Publications

Mycobacterium tuberculosis (Mtb) establishes a persistent infection, despite inducing antigen-specific T-cell responses. Although T cells arrive at the site of infection, they do not provide sterilizing immunity. The molecular basis of how Mtb impairs T-cell function is not clear. Mtb has been reported to block major histocompatibility complex class II (MHC-II) antigen presentation; however, no bacterial effector or host-cell target mediating this effect has been identified. We recently found that Mtb EsxH, which is secreted by the Esx-3 type VII secretion system, directly inhibits the endosomal sorting complex required for transport (ESCRT) machinery. Here, we showed that ESCRT is required for optimal antigen processing; correspondingly, overexpression and loss-of-function studies demonstrated that EsxH inhibited the ability of macrophages and dendritic cells to activate Mtb antigen-specific CD4 T cells. Compared with the wild-type strain, the esxH-deficient strain induced fivefold more antigen-specific CD4 T-cell proliferation in the mediastinal lymph nodes of mice. We also found that EsxH undermined the ability of effector CD4 T cells to recognize infected macrophages and clear Mtb. These results provide a molecular explanation for how Mtb impairs the adaptive immune response.

BACKGROUND

Sleep-disordered breathing in general and obstructive sleep apnea in particular are commonly encountered conditions in allergy practice. Physiologically, nasal (or nasopharyngeal) obstruction from rhinitis, nasal polyposis, or adenotonsillar hypertrophy are credible contributors to snoring and nocturnal respiratory obstructive events. Nevertheless, existing practice parameters largely relegate the role of the allergist to adjunctive treatment in cases of continuous positive airway pressure intolerance.

OBJECTIVES

To survey active American Academy of Allergy, Asthma & Immunology members regarding their perceptions and practices concerning sleep-disordered breathing in adult and pediatric patients with rhinitis, and to review the medical literature concerning this connection to identify therapeutic implications and research gaps.

METHODS

Members of the Work Group on Rhinitis and Sleep-disordered Breathing composed and distributed a Web-based clinically oriented survey to active American Academy of Allergy, Asthma & Immunology members in mid-2015. The group, in addition, conducted an English-language literature review using PubMed and other sources.

RESULTS

Survey results were returned by 339 of 4881 active members (7%). More than two-third of respondents routinely asked about sleep problems, believed that sleep-disordered breathing was a problem for at least a "substantial minority" (10%-30%) of their adult patients, and believed that medical therapy for upper airway inflammatory conditions could potentially help ameliorate sleep-related complaints. Literature review supported the connection between high-grade nasal congestion/adenotonsillar hypertrophy and obstructive sleep apnea, and at least in the case of pediatric patients, supported the use of anti-inflammatory medication in the initial management of obstructive sleep apnea of mild-to-moderate severity.

CONCLUSIONS

Clinical allergy practice and the medical literature support a proactive role for allergists in the diagnosis and management of sleep-disordered breathing.

Treatment options are limited for severe asthma, and the need for additional therapies remains great. Previously, we demonstrated that integrin αvβ6-deficient mice are protected from airway hyperresponsiveness, due in part to increased expression of the murine ortholog of human chymase. Here, we determined that chymase protects against cytokine-enhanced bronchoconstriction by cleaving fibronectin to impair tension transmission in airway smooth muscle (ASM). Additionally, we identified a pathway that can be therapeutically targeted to mitigate the effects of airway hyperresponsiveness. Administration of chymase to human bronchial rings abrogated IL-13-enhanced contraction, and this effect was not due to alterations in calcium homeostasis or myosin light chain phosphorylation. Rather, chymase cleaved fibronectin, inhibited ASM adhesion, and attenuated focal adhesion phosphorylation. Disruption of integrin ligation with an RGD-containing peptide abrogated IL-13-enhanced contraction, with no further effect from chymase. We identified α5β1 as the primary fibronectin-binding integrin in ASM, and α5β1-specific blockade inhibited focal adhesion phosphorylation and IL-13-enhanced contraction, with no additional effect from chymase. Delivery of an α5β1 inhibitor into murine airways abrogated the exaggerated bronchoconstriction induced by allergen sensitization and challenge. Finally, α5β1 blockade enhanced the effect of the bronchodilator isoproterenol on airway relaxation. Our data identify the α5β1 integrin as a potential therapeutic target to mitigate the severity of airway contraction in asthma.

OBJECTIVES

To understand outcomes of transurethral resection of the prostate (TURP) or transurethral laser incision of the prostate (TULIP) for the treatment of bladder outlet obstruction in men with high levels of functional dependence, which are poorly understood.

DESIGN

Retrospective cohort study.

SETTING

U.S. nursing homes (NHs).

PARTICIPANTS

Male NH residents aged 65 and older who underwent TURP or TULIP in the United States between 2005 and 2008 (N = 2,869).

MEASUREMENTS

Changes in activities of daily living (ADLs), Foley catheter status, and survival up to 12 months after surgery were examined. Multivariate regression was used to determine risk of having a Foley catheter 1 year after surgery.

RESULTS

Sixty-one percent of the cohort had a Foley catheter before the procedure. Of men with a Foley catheter at baseline, 64% had a Foley catheter, 4% had no Foley catheter, and 32% had died by 1-year after the procedure. Having a Foley catheter at baseline (risk ratio (RR) = 1.39, 95% confidence interval (CI) = 1.29-1.50) and poor baseline functional status (RR = 1.34, 95% CI = 1.18-1.52 for individuals in the worst quartile of function) were associated with greater risk of having a Foley catheter at 1-year.

CONCLUSION

Poor baseline functional status and having a Foley catheter preoperatively were associated with greater risk of TURP or TULIP failure, as measured by the presence of a Foley catheter at 1 year. Preoperative measurement of ADLs may aid in surgical decision-making in this population.