Iatrogenic laryngotracheal stenosis (iLTS) is characterized by fibroinflammatory narrowing of the upper airway and is most commonly caused by intubation injury. Evidence suggests a key role for CD4 T ...cells in its pathogenesis. The objective of this study is to validate emerging multiplex immunofluorescence (mIF) technology for use in the larynx and trachea while quantitatively characterizing the immune cell infiltrate in iLTS. In addition to analyzing previously unstudied immune cell subsets, this study aims to validate previously observed elevations in the immune checkpoint PD-1 and its ligand PD-L1 while exploring their spatial and cellular distributions in the iLTS microenvironment.
Controlled ex vivo cohort study.
Tertiary care center.
mIF staining was performed with formalin-fixed, paraffin-embedded slides from 10 patients with iLTS who underwent cricotracheal resection and 10 control specimens derived from rapid autopsy for CD4, CD8, CD20, FoxP3, PD-1, PD-L1, and cytokeratin.
There was greater infiltration of CD4
T cells, CD8
T cells, CD20
B cells, FoxP3
CD4
Tregs, and FoxP3
CD8
early effector T cells in the submucosa of iLTS specimens as compared with controls (
< .05 for all). PD-1 was primarily expressed on T cells and PD-L1 predominantly on CD4
cells and "other" cells.
This study leverages the power of mIF to quantify the iLTS immune infiltrate in greater detail. It confirms the highly inflammatory nature of iLTS, with CD4
cells dominating the immune cell infiltrate; it further characterizes the cellular and spatial distribution of PD-1 and PD-L1; and it identifies novel immunologic targets in iLTS.
Iatrogenic laryngotracheal stenosis (LTS) is pathologic airway narrowing due to scar formation following endotracheal intubation or tracheostomy. It is a chronic and recurrent disease that results in ...significant morbidity or even mortality. Current data suggests that inflammatory pathways play a significant role in mediating the deposition of collagen and extracellular matrix to generate this scar. In particular, the T-helper 2 cell and M2 macrophage axis appears to be activated in both animal models and patients with iatrogenic LTS. Interleukin-6 production in response to hypoxia has also been implicated. In this paper, we review the data supporting the roles of various inflammatory pathways in the pathogenesis of iatrogenic LTS, discuss potential therapeutic approaches targeting these mechanisms, and outline areas for future study.
Laryngotracheal stenosis (LTS) is pathologic fibrotic narrowing of the larynx and trachea characterized by hypermetabolic fibroblasts and CD4+ T cell-mediated inflammation. However, the role of CD4+ ...T cells in promoting LTS fibrosis is unknown. The mTOR signaling pathways have been shown to regulate the T cell phenotype. Here we investigated the influence of mTOR signaling in CD4+ T cells on LTS pathogenesis. In this study, human LTS specimens revealed a higher population of CD4+ T cells expressing the activated isoform of mTOR. In a murine LTS model, targeting mTOR with systemic sirolimus and a sirolimus-eluting airway stent reduced fibrosis and Th17 cells. Selective deletion of mTOR in CD4+ cells reduced Th17 cells and attenuated fibrosis, demonstrating CD4+ T cells' pathologic role in LTS. Multispectral immunofluorescence of human LTS revealed increased Th17 cells. In vitro, Th17 cells increased collagen-1 production by LTS fibroblasts, which was prevented with sirolimus pretreatment of Th17 cells. Collectively, mTOR signaling drove pathologic CD4+ T cell phenotypes in LTS, and targeting mTOR with sirolimus was effective at treating LTS through inhibition of profibrotic Th17 cells. Finally, sirolimus may be delivered locally with a drug-eluting stent, transforming clinical therapy for LTS.
Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity e.g. body mass index (BMI) ≥ 40 kg/m(2), but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI ...variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.
Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of ...Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10−28) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits.
A Toddler With Nasal Congestion and a Limp Davis, Ruth J; Boyce, Alison M; Mydlarz, Wojciech K
JAMA otolaryngology-- head & neck surgery,
02/2017, Letnik:
143, Številka:
2
Journal Article
African Americans (AAs) have been underrepresented in polygenic risk score (PRS) studies. Here, we integrated genome-wide data from multiple observational studies on type 2 diabetes (T2D), ...encompassing a total of 101,987 AAs, to train and optimize an AA-focused T2D PRS (PRSAA), using a Bayesian polygenic modeling method. We further tested the score in three independent studies with a total of 7,275 AAs and compared the PRSAA with other published scores. Results show that a 1-SD increase in the PRSAA was associated with 40-60% increase in the odds of T2D (odds ratio OR 1.60, 95% CI 1.37-1.88; OR 1.40, 95% CI 1.16-1.70; and OR 1.45, 95% CI 1.30-1.62) across three testing cohorts. These models captured 1.0-2.6% of the variance (R2) in T2D on the liability scale. The positive predictive values for three calculated score thresholds (the top 2%, 5%, and 10%) ranged from 14 to 35%. The PRSAA, in general, performed similarly to existing T2D PRS. The need remains for larger data sets to continue to evaluate the utility of within-ancestry scores in the AA population.
Hispanic Immigrants (HI) have lower vaccination rates than their non-Hispanic white counterparts. Culturally appropriate interventions are more influential in evoking change among viewers; therefore, ...it is important to understand the cultural factors of specific ethnic groups. In this study, we identify cultural barriers to vaccination of Hispanic Immigrants. An electronic survey was administered among HI parents living in the United States. Using structural equation modeling, we found that high religious practice and positive religious beliefs towards vaccination correspond with positive vaccine attitudes (+0.20 and +0.587, respectively). Trust in institutions is strongly correlated with strong positive vaccine attitudes (+0.734). While trusting one’s folk practitioner more than a medical doctor leads to negative vaccine attitudes (-0.596), the use of home remedies is associated with positive vaccine attitudes (+0.486). The cultural competence of a medical practitioner, especially regarding folk medicine, is essential to lower cultural barriers HI patients face in vaccination.
BACKGROUNDSepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different ...therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients generally relies on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision.METHODSAn ex vivo whole-blood enzyme-linked immunosorbent spot (ELISpot) assay for cellular production of interferon γ (IFN-γ) was evaluated in 107 septic and 68 nonseptic patients from 5 academic health centers using blood samples collected on days 1, 4, and 7 following ICU admission.RESULTSCompared with 46 healthy participants, unstimulated and stimulated whole-blood IFN-γ expression was either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole-blood IFN-γ expression was significantly reduced on ICU days 1, 4, and 7 (all P < 0.05), due to both significant reductions in total number of IFN-γ-producing cells and amount of IFN-γ produced per cell (all P < 0.05). Importantly, IFN-γ total expression on days 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6, and procalcitonin. Septic patients with low IFN-γ expression were older and had lower ALCs and higher soluble PD-L1 and IL-10 concentrations, consistent with an immunosuppressed endotype.CONCLUSIONSA whole-blood IFN-γ ELISpot assay can both identify septic patients at increased risk of late mortality and identify immunosuppressed septic patients.TRIAL REGISTRYN/A.FUNDINGThis prospective, observational, multicenter clinical study was directly supported by National Institute of General Medical Sciences grant R01 GM-139046, including a supplement (R01 GM-139046-03S1) from 2022 to 2024.
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