Publications

A variety of foreign "invaders" such as viruses, bacteria and other particulates e.g., cigarette smoke, are inhaled, deposit on the airway surface and invade the "host." Mucins produced by the surface airway epithelium and by the submucosal glands are secreted into the airway lumen. Deposited particulates adhere to the mucus and are cleared via mucociliary transport and via cough. Mucins are major constituents of mucus, which is important in the clearance of inhaled materials. Normally, secreted mucus is cleared without symptoms or interference with lung function. However, in obstructive airway diseases such as COPD, asthma, and cystic fibrosis, excessive mucus is produced. Because of the prominence of mucous hypersecretion as a cause of cough, this discussion focuses on mechanisms regulating normal production of mucins and the mechanisms underlying exaggerated mucin secretion in chronic obstructive airway diseases. Mucins are produced by airway epithelial cells via a cascade of signals (the Epidermal Growth Factor Cascade) and secreted on the luminal epithelial surface, often in response to the deposition of inhaled irritants. Normally, only minimal amounts of mucins are secreted, which assist in clearance of the inhaled particulates. However, in disease, additional pathways are induced via positive feedback systems, which lead to mucous hypersecretion. In the large conducting airways, where cough receptors are concentrated, mucous hypersecretion causes stimulation of neural receptors that result in cough. However, in small airways (e.g., bronchioles), because of their small diameters, mucous hypersecretion leads to plugging of the airways. Because there are so many small airways, their plugging is difficult to detect early, and this locus is known as a "silent zone." In chronic obstructive airway diseases, plugging of small airways may persist and increase over time, finally resulting in severe airway obstruction. Different obstructive airway diseases induce inflammatory signaling (including mucous hypersecretion) via different stimuli, but often via similar signaling pathways. Application of present knowledge of signaling that occurs with mucous hypersecretion can lead to novel therapies for hypersecretion and cough induced in conducting airways and could prevent plugging in small airways that can lead to clinical deterioration and death.

Quantification of minimal residual disease (MRD) following allogeneic hematopoietic cell transplantation (allo-HCT) predicts post-transplant relapse in patients with chronic lymphocytic leukemia (CLL). We utilized an MRD-quantification method that amplifies immunoglobulin heavy chain (IGH) loci using consensus V and J segment primers followed by high-throughput sequencing (HTS), enabling quantification with a detection limit of one CLL cell per million mononuclear cells. Using this IGH-HTS approach, we analyzed MRD patterns in over 400 samples from 40 CLL patients who underwent reduced-intensity allo-HCT. Nine patients relapsed within 12 months post-HCT. Of the 31 patients in remission at 12 months post-HCT, disease-free survival was 86% in patients with MRD <10(-4) and 20% in those with MRD ≥10(-4) (relapse hazard ratio (HR) 9.0; 95% confidence interval (CI) 2.5-32; P<0.0001), with median follow-up of 36 months. Additionally, MRD predicted relapse at other time points, including 9, 18 and 24 months post-HCT. MRD doubling time <12 months with disease burden ≥10(-5) was associated with relapse within 12 months of MRD assessment in 50% of patients, and within 24 months in 90% of patients. This IGH-HTS method may facilitate routine MRD quantification in clinical trials.

Eosinophils in visceral adipose tissue (VAT) have been implicated in metabolic homeostasis and the maintenance of alternatively activated macrophages (AAMs). The absence of eosinophils can lead to adiposity and systemic insulin resistance in experimental animals, but what maintains eosinophils in adipose tissue is unknown. We show that interleukin-5 (IL-5) deficiency profoundly impairs VAT eosinophil accumulation and results in increased adiposity and insulin resistance when animals are placed on a high-fat diet. Innate lymphoid type 2 cells (ILC2s) are resident in VAT and are the major source of IL-5 and IL-13, which promote the accumulation of eosinophils and AAM. Deletion of ILC2s causes significant reductions in VAT eosinophils and AAMs, and also impairs the expansion of VAT eosinophils after infection with Nippostrongylus brasiliensis, an intestinal parasite associated with increased adipose ILC2 cytokine production and enhanced insulin sensitivity. Further, IL-33, a cytokine previously shown to promote cytokine production by ILC2s, leads to rapid ILC2-dependent increases in VAT eosinophils and AAMs. Thus, ILC2s are resident in VAT and promote eosinophils and AAM implicated in metabolic homeostasis, and this axis is enhanced during Th2-associated immune stimulation.