapalli, E. Goleva, C. Kolakowski, E. Min, B. Day, D.Y. Leung, Obesity impairs apoptotic cell clearance in asthma, J Allergy Clin Immunol, Vol. 131, 2013, 1041-1047, 1047.e1-3 2 M.L. Huynh, K.C. Malcolm, C. Kotaru, J.A. Tilstra, J.Y. Westcott, V.A. Fadok, Defective apoptotic cell phagocytosis attenuates prostaglandin E2 and 15-hydroxyeicosatetraenoic acid in severe asthma alveolar macrophages, Am J Respir Crit Care Med, Vol. 172, 2005, 972-979 3 J.L. Simpson, P.G. Gibson, I.A. Yang, J. Upham, A. James, P.N. Reynolds, Impaired macrophage phagocytosis in non-eosinophilic asthma, Clin Exp Allergy, Vol. 43, 2013, 29-35 4 A.M. Grabiec, T. Hussell, The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation, Semin Immunopathol, Vol. 38, 2016, 409-423 5 T. Fujimori, A.M. Grabiec, M. Kaur, T.J. Bell, N. Fujino, P.C. Cook, The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung, Mucosal Immunol, Vol. 8, 2015, 1021-1030 6 E.T. Schmid, I.K. Pang, E.A. Carrera Silva, L. Bosurgi, J.J. Miner, M.S. Diamond, AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity, Elife, Vol. 5, 2016, e12414 7 C.P. Ko, Y.L. Yu, P.C. Hsiao, S.F. Yang, C.B. Yeh, Plasma levels of soluble Axl correlate with severity of community-acquired pneumonia, Mol Med Rep, Vol. 9, 2014, 1400-1404 8 M. Contoli, S.D. Message, V. Laza-Stanca, M.R. Edwards, P.A. Wark, N.W. Bartlett, Role of deficient type III interferon-lambda production in asthma exacerbations, Nat Med, Vol. 12, 2006, 1023-1026 9 R. Djukanovic, T. Harrison, S.L. Johnston, F. Gabbay, P. Wark, N.C. Thomson, The effect of inhaled IFN-beta on worsening of asthma symptoms caused by viral infections: a randomized trial, Am J Respir Crit Care Med, Vol. 190, 2014, 145-154
Abstract
At barrier sites, resident immune cell populations help to maintain tissue homeostasis and function. These cells receive and integrate key signals from the local environment including ...stromal/epithelial cells and the commensal microbiome. Studies of the skin and gastrointestinal tract have revealed the importance of these signals for the development of host immune response. However, which commensal or tissue-specific cues are important for the immune system at the oral barrier remains minimally explored. Th17 cells have been described as key mediators of immunity at the oral barrier but also essential for periodontitis, a highly prevalent inflammatory pathology that affects the gingiva. In this study we focused in the identification of the mechanisms controlling the induction and regulation of Th17 cells in the gingiva. Our data show that IL-17-producing CD4+ T cells increase with age and their accumulation at the oral barrier occurs independently of commensal colonization. Moreover, we demonstrate that IL-6 elicited by physiological mechanical damage during mastication shapes the function of T cells at the oral mucosa, promoting Th17 differentiation. Finally, we observe that long-term mechanical damage through mastication induces IL-17 mediated bone loss at the gingival barrier. Our data highlight the notion that a variety of signals may be essential to shape the immune responses at different barrier sites, and particularly at the oral cavity, unique mechanisms modulates homeostatic and also pathogenic Th17 responses.
Studies of repertoires of mouse monoclonal CD4(+) T cells have revealed several mechanisms of self-tolerance; however, which mechanisms operate in normal repertoires is unclear. Here we studied ...polyclonal CD4(+) T cells specific for green fluorescent protein expressed in various organs, which allowed us to determine the effects of specific expression patterns on the same epitope-specific T cells. Peptides presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas peptides excluded from the thymus were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self antigens. Thus, the immunotolerance of polyclonal CD4(+) T cells was maintained by distinct mechanisms, according to self-peptide expression patterns.
