Approach to diagnosing and managing granulomatous-lymphocytic interstitial lung disease.

Granulomatous-lymphocytic interstitial lung disease (GLILD) is a lymphoproliferative and granulomatous pulmonary manifestation of primary immune deficiency diseases, notably common variable immunodeficiency (CVID), and is an important contributor of excess morbidity. As with all forms of ILD, the significance of utilizing a multidisciplinary team discussion to enhance diagnostic and treatment confidence of GLILD cannot be overstated. In this review, key clinical, radiological, and pathological features are integrated into a diagnostic algorithm to facilitate a consensus diagnosis.

NFκB1 inhibits memory formation and supports effector function of ILC2s in memory-driven asthma.

Background: ILC2s are capable of generating memory. The mechanism of memory induction and memory-driven effector function (trained immunity) in ILC2s is unknown.

Objective: NFκB1 is preferentially expressed at a high level in ILC2s.

Identification of a heterozygous pathogenic variant in IRAK4 in an adult patient with pneumococcal sepsis, monoclonal gammopathy of uncertain significance, and idiopathic systemic capillary leak syndrome.

IRAK-4 haploinsufficiency can present with pneumococcal sepsis and poor pneumococcal vaccine response in adults. Further research can determine the significance of unrecognized pathogenic variants in in adults presenting with pneumococcal sepsis and the utility of immunoglobulin replacement in these patients.

Bacterial DNA amplifies neutrophilic inflammation in IL-17-exposed airways.

Background: Neutrophilic asthma (NA) is associated with increased airway interleukin (IL)-17 and abnormal bacterial community such as dominance of nontypeable (NTHi), particularly during asthma exacerbations. Bacteria release various products including DNA, but whether they cooperate with IL-17 in exaggerating neutrophilic inflammation is unclear. We sought to investigate the role of bacteria-derived DNA in airway neutrophilic inflammation related to IL-17-high asthma and underlying mechanisms ( Toll-like receptor 9 (TLR9)/IL-36γ signalling axis).

Isolation and Characterization of Conventional and Non-conventional Type 2 Innate Lymphoid Cells (ILC2s) from Human Peripheral Blood Mononuclear Cells (PBMCs).

Innate lymphoid cells (ILCs) are a relatively new family of lymphoid cells that lack lineage cell surface markers but produce various effector cytokines. Based on phenotype and function, the group 2 ILCs (ILC2s) mirror the features of the adaptive CD4 Th2 cell subset. In humans, they are traditionally characterized as the LinIL7RαCRΤΗ2CD161 cell population that produces type 2 cytokines - IL-5 and IL-13.

Refractory neutrophilic asthma and ciliary genes.

Background: Refractory asthma (RA) remains poorly controlled, resulting in high health care utilization despite guideline-based therapies. Patients with RA manifest higher neutrophilia as a result of increased airway inflammation and subclinical infection, the underlying mechanisms of which remain unclear.

Objective: We sought to characterize and clinically correlate gene expression differences between refractory and nonrefractory (NR) asthma to uncover molecular mechanisms driving group distinctions.

Role of type-2 innate lymphoid cells (ILC2s) in type-2 asthma.

Purpose Of Review: The purpose of this review is to provide a synthesis of recent discoveries about type-2 innate lymphoid cells, especially, as they relate to the pathogenesis of asthma.

Recent Findings: We focused on features and characteristics of type-2 innate lymphoid cells (ILC2s) that distinguish them from other type-2 cells, especially Th2 cells. We collected and reviewed data related to human asthma and airway ILC2s.

Intimate Partner Violence and Adult Asthma Morbidity: A Population-Based Study.

Background: The etiologies for difficult-to-control asthma are complex and incompletely understood. Intimate partner violence (IPV) is a pervasive problem and may play a role in difficult-to-control asthma. IPV is associated with increased prevalence of asthma.

Management Strategies to Reduce Exacerbations in non-T2 Asthma.

There have been considerable advances in our understanding of asthmatic airway inflammation, resulting in a paradigm shift of classifying individuals on the basis of either the presence or the absence of type 2 (T2) inflammatory markers. Several novel monoclonal antibody therapies targeting T2 cytokines have demonstrated significant clinical effects including reductions in acute exacerbations and improvements in asthma-related quality of life and lung function for individuals with T2-high asthma. However, there have been fewer advancements in developing therapies for those without evidence of T2 airway inflammation (so-called non-T2 asthma).

The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma.

Repetitive exposure of Rag1-/- mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3-15 wk later. This memory was associated with lung ICOS+ST2+ ILC2s. Genetic, pharmacologic, and antibody-mediated inhibition and adoptive transfer established an essential role for ILC2s in memory-driven asthma.

Sprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases.

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines.

IL-33/ST2 signaling modulates Afghanistan particulate matter induced airway hyperresponsiveness in mice.

