Unsuspected pulmonary alveolar proteinosis in a patient with acquired immunodeficiency syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Diffuse lung infiltrates are a common finding in patients with acquired immunodeficiency syndrome and causes range from infectious processes to malignancies or interstitial lung diseases. Pulmonary alveolar proteinosis is a rare pulmonary disorder rarely reported in patients infected with human immunodeficiency virus. Secondary pulmonary alveolar proteinosis is associated with conditions involving functional impairment or reduced numbers of alveolar macrophages. It can be caused by hematologic malignancies, inhalation of toxic dust, fumes or gases, infectious or pharmacologic immunosuppression, or lysinuric protein intolerance.</p> <p>Case presentation</p> <p>A 42-year-old African American man infected with human immunodeficiency virus was admitted with chronic respiratory symptoms and diffuse pulmonary infiltrates. Chest computed tomography revealed bilateral spontaneous pneumothoraces, for which he required bilateral chest tubes. Initial laboratory investigations did not reveal any contributory conditions. Histological examination of a lung biopsy taken during video-assisted thoracoscopy showed pulmonary alveolar proteinosis concurrent with cytomegalovirus pneumonitis. After ganciclovir treatment, our patient showed radiologic and clinical improvement.</p> <p>Conclusion</p> <p>The differential diagnosis for patients with immunosuppression and lung infiltrates requires extensive investigations. As pulmonary alveolar proteinosis is rare, the diagnosis can be easily missed. Our case highlights the importance of invasive investigations and histology in the management of patients infected with human immunodeficiency virus and pulmonary disease who do not respond to empiric therapy.</p

Association between colony-stimulating factor 1 receptor gene polymorphisms and asthma risk

Colony-stimulating factor 1 receptor (CSF1R) is expressed in monocytes/macrophages and dendritic cells. These cells play important roles in the innate immune response, which is regarded as an important aspect of asthma development. Genetic alterations in the CSF1R gene may contribute to the development of asthma. We investigated whether CSF1R gene polymorphisms were associated with the risk of asthma. Through direct DNA sequencing of the CSF1R gene, we identified 28 single nucleotide polymorphisms (SNPs) and genotyped them in 303 normal controls and 498 asthmatic patients. Expression of CSF1R protein and mRNA were measured on CD14-positive monocytes and neutrophils in peripheral blood of asthmatic patients using flow cytometry and real-time PCR. Among the 28 polymorphisms, two intronic polymorphism (+20511C>T and +22693T>C) were associated with the risk of asthma by logistic regression analysis. The frequencies of the minor allele at CSF1R +20511C>T and +22693T>C were higher in asthmatic subjects than in normal controls (4.6 vs. 7.7%, p = 0.001 in co-dominant and dominant models; 16.4 vs. 25.8%, p = 0.0006 in a recessive model). CSF1R mRNA levels in neutrophils of the asthmatic patients having the +22693CC allele were higher than in those having the +22693TT allele (p = 0.026). Asthmatic patients with the +22693CC allele also showed significantly higher CSF1R expression on CD14-positive monocytes and neutrophils than did those with the +22693TT allele (p = 0.045 and p = 0.044). The +20511C>T SNP had no association with CSF1R mRNA or protein expression. In conclusion, the minor allele at CSF1R +22693T>C may have a susceptibility effect in the development of asthma, via increased CSF1R protein and mRNA expression in inflammatory cells

Real-Time Monitoring of Tumorigenesis, Dissemination, & Drug Response in a Preclinical Model of Lymphangioleiomyomatosis/Tuberous Sclerosis Complex

Background: TSC2-deficient cells can proliferate in the lungs, kidneys, and other organs causing devastating progressive multisystem disorders such as lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC). Preclinical models utilizing LAM patient-derived cells have been difficult to establish. We developed a novel animal model system to study the molecular mechanisms of TSC/LAM pathogenesis and tumorigenesis and provide a platform for drug testing. Methods and Findings: TSC2-deficient human cells, derived from the angiomyolipoma of a LAM patient, were engineered to co-express both sodium-iodide symporter (NIS) and green fluorescent protein (GFP). Cells were inoculated intraparenchymally, intravenously, or intratracheally into athymic NCr nu/nu mice and cells were tracked and quantified using single photon emission computed tomography (SPECT) and computed tomography (CT). Surprisingly, TSC2-deficient cells administered intratracheally resulted in rapid dissemination to lymph node basins throughout the body, and histopathological changes in the lung consistent with LAM. Estrogen was found to be permissive for tumor growth and dissemination. Rapamycin inhibited tumor growth, but tumors regrew after the drug treatment was withdrawn. Conclusions: We generated homogeneous NIS/GFP co-expressing TSC2-deficient, patient-derived cells that can proliferate and migrate in vivo after intratracheal instillation. Although the animal model we describe has some limitations, we demonstrate that systemic tumors formed from TSC2-deficient cells can be monitored and quantified noninvasively over time using SPECT/CT, thus providing a much needed model system for in vivo drug testing and mechanistic studies of TSC2-deficient cells and their related clinical syndromes

Prostaglandin E2 signaling through E prostanoid receptor 2 impairs proliferative response of double negative regulatory T cells.

