Advances in genomics have allowed unbiased genetic studies of human disease with unexpected insights into the molecular mechanisms of cellular immunity and autoimmunity1. We performed whole exome sequencing (WES) and targeted sequencing in patients with an apparent Mendelian syndrome of autoimmune disease characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease (ILD). In five families, we identified four unique deleterious variants in the Coatomer subunit alpha (COPA) gene all located within the same functional domain. We hypothesized that mutant COPA leads to a defect in intracellular transport mediated by coat protein complex I (COPI)2–4. We show that COPA variants impair binding of proteins targeted for retrograde Golgi to ER transport and demonstrate that expression of mutant COPA leads to ER stress and the upregulation of Th17 priming cytokines. Consistent with this pattern of cytokine expression, patients demonstrated a significant skewing of CD4+ T cells toward a T helper 17 (Th17) phenotype, an effector T cell population implicated in autoimmunity5,6. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease. These findings provide a unique opportunity to understand how alterations in cellular homeostasis caused by a defect in the intracellular trafficking pathway leads to the generation of human autoimmune disease.
Background: Hematopoietic Stem Cell Transplant (HSCT) is an established treatment for malignant and non-malignant conditions and pulmonary disease is a leading cause of late term morbidity and mortality. Accurate and early detection of pulmonary complications is a critical step in improving long term outcomes. Existing guidelines for surveillance of pulmonary complications post-HSCT contain conflicting recommendations.Aim: To determine the breadth of current practice in monitoring for pulmonary complications of pediatric HSCT.Methods: An institutional review board approved, online, anonymous multiple-choice survey was distributed to HSCT and pulmonary physicians from the United States of America and Australasia using the REDcap platform. The survey was developed by members of the American Thoracic Society Working Group on Complications of
Introduction Rubinstein‐Taybi syndrome (RSTS) is a rare genetic syndrome caused primarily by a mutation in the CREBBP gene found on chromosome 16. Patients with RSTS are at greater risk for a variety of medical problems, including upper airway obstruction and aspiration. Childhood interstitial lung disease (ILD) thus far has not been definitively linked to RSTS. Here we present three patients with RSTS who developed ILD and discuss possible mechanisms by which a mutation in CREBBP may be involved in the development of ILD. Methods Routine hematoxylin and eosin staining was performed on lung biopsy tissue for histological analysis. Immunofluorescent staining was performed on lung biopsy tissue for markers of fibrosis, surfactant deficiency and histone acetylation. Cases 1 and 2 had standard clinical microarray analysis. Case 3 had whole exome sequencing. Bioinformatics analyses were performed to identify possible causative genes using ToppGene. Results Computed tomography images in all cases showed consolidated densities overlying ground glass opacities. Lung histopathology revealed accumulation of proteinaceous material within alveolar spaces, evidence of fibrosis, and increased alveolar macrophages. Immunofluorescent staining showed increase in surfactant protein C staining, patchy areas of increased anti‐smooth muscle antibody staining, and increased staining for acetylated histone 2 and histone 3 lysine 9. Discussion Clinical characteristics, radiographic imaging, lung histopathology, and immunofluorescent staining results shared by all cases demonstrated findings consistent with ILD. Immunofluorescent staining suggests two possible mechanisms for the development of ILD: abnormal surfactant metabolism and/or persistent activation of myofibroblasts. These two pathways could be related to dysfunctional CREBBP protein.
Background/Purpose: Pulmonary hemorrhage (PH) is a rare and devastating manifestation of SLE, occurring in 1–5% of adult cohorts with mortality rates ranging from 70%‐90%. The majority of PH reported in SLE refers to the adult population, and there is a paucity of data in pediatrics. Therefore, we describe our experience with PH in pediatric SLE, outlining disease presentation, treatment, and outcomes. Methods: We reviewed records of pediatric SLE patients who presented with pulmonary involvement diagnosed between January 2000 and August 2010. Inclusion criteria included > 4 SLE classification criteria and PH based on pulmonary evaluation by BAL, lung biopsy and/or characteristic imaging with worsening anemia. We describe our pediatric cohort, presenting symptoms, diagnostic modalities, various interventions and overall outcomes. Results: Seven of 401 (1.7%) SLE patients met inclusion criteria for PH. Patients were predominantly male (71.4%) and Hispanic (57.1%). Median age of PH presentation was 13.5 years (range 2.0–15.2). Episodes were primarily within the first 3 months of SLE diagnosis (71.4%) and were a presenting manifestation for SLE in 28.6% of our patients. All patients presented with a new cough, dyspnea, hypoxemia, anemia and abnormal CXR. Hemoptysis was present in 28.6%. Four out of 6 children had chest CT findings with diffuse ground glass opacities (66.6%) and 3 with nodules (50%). Additional non‐pulmonary features included fever (71.4%), renal disease (57.1%), cytopenias (71.4%), cardiac disease (50.0%), and positive antiphospholipid antibodies (85.7%). Eighty‐five percent required supplemental oxygen and 57.1% required mechanical ventilation. Hemosiderin‐laden macrophages without infection were observed in 3 BAL's. Out of the two lung biopsies performed, both revealed diffuse hemorrhage and one demonstrated immunoglobulin and complement deposition. All were treated with pulse doses of methylprednisolone infusions. Other therapeutic interventions included cyclophosphamide (42.8%), plasma exchange (42.8%), rituximab (85.7%) and IVIG (14.2%). Survival rate was 87.5%. All patients were maintained on corticosteroids and 66.6% received monthly cyclophosphamide infusions. Subsequent outpatient therapies included IVIG (33.3%), azathioