Increased ILC2s in the eosinophilic nasal polyp endotype are associated with corticosteroid responsiveness.

Group 2 innate lymphoid cells (ILC2s) have recently been identified in human nasal polyps, but whether numbers of ILC2s differ by polyp endotype or are influenced by corticosteroid use is unknown. Here, we show that eosinophilic nasal polyps contained double the number of ILC2s vs. non-eosinophilic polyps. Polyp ILC2s were also reduced by 50% in patients treated with systemic corticosteroids. Further, using a fungal allergen challenge mouse model, we detected greatly reduced Th2 cytokine-producing and Ki-67+ proliferating lung ILC2s in mice receiving dexamethasone. Finally, ILC2 Annexin V staining revealed extensive apoptosis after corticosteroid treatment in vivo and in vitro. Thus, ILC2s are elevated in the eosinophilic nasal polyp endotype and systemic corticosteroid treatment correlated with reduced polyp ILC2s. Finally, allergen-challenged mice showed reduced ILC2s and increased ILC2 apoptosis after corticosteroid treatment suggesting that ILC2 may be responsive to corticosteroids in eosinophilic respiratory disease.

Current update on cellular and molecular mechanisms of hereditary angioedema.

OBJECTIVE: To provide an update on the molecular mechanisms of hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed databases were searched to identify pertinent articles using the following key terms: hereditary angioedema, angioedema, C1 inhibitor, bradykinin, contact system, factor XII, mechanism, pathophysiology, severity, permeability, and estrogen. STUDY SELECTIONS: Articles were selected based on their relevance to the subject matter. RESULTS: Although the biochemical basis of "classic" HAE is known to result from C1 esterase inhibitor (C1INH) deficiency, a new form, HAE with normal C1INH, has been identified. HAE types I and II are caused by mutations in the SERPING1 gene that result in decreased plasma levels of functional C1INH. In HAE with normal C1INH, mutations in the F12 gene have been identified in a subset of individuals, but the genetic defect remains unknown in most patients. The primary mediator of swelling in HAE is bradykinin, a product of the plasma contact system that increases vascular permeability. HAE disease severity is highly variable and may be influenced by polymorphisms in other genes and other factors, such as hormones, trauma, stress, and infection. CONCLUSION: Hereditary angioedema is a heterogeneous disorder with a complex pathophysiology. Implicated genes include SERPING1 and FXII in patients with HAE from C1INH deficiency and HAE with normal C1INH levels, respectively. Disease severity is highly variable.

Prevalence of Kawasaki disease in young adults with suspected myocardial ischemia.

BACKGROUND: Up to 25% of patients with untreated Kawasaki disease (KD) and 5% of those treated with intravenous immunoglobulin will develop coronary artery aneurysms. Persistent aneurysms may remain silent until later in life when myocardial ischemia can occur. We sought to determine the prevalence of coronary artery aneurysms suggesting a history of KD among young adults undergoing coronary angiography for evaluation of possible myocardial ischemia. METHODS AND RESULTS: We reviewed the medical histories and coronary angiograms of all adults <40 years of age who underwent coronary angiography for evaluation of suspected myocardial ischemia at 4 San Diego hospitals from 2005 to 2009 (n=261). History of KD-compatible illness and cardiac risk factors were obtained by medical record review. Angiograms were independently reviewed for the presence, size, and location of aneurysms and coronary artery disease by 2 cardiologists blinded to the history. Patients were evaluated for number of risk factors, angiographic appearance of their coronary arteries, and known history of KD. Of the 261 young adults who underwent angiography, 16 had coronary aneurysms. After all clinical criteria were assessed, 5.0% had aneurysms definitely (n=4) or presumed (n=9) secondary to KD as the cause of their coronary disease. CONCLUSIONS: Coronary sequelae of KD are present in 5% of young adults evaluated by angiography for myocardial ischemia. Cardiologists should be aware of this special subset of patients who may benefit from medical and invasive management strategies that differ from the strategies used to treat atherosclerotic coronary artery disease.

Diagnosis and management of eosinophilic asthma: a US perspective.

Eosinophilic asthma is now recognized as an important subphenotype of asthma based on the pattern of inflammatory cellular infiltrate in the airway. Eosinophilic asthma can be associated with increased asthma severity, atopy, late-onset disease, and steroid refractoriness. Induced sputum cell count is the gold standard for identifying eosinophilic inflammation in asthma although several noninvasive biomarkers, including fractional exhaled nitric oxide and periostin, are emerging as potential surrogates. As novel therapies and biologic agents become increasingly available, there is an increased need for specific phenotype-directed treatment strategies. Greater recognition and understanding of the unique immunopathology of this asthma phenotype has important implications for management of the disease and the potential to improve patient outcomes. The present review provides a summary of the clinical features, pathogenesis, diagnosis, and management of eosinophilic asthma.

STAT6 and lung inflammation.

Lung inflammation has many etiologies, including diseases of Th2-type immunity, such as asthma and anti-parasitic responses. Inflammatory diseases of the lung involve complex interactions among structural cells (airway epithelium, smooth muscle, and fibroblasts) and immune cells (B and T cells, macrophages, dendritic cells, and innate lymphoid cells). Signal transducer and activator of transcription 6 (STAT6) has been demonstrated to regulate many pathologic features of lung inflammatory responses in animal models including airway eosinophilia, epithelial mucus production, smooth muscle changes, Th2 cell differentiation, and IgE production from B cells. Cytokines IL-4 and IL-13 that are upstream of STAT6 are found elevated in human asthma and clinical trials are underway to therapeutically target the IL-4/IL-13/STAT6 pathway. Additionally, recent work suggests that STAT6 may also regulate lung anti-viral responses and contribute to pulmonary fibrosis. This review will focus on the role of STAT6 in lung diseases and mechanisms by which STAT6 controls immune and structural lung cell function.

Type 2 Innate Lymphoid Cells in Allergic Disease.

Type II innate lymphoid cells (ILC2) are a novel population of lineage-negative cells that produce high levels of Th2 cytokines IL-5 and IL-13. ILC2 are found in human respiratory and gastrointestinal tissue as well as in skin. Studies from mouse models of asthma and atopic dermatitis suggest a role for ILC2 in promoting allergic inflammation. The epithelial cytokines IL-25, IL-33, and TSLP, as well as the lipid mediator leukotriene D4, have been shown to potently activate ILC2 under specific conditions and supporting the notion that many separate pathways in allergic disease may result in stimulation of ILC2. Ongoing investigations are required to better characterize the relative contribution of ILC2 in allergic inflammation as well as mechanisms by which other cell types including conventional T cells regulate ILC2 survival, proliferation, and cytokine production. Importantly, therapeutic strategies to target ILC2 may reduce allergic inflammation in afflicted individuals. This review summarizes the development, surface marker profile, cytokine production, and upstream regulation of ILC2, and focuses on the role of ILC2 in common allergic diseases.