Altered peripheral blood leukocyte subpopulations, function, and gene expression in children with Down syndrome: implications for respiratory tract infection.

Objectives: We tested the hypothesis that aberrant expression of Hsa21-encoded interferon genes in peripheral blood immune cells would correlate to immune cell dysfunction in children with Down syndrome (DS).

Study Design: We performed flow cytometry to quantify peripheral blood leukocyte subtypes and measured their ability to migrate and phagocytose. In matched samples, we measured gene expression levels for constituents of interferon signaling pathways.

Increased lethality of respiratory infection by in the Dp16 mouse model of Down syndrome.

Objectives: We sought to investigate whether the Dp16 mouse model of Down syndrome (DS) is more susceptible to severe and lethal respiratory tract infection by .

Study Design: We infected controls and Dp16 mice with and measured survival rates. We compared cytokine production by primary lung cell cultures exposed to .

Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome.

People with Down syndrome (DS; trisomy 21) display a different disease spectrum relative to the general population, including lower rates of solid malignancies and higher incidence of neurological and autoimmune conditions. However, the mechanisms driving this unique clinical profile await elucidation. We completed a deep mapping of the immune system in adults with DS using mass cytometry to evaluate 100 immune cell types, which revealed global immune dysregulation consistent with chronic inflammation, including key changes in the myeloid and lymphoid cell compartments.

The TRPM2 ion channel contributes to cytokine hyperproduction in a mouse model of Down Syndrome.

Trisomy 21 (Down Syndrome, DS) is the most common chromosomal anomaly. Although DS is mostly perceived as affecting cognitive abilities and cardiac health, individuals with DS also exhibit dysregulated immune functions. Levels of pro-inflammatory cytokines are increased, but intrinsic alterations of innate immunity are understudied in DS.

What people with Down Syndrome can teach us about cardiopulmonary disease.

Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with cognitive impairment, congenital malformations (particularly cardiovascular) and dysmorphic features. Immune disturbances in Down syndrome account for an enormous disease burden ranging from quality-of-life issues (autoimmune alopecia) to more serious health issues (autoimmune thyroiditis) and life-threatening issues (leukaemia, respiratory tract infections and pulmonary hypertension).

Applying Biotechnology and Bioengineering to Pediatric Lung Disease: Emerging Paradigms and Platforms.

Pediatric lung diseases remain a costly worldwide health burden. For many children with end-stage lung disease, lung transplantation remains the only therapeutic option. Due to the limited number of lungs available for transplantation, alternatives to lung transplant are desperately needed.

Biomarkers for pediatric pulmonary arterial hypertension: challenges and recommendations.

Pediatric pulmonary arterial hypertension (PAH) is an uncommon disease that can occur in neonates, infants, and children, and is associated with high morbidity and mortality. Despite advances in treatment strategies over the last two decades, the underlying structural and functional changes to the pulmonary arterial circulation are progressive and lead eventually to right heart failure. The management of PAH in children is complex due not only to the developmental aspects but also because most evidence-based practices derive from adult PAH studies.

Animal Models of Pulmonary Hypertension: Matching Disease Mechanisms to Etiology of the Human Disease.

Recently a great deal of progress has been made in our understanding of pulmonary hypertension (PH). Research from the past 30 years has resulted in newer treatments that provide symptomatic improvements and delayed disease progression. Unfortunately, the cure for patients with this lethal syndrome remains stubbornly elusive.

Proteomics of pulmonary hypertension: could personalized profiles lead to personalized medicine?

Pulmonary hypertension (PH) is a fatal syndrome that arises from a multifactorial and complex background, is characterized by increased pulmonary vascular resistance and right heart afterload, and often leads to cor pulmonale. Over the past decades, remarkable progress has been made in reducing patient symptoms and delaying the progression of the disease. Unfortunately, PH remains a disease with no cure.

Biomarkers for pediatric pulmonary arterial hypertension - a call to collaborate.

Therapeutic approaches in pediatric pulmonary arterial hypertension (PAH) are based primarily on clinician experience, in contrast to the evidence-based approach in adults with pulmonary hypertension. There is a clear and present need for non-invasive and objective biomarkers to guide the accurate diagnosis, treatment, and prognosis of this disease in children. The multifaceted spectrum of disease, clinical presentation, and association with other diseases makes this a formidable challenge.

Bronchus-associated lymphoid tissue in pulmonary hypertension produces pathologic autoantibodies.

Rationale: Autoimmunity has long been associated with pulmonary hypertension. Bronchus-associated lymphoid tissue plays important roles in antigen sampling and self-tolerance during infection and inflammation.

Objectives: We reasoned that activated bronchus-associated lymphoid tissue would be evident in rats with pulmonary hypertension, and that loss of self-tolerance would result in production of pathologic autoantibodies that drive vascular remodeling.

Activation of the unfolded protein response is associated with pulmonary hypertension.

Pulmonary hypertension remains an important cause of morbidity and mortality. Although there is currently no cure, descriptions of defective intracellular trafficking and protein misfolding in vascular cell models of pulmonary hypertension have been recently reported. We tested the hypothesis that activation of the unfolded protein response (UPR) would be associated with the development of severe PH.

Plasma proteomics of differential outcome to long-term therapy in children with idiopathic pulmonary arterial hypertension.

Purpose: The prognosis for children with IPAH unresponsive to therapy is poor. We investigated the plasma proteome for a molecular basis of good versus poor outcome to long-term vasodilator therapy.

Experimental Design: Plasma was collected at baseline or shortly after therapy initiation and following chronic vasodilator therapy, then divided into those with good outcome (n = 8), and those with a poor outcome (n = 7).

Circulating myeloid-derived suppressor cells are increased and activated in pulmonary hypertension.

Background: Myeloid-derived suppressor cells (MDSCs) are increased in inflammatory and autoimmune disorders and orchestrate immune cell responses therein. Pulmonary hypertension (PH) is associated with inflammation, autoimmunity, and lung vascular remodeling. Immature myeloid cells are found in the lungs of humans and animals with PH, and we hypothesized that they would be increased in the blood of patients with PH compared with control subjects.

Endothelin-1, the unfolded protein response, and persistent inflammation: role of pulmonary artery smooth muscle cells.

Endothelin-1 is a potent vasoactive peptide that occurs in chronically high levels in humans with pulmonary hypertension and in animal models of the disease. Recently, the unfolded protein response was implicated in a variety of diseases, including pulmonary hypertension. In addition, evidence is increasing for pathological, persistent inflammation in the pathobiology of this disease.

Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats.

Mechanisms by which endothelin (ET)-1 mediates chronic pulmonary hypertension remain incompletely understood. Although activation of the ET type A (ET(A)) receptor causes vasoconstriction, stimulation of ET type B (ET(B)) receptors can elicit vasodilation or vasoconstriction. We hypothesized that the ET(B) receptor attenuates the development of hypoxic pulmonary hypertension and studied a genetic rat model of ET(B) receptor deficiency (transgenic sl/sl).