Frances Eun-Hyung Lee

Long-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection.

Long-lived plasma cells are critical to humoral immunity as a lifelong source of protective antibodies. Antigen-activated B cells—with T-cell help—undergo affinity maturation within germinal centres and persist as long-lived IgG plasma cells in the bone marrow. Here we show that antigen-specific, induced IgM plasma cells also persist for a lifetime. Unlike long-lived IgG plasma cells, which develop in germinal centres and then home to the bone marrow, IgM plasma cells are primarily retained within the spleen and can develop even in the absence of germinal centres. Interestingly, their expressed IgV loci exhibit somatic mutations introduced by the activation-induced cytidine deaminase (AID). However, these IgM plasma cells are probably not antigen-selected, as replacement mutations are spread through the variable segment and not enriched within the CDRs. Finally, antibodies from long-lived IgM plasma cells provide protective host immunity against a lethal virus challenge.

A Vision-Based Respiration Monitoring System for Passive Airway Resistance Estimation

Objective: Airway resistance is the mechanical cause of most of the symptoms in obstructive pulmonary disease, and can be considered as the primary measure of disease severity. A low-cost and noninvasive method to measure the airway resistance that does not require patient effort could be of great benefit in evaluating the severity of lung diseases, especially in patient population that are unable to use spirometry, such as young children. Methods: The Vision-Based Passive Airway Resistance Estimation (VB-PARE) technology is a passive method to measure airway resistance noninvasively. The airway resistance is estimated from: 1) airflow extracted from processing depth data captured by a Microsoft Kinect, and 2) Pulsus Paradoxus extracted from a pulse oximeter (SpO2). Results: To verify the validity and accuracy of the VB-PARE, two phases of experiment were conducted. In Phase I, spontaneous breathing data was collected from 14 healthy participants with externally induced airway obstruction, and the accuracy of 76.2± 13.8% was achieved in predicting three levels of obstruction severity. In Phase II, VB-PARE outputs were compared with the clinical results from 14 patients. VB-PARE estimated the tidal volume with an average error of 0.07±0.06 liter. Also, patients with airway obstruction were detected with 80% accuracy. Conclusion: Using the information extracted from Kinect and SpO2, here, we present a quantitative method to measure the severity of airway obstruction without requiring active patient involvement. Significance: The proposed VB-PARE system contributes to the state-of-art respiration monitoring methods by expanding the idea of passive and noninvasive airway resistance measurement.

Frontline Science: Pathological conditioning of human neutrophils recruited to the airway milieu in cystic fibrosis

Recruitment of neutrophils to the airways, and their pathological conditioning therein, drive tissue damage and coincide with the loss of lung function in patients with cystic fibrosis (CF). So far, these key processes have not been adequately recapitulated in models, hampering drug development. Here, we hypothesized that the migration of naïve blood neutrophils into CF airway fluid in vitro would induce similar functional adaptation to that observed in vivo, and provide a model to identify new therapies. We used multiple platforms (flow cytometry, bacteria‐killing, and metabolic assays) to characterize functional properties of blood neutrophils recruited in a transepithelial migration model using airway milieu from CF subjects as an apical chemoattractant. Similarly to neutrophils recruited to CF airways in vivo, neutrophils migrated into CF airway milieu in vitro display depressed phagocytic receptor expression and bacterial killing, but enhanced granule release, immunoregulatory function (arginase‐1 activation), and metabolic activities, including high Glut1 expression, glycolysis, and oxidant production. We also identify enhanced pinocytic activity as a novel feature of these cells. In vitro treatment with the leukotriene pathway inhibitor acebilustat reduces the number of transmigrating neutrophils, while the metabolic modulator metformin decreases metabolism and oxidant production, but fails to restore bacterial killing. Interestingly, we describe similar pathological conditioning of neutrophils in other inflammatory airway diseases. We successfully tested the hypothesis that recruitment of neutrophils into airway milieu from patients with CF in vitro induces similar pathological conditioning to that observed in vivo, opening new avenues for targeted therapeutic intervention.