National Jewish Health

About: National Jewish Health is a healthcare organization based out in Denver, Colorado, United States. It is known for research contribution in the topics: T cell & Asthma. The organization has 883 authors who have published 833 publications receiving 79201 citations. The organization is also known as: National Jewish Medical and Research Center.

The PMA-induced specific association of LFA-1 and talin in intact cloned T helper cells.

Abstract: Previous experiments with individual cell couples formed between cloned T helper (Th) cells and antigen-presenting cells have led us to suggest that the cytoskeletal protein talin may be associated with the cell surface protein LFA-1 in the Th cell. In order to examine this suggestion, we induced the surface capping of LFA-1 with suitable specific antibody reagents on the intact Th cells, and then determined by double immunofluorescence microscopic experiments, whether talin was co-clustered with the LFA-1 caps. With untreated Th cells, capping of LFA-1 did not result in any redistribution of intracellular talin. However, if the intact Th cells were treated with the phorbol ester PMA, the capping of LFA-1 resulted in a co-clustering of talin with the LFA-1 caps, but not a alpha-actinin. The capping of TCR or CD4 on the Th cells with or without pretreatment with PMA did not lead to any such co-clustering of talin with these caps. PMA treatment of the Th cells therefore induces a direct or indirect association of talin with LFA-1 underneath the Th cell surface. PMA treatment of the Th cells also increased their polarized spreading and adherence to substrata, as had been observed before. We found, furthermore, that this increased adherence upon PMA-treatment was inhibited by the presence of antibodies to LFA-1. The association of talin, and very likely also F-actin microfilaments, with LFA-1 appears to mediate a generalized increased adhesivity of the Th cells. The relevance of these findings with isolated Th cells to the interaction of Th cells with specific antigen-presenting cells is discussed.

Measurement of utility in asthma: evidence indicating that generic instruments may miss clinically important changes.

Abstract: Accurate assessment of preference-based health-related quality of life is important in determining the value of asthma interventions. To examine the sensitivity and responsiveness of the EQ-5D and the AQL-5D to differences in asthma control measured by the Asthma Control Questionnaire (ACQ-5). The Observational Study of Asthma Control and Outcomes was a prospective survey of persistent asthma patients ≥12 years old in Kaiser Colorado. Patients received a survey three times in 1 year, including the ACQ-5, AQL-5D and EQ-5D-3L (including VAS). Censored Least Absolute Deviations (CLAD) and logistic regression were used, controlling for sociodemographics and smoking. There were 6666 completed surveys (1799 individuals completed all three survey waves). After controlling for covariates, each one-point increase in ACQ-5 was associated with a decrease of 0.066, 0.058, 0.074 and 6.12 in EQ-5D(US), EQ-5D(UK), AQL-5D and VAS scores. Uncontrolled asthma (ACQ-5 > 1.5) was associated with a decrease of 0.15, 0.17, 0.11 and 10, respectively (vs. ACQ ≤ 1.5). AQL-5D scores were statistically significantly different across categories of ACQ-5 scores of 0.5 (the minimum clinically important difference [MCID]), while EQ-5D scores were not significant across most categories. The AQL-5D appeared more robust to changes in control over time (responsiveness) compared to EQ-5D-3L. The AQL-5D appears more responsive to changes in asthma control over time and more sensitive to detecting differences corresponding to the ACQ-5 MCID than the EQ-5D-3L. Using the EQ-5D-3L without an asthma-specific measure such as the AQL-5D may miss clinically important changes in asthma control.

The responses of mature T cells are not necessarily antagonized by their positively selecting peptide.

Abstract: Transgenic mice have been produced in which all detectable MHC class II proteins, IAb, are bound to a single peptide Hence, all of the CD4+ class II-restricted T cells in these animals are positively selected in the thymus by reaction with this single class II/peptide combination It has been suggested that the peptide involved in positive selection of a particular T cell might antagonize the responses of that T cell to other peptides, a phenomenon that might serve to inhibit autoimmune reactions To test this idea, we took advantage of the fact that T cells from the class II single-peptide mice react strongly in primary mixed lymphocyte cultures with IAb molecules from wild-type H-2b mice, ie, loaded with a heterogeneous collection of self peptides The responses of the T cells to other class II-bound peptides were not inhibited by high concentrations of the selecting peptide Therefore, peptides involved in positive selection of T cells do not necessarily inhibit or antagonize the responses of mature T cells to Ag

Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes

Abstract: Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown.1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence2–4 and coronary heart disease prevalence.5 Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP).6 Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer. Aggregates of rare germline loss-of-function variants in CHEK2, a DNA damage repair gene, predisposed to CHIP acquisition. Overall, we observe that germline genetic variation altering hematopoietic stem cell function and the fidelity of DNA-damage repair increase the likelihood of somatic mutations leading to CHIP.

Overview of Innate Lung Immunity and Inflammation.

Abstract: The nasal passages, conducting airways and gas-exchange surfaces of the lung, are constantly exposed to substances contained in the air that we breathe. While many of these suspended substances are relatively harmless, some, for example, pathogenic microbes, noxious pollutants, and aspirated gastric contents can be harmful. The innate immune system, lungs and conducting airways have evolved specialized mechanisms to protect the respiratory system not only from these harmful inhaled substances but also from the overly exuberant innate immune activation that can arise during the host response to harmful inhaled substances. Herein, we discuss the cell types that contribute to lung innate immunity and inflammation and how their activities are coordinated to promote lung health.