Increased symptoms of asthma-like respiratory illnesses have been reported in soldiers returning from tours of duty in Afghanistan. Inhalation of desert particulate matter (PM) may contribute to this deployment-related lung disease (DRLD), but little is known about disease mechanisms. The IL-33 signaling pathway, including its receptor ST2, has been implicated in the pathogenesis of lung diseases including asthma, but its role in PM-mediated airway dysfunction has not been studied.

Maternal diesel particle exposure promotes offspring asthma through NK cell-derived granzyme B.

Mothers living near high-traffic roads before or during pregnancy are more likely to have children with asthma. Mechanisms are unknown. Using a mouse model, here we showed that maternal exposure to diesel exhaust particles (DEP) predisposed offspring to allergic airway disease (AAD, murine counterpart of human asthma) through programming of their NK cells; predisposition to AAD did not develop in DEP pups that lacked NK cells and was induced in normal pups receiving NK cells from WT DEP pups.

Volumetric assessment of paranasal sinus opacification on computed tomography can be automated using a convolutional neural network.

Background: Computed tomography (CT) plays a key role in evaluation of paranasal sinus inflammation, but improved, and standardized, objective assessment is needed. Computerized volumetric analysis has benefits over visual scoring, but typically relies on manual image segmentation, which is difficult and time-consuming, limiting practical applicability. We hypothesized that a convolutional neural network (CNN) algorithm could perform automatic, volumetric segmentation of the paranasal sinuses on CT, enabling efficient, objective measurement of sinus opacification.

Optimal identification of human conventional and nonconventional (CRTH2IL7Rα) ILC2s using additional surface markers.

Background: Human type 2 innate lymphoid cells (ILC2s) are identified by coupled detection of CRTH2 and IL7Rα on lineage negative (Lin) cells. Type 2 cytokine production by CRTH2IL7Rα innate lymphoid cells (ILCs) is unknown.

Objective: We sought to identify CRTH2IL7Rα type 2 cytokine-producing ILCs and their disease relevance.

Interleukin 1 Receptor-Like 1 (IL1RL1) Promotes Airway Bacterial and Viral Infection and Inflammation.

Interleukin 1 receptor-like 1 (IL1RL1), also known as suppression of tumorigenicity 2 (ST2), is the receptor for interleukin 33 (IL-33) and has been increasingly studied in type 2 inflammation. An increase in airway IL-33/ST2 signaling in asthma has been associated with eosinophilic inflammation, but little is known about the role of ST2 in neutrophilic inflammation. Airway and human rhinovirus (HRV) infections are linked to neutrophilic inflammation during acute exacerbations of asthma.

Toll-Interacting Protein, Tollip, Inhibits IL-13-Mediated Pulmonary Eosinophilic Inflammation in Mice.

Toll-interacting protein (Tollip) is a key negative regulator of innate immunity by preventing excessive proinflammatory responses. Tollip genetic variation has been associated with airflow limitation in asthma subjects and Tollip expression. Whether Tollip regulates lung inflammation in a type 2 cytokine milieu (e.

Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin-driven IL-9 and IL-13 type 2 innate lymphoid cell subpopulations.

Background: IL-33 plays an important role in the development of experimental asthma.

Objective: We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of asthma in a mouse model.

Methods: We studied allergen-induced experimental asthma in ST2 knockout (KO) and wild-type control mice.

The R213G polymorphism in SOD3 protects against allergic airway inflammation.

Oxidative stress is important in the pathogenesis of allergic asthma. Extracellular superoxide dismutase (EC-SOD; SOD3) is the major antioxidant in lungs, but its role in allergic asthma is unknown. Here we report that asthmatics have increased SOD3 transcript levels in sputum and that a single nucleotide polymorphism (SNP) in SOD3 (R213G; rs1799895) changes lung distribution of EC-SOD, and decreases likelihood of asthma-related symptoms.

Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin.

Background: Type 2 innate lymphoid cells (ILC2s) represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown.

Objective: We sought to assess steroid resistance of human blood and airway ILC2s from asthmatic patients and to examine its mechanism of induction.

Airway and serum biochemical correlates of refractory neutrophilic asthma.

Background: Despite progress in the diagnosis and management of asthma, many patients have poorly controlled or refractory asthma (RA). The mechanism of this RA is not well understood.

Objective: We sought to explore the relationship between neutrophils and other biomarkers of RA.

Mechanism of T2/T17-predominant and neutrophilic T2/T17-low subtypes of asthma.

Background: The mechanism of T2/T17-predominant and T2/T17-low asthma is unknown.

Objective: We sought to study the immune mechanism of T2/T17-predominant and T2/T17-low asthma.

Methods: In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with T2/T17-predominant asthma and 22 patients with T2/T17-low asthma.

Nonsteroidal anti-inflammatory-induced inhibition of signal transducer and activator of transcription 6 (STAT-6) phosphorylation in aspirin-exacerbated respiratory disease.

Background: Aspirin desensitization provides long-term clinical benefits. The exact mechanisms of aspirin desensitization are not clearly understood.

Objective: We sought to evaluate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on T-cell activation of the IL-4 pathway in aspirin-sensitive patients with asthma and control subjects.