Introduction Automated manual lymphatic drainage therapy (AMLDT) is available for home use in the form of a pneumatic mat of 16 pressurized air channels that inflate and deflate to mimic the stretch ...and release action of manual lymphatic drainage therapy. Four cases (a patient with complex regional pain syndrome and lymphedema, a healthy patient, a breast cancer survivor with chronic pain, and a patient with a history of abdominal surgery) underwent near-infrared fluorescence lymphatic imaging (NIRFLI) with AMLDT to evaluate the effect of AMLDT on lymphatic pumping and pain. Methods Each patient received 32–36 injections of 25 μg indocyanine green (ICG) on the anterior and posterior sides of their body and underwent 1 h of NIRFLI to assess the drainage of ICG laden lymph toward regional nodal basins at baseline. Each patient lay supine on the mat for 1 h of AMLDT with NIRFLI to assess lymphatic flow during treatment. A final NIFRFLI assessment was done 30–60 min posttreatment with the patient in the supine and prone position. Patients reported baseline and posttreatment pain using the Visual Analogue Scale. An imager analyzed NIRFLI images using ImageJ (US National Institutes of Health). Using time stamps of the first and last images to determine time lapsed and the number of pulses observed in a timeframe, pulsing frequency (pulses/min) was obtained to assess lymphatic function. Results All 4 cases completed the NIRFLI and AMLDT without complications; all 3 patients with baseline pain reported reduced pain posttreatment. AMLDT appeared to alter lymphatic contractility, with both increased and decreased pulsing frequencies observed, including in nonaffected limbs. Pulsing frequencies were very heterogeneous among patients and varied within anatomic regions of the same patient. Discussion This proof-of-concept study suggests that AMLDT may impact lymphatic contractility. Further research on its effect on lymphatic function is warranted.
serovar Gallinarum causes devastating outbreaks of fowl typhoid across the globe, especially in developing countries. With the use of antimicrobial agents being reduced due to legislation and the ...absence of licensed vaccines in some parts of the world, an attractive complementary control strategy is to breed chickens for increased resistance to
. The potential for genetic control of salmonellosis has been demonstrated by experimental challenge of inbred populations. Quantitative trait loci (QTL) associated with resistance have been identified in many genomic regions. A major QTL associated with systemic salmonellosis has been identified in a region termed
. In the present study, two outbreaks of fowl typhoid in 2007 and 2012 in the United Kingdom were used to investigate the genetic architecture of
resistance in commercial laying hens. In the first outbreak 100 resistant and 150 susceptible layers were genotyped using 11 single nucleotide polymorphism (SNP) and 3 microsatellite markers located in the previously identified
region on chromosome 5. From the second outbreak 100 resistant and 200 susceptible layers, belonging to a different line, were genotyped with a high-density (600 K) genome-wide SNP array. Substantial heritability estimates were obtained in both populations (
= 0.22 and 0.26, for the layers in the first and second outbreak, respectively). Significant associations with three markers on chromosome 5 located close to
and
genes, coding for RAC-alpha serine/threonine protein kinase, and the CD27-binding protein
, respectively, were identified in the first outbreak. From analysis of the second outbreak, eight genome-wide significant associations with
resistance were identified on chromosomes 1, 6, 7, 11, 23, 24, 26, 28 and several others with suggestive genome-wide significance were found. Pathway and network analysis revealed the presence of many innate immune pathways related to
resistance. Although, significant associations with SNPs located in the
locus were not identified by the genome-wide scan for layers from the second outbreak, pathway analysis revealed P13K/AKT signaling as the most significant pathway. In summary, resistance to fowl typhoid is a heritable polygenic trait that could possibly be enhanced through selective breeding.
Background. Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. ...Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use. Methods. Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing. Results. Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 57%), compared with the TDF arm (1 of 19 5.3%; P = .01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment. Conclusions. These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.
Rheumatoid arthritis (RA) is the most common, crippling human autoimmune disease. Using Western blotting and tandem mass spectroscopy, we have identified the endoplasmic reticulum chaperone BiP, a ...78-kDa glucose-regulated protein, as a possible autoantigen. It preferentially stimulated increased proliferation of synovial T cells from patients with RA but not from patients with other arthritides. Mice with established collagen- or pristane-induced arthritis developed IgG Abs to BiP. Although BiP injected in CFA failed to induce arthritis in several strains of rats and mice, including HLA-DR4(+/-)- and HLA-DR1(+/+)-transgenic animals, it completely inhibited the development of arthritis when given i.v. 1 wk before the injection of type II collagen arthritis. Preimmunization with BiP suppressed the development of adjuvant arthritis in Lewis rats in a similar manner. This is the first report of a mammalian chaperone that is an autoantigen in human RA and in experimental arthritis and that can also prevent the induction of experimental arthritis. These findings may stimulate the development of new immunotherapies for the treatment of RA.
Arctic tern (Sterna paradisaea) populations are thought to be in decline across much of their range. For long-lived seabirds, determining adult survival rates is key to understanding current ...population trends and predicting trajectories. We therefore examined adult survival of terns banded at our field site in the Canadian High Arctic between 2007 and 2016. Apparent adult survival was 0.883, comparable to values for other tern species and for other Arctic larids. However, using this survival rate plus first year survival values from a recent study in Iceland, we project a declining trend for terns in the Canadian High Arctic, consistent with recent reports from local ecological knowledge and limited regional surveys. Our data suggest that low adult survival is not responsible for declining tern populations, and that studies should investigate whether dispersal to new nesting locations may be underway, or that young terns are not surviving well or recruiting to the population.
PDF
