No abstract

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor b (TGF-b) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.

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We have developed a novel diagnostic technology to monitor the human cytomegalovirus (HCMV)-specific CD8+ T-cell responses that is based on the detection of secreted interferon-gamma (IFN-gamma) in the whole blood (referred to as QuantiFERON -CMV). Evaluation of QuantiFERON -CMV in healthy individuals revealed that this technology was at least as sensitive and with some HCMV epitopes more sensitive than the ELISPOT for detecting ex vivo IFN-gamma. Results from QuantiFERON -CMV assays showed 97% (36/37 individuals) agreement with the anti-HCMV serology test in healthy individuals. Furthermore, we also show that this technology can be used to assess HCMV-specific T-cell responses in transplant patients. This study shows that QuantiFERON -CMV is a simple, reproducible, and reliable test for the detection of IFN-gamma in response to HCMV CD8+ T-cell epitopes, and may be a valuable diagnostic test for the detection of HCMV infection and a useful clinical tool for monitoring the immune response in immunosuppressed patients during therapy.