Highlights d Individuals with trisomy 21, or Down syndrome, have a unique disease spectrum d Mass cytometry reveals global immune dysregulation affecting key cell types d Changes in myeloid and lymphoid subsets are associated with inflammatory states d Trisomy 21 causes overexpression of IFN receptors and hypersensitivity to IFN-a

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). Cardiovascular and pulmonary diseases account for ∼75% of the mortality seen in persons with Down syndrome. This review summarises the cardiovascular, respiratory and immune challenges faced by individuals with Down syndrome, and the genetic underpinnings of their pathobiology. We strongly advocate increased comparative studies of cardiopulmonary disease in persons with and without Down syndrome, as we believe these will lead to new strategies to prevent and treat diseases affecting millions of people worldwide.

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. Methods: We used animal models, histology, and gene expression assays to evaluate the role of bronchus-associated lymphoid tissue in pulmonary hypertension. Measurements and Main Results: Bronchus-associated lymphoid tissue was more numerous, larger, and more active in pulmonary hypertension compared with control animals. We found dendritic cells in and around lymphoid tissue, which were composed of CD31 T cells over a core of CD45RA 1 B cells. Antirat IgG and plasma from rats with pulmonary hypertension decorated B cells in lymphoid tissue, resistance vessels, and adventitia of large vessels. Lymphoid tissue in diseased rats was vascularized by aquaporin-1 1 high endothelial venules and vascular cell adhesion molecule-positive vessels. Autoantibodies are produced in bronchus-associated lymphoid tissue and, when bound to pulmonary adventitial fibroblasts, change their phenotype to one that may promote inflammation. Passive transfer of autoantibodies into rats caused pulmonary vascular remodeling and pulmonary hypertension. Diminution of lymphoid tissue reversed pulmonary hypertension, whereas immunologic blockade of CCR7 worsened pulmonary hypertension and hastened its onset. Conclusions: Bronchus-associated lymphoid tissue expands in pulmonary hypertension and is autoimmunologically active. Loss of self-tolerance contributes to pulmonary vascular remodeling and pulmonary hypertension. Lymphoid tissue-directed therapies may be beneficial in treating pulmonary hypertension.Keywords: hypertension; pulmonary; lymphoid tissue; inflammation; autoimmunity Pulmonary hypertension (PH) is characterized by progressive increases in pulmonary artery pressure and pulmonary vascular resistance resulting in right ventricular failure (1). The primary histopathologic finding in PH is vascular remodeling, in which the pulmonary vasculature becomes stiff, occluded, and fibrotic (2). Vascular remodeling seems to require lung infiltration of inflammatory cells, and continual influx likely sustains a cycle of perpetual inflammation and remodeling by poorly defined mechanisms (3).The bronchovascular space is a structure that marries sterile (vasculature) and nonsterile (airway) components. Bronchusassociated lymphoid tissues (BALTs) are tertiary lymphoid organs that provide an elegant immune surveillance apparatus ensuring airway and vessel homeostatic patency. They are histologically similar to lymph nodes containing afferent lymphatic connection, B cells, T cells, antigen-presenting cells, stroma, and a vascular supply (4). The chief antigen-presenting cells in BALT are dendritic ce...

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. We investigated whether endothelin-1 might engage the unfolded protein response and thus link inflammation and the production of hyaluronic acid by pulmonary artery smooth muscle cells. Using immunoblot, real-time PCR, immunofluorescence, and luciferase assays, we found that endothelin-1 induces both a transcriptional and posttranslational activation of the three major arms of the unfolded protein response. The pharmacologic blockade of endothelin A receptors, but not endothelin B receptors, attenuated the observed release, as did a pharmacologic blockade of extracellular signal-regulated kinases 1 and 2 (ERK-1/2) signaling. Using short hairpin RNA and ELISA, we observed that the release by pulmonary artery smooth muscle cells of inflammatory modulators, including hyaluronic acid, is associated with endothelin-1-induced ERK-1/2 phosphorylation and the unfolded protein response. Furthermore, the synthesis of hyaluronic acid induced by endothelin-1 is permissive for persistent THP-1 monocyte binding. These results suggest that endothelin-1, in part because it induces the unfolded protein response in pulmonary artery smooth muscle cells, triggers proinflammatory processes that likely contribute to vascular remodeling in pulmonary hypertension.Keywords: unfolded protein response; endothelin; pulmonary artery smooth muscle; hyaluronic acid; inflammation Pulmonary hypertension (PH) is a disease characterized by extensive pulmonary vascular remodeling, present along the entire length of the vascular tree (1). Eventually, the increased impedance to flow causes right heart failure and death (2). Evidence is mounting that the recruitment of inflammatory cells and the development of persistent inflammation are key components of the pathological vascular remodeling observed in PH (3). In patients with idiopathic PH, macrophages and lymphocytes are found in bronchovascular locations and in occlusive neointimal lesions, and express a panoply of chemokines including CCL2, CCL5, and CX3CL1 (4-7). Concentrations of proinflammatory cytokines, including IL-1 and IL-6, are elevated in both human idiopathic pulmonary artery hypertension (PAH) (8) and in the monocrotaline (MCT) model of PH (9, 10). Depletion of the circulating pool of macrophages is sufficient to prevent hypoxia-driven PH (11), and dexamethasone treatment reverses MCT PH (12). Taken together, these studies suggest that PH is a syndrome characterized by the complex disturbance of innate and acquired immune cells, and of mediators and effectors of inflammation.Building on studies that pointed to the importance of extracellular matrix metabolism in pulmonary vessel homeostasis (13,14), rec...