Limited data are available on the mechanisms that constrain the function of regulatory populations of T cells. Prostaglandin E2 (PGE2) is an endogenous membrane phospholipid metabolite that has important immunomodulatory effects on T cell function. Our previous microarray data indicated that E prostanoid receptor 2 (EP2), a receptor for PGE2, is expressed by regulatory alphabetaTCR(+) CD4(-) CD8(-) NK1.1(-) double negative T (DN Treg) cell clones but not by their non-regulatory natural mutants. Hence, the hypothesis that PGE2 may influence DN Treg cell proliferation and/or regulatory function was tested in this study. Our data indicate that PGE2 acts via the EP2 receptor on DN Treg cells to inhibit their proliferation, an effect reproduced by the EP2-specific agonist butaprost and abrogated by the EP2 antagonist AH6809. In contrast, PGE2 did not affect the ability of DN Treg cells to kill syngeneic CD8(+) T cells activated by allogeneic stimulation. Together, these findings suggest a role for PGE2 in limiting the expansion of DN Treg cells

Rare lung disease II: pulmonary alveolar proteinosis.

The present article is the second in a series on rare lung diseases. It focuses on pulmonary alveolar proteinosis (PAP), a disorder in which lipoproteinaceous material accumulates in the alveolar space. PAP was first described in 1958, and for many years the nature of the material accumulating in the lungs was unknown. Major insights into PAP have been made in the past decade, and these have led to the notion that PAP is an autoimmume disorder in which autoantibodies interfere with signalling through the granulocyte-macrophage colony-stimulating factor receptor, leading to macrophage and neutrophil dysfunction. This has spurred new therapeutic approaches to this disorder. The discussion of PAP will begin with a case report, then will highlight the classification of PAP and review recent insights into the pathogenesis of PAP. The approach to therapy and the prognosis of PAP will also be discussed

Harnessing regulatory t cells for clinical use in transplantation: The end of the beginning

Owing to the adverse effects of immunosuppression and an inability to prevent chronic rejection, there is a pressing need for alternative strategies to control alloimmunity. In three decades, regulatory T cells (Tregs) have evolved from a hypothetical mediator of adoptively transferred tolerance to a well-defined population that can be expanded ex vivo and returned safely to patients in clinical trials. Herein, we review the historical developments that have permitted these advances and the current status of clinical trials examining Tregs as a cellular therapy in transplantation. We conclude by discussing the critical unanswered questions that face this field in the coming years. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons

Harnessing regulatory T cells for clinical use in transplantation: the end of the beginning.

Owing to the adverse effects of immunosuppression and an inability to prevent chronic rejection, there is a pressing need for alternative strategies to control alloimmunity. In three decades, regulatory T cells (Tregs) have evolved from a hypothetical mediator of adoptively transferred tolerance to a well-defined population that can be expanded ex vivo and returned safely to patients in clinical trials. Herein, we review the historical developments that have permitted these advances and the current status of clinical trials examining Tregs as a cellular therapy in transplantation. We conclude by discussing the critical unanswered questions that face this field in the coming years

Quantification of CD4(+) T cell alloreactivity and its control by regulatory T cells using time lapse microscopy and immune synapse detection.

Assays designed to select transplant recipients for immunosuppression withdrawal have met with limited success, perhaps because they measure events downstream of T cell-alloantigen interactions. Using in vitro time lapse microscopy in a mouse transplant model we asked whether transplant outcome would result in changes in the proportion of CD4(+) T cells forming prolonged interactions with donor dendritic cells. By blocking CD4-MHC class II and CD28-B7 interactions, we defined immunologically relevant interactions as those ≥500s. Using this threshold, T cell-dendritic cell (T-DC) interactions were examined in rejection, tolerance and T cell control mediated by regulatory T cells. The frequency of T-DC contacts ≥500s increased with T cells from mice during acute rejection and decreased with T cells from mice rendered unresponsive to alloantigen. Regulatory T cells reduced prolonged T-DC contacts. Importantly, this effect was replicated with human polyclonally expanded naturally occurring regulatory T cells, which we have previously shown can control rejection of human tissues in humanized mouse models. Finally, in a proof-of-concept translational context, we have been able to visualize differential allogeneic immune synapse formation in polyclonal CD4(+) T cells using high-throughput imaging flow cytometry. This article is protected by copyright. All rights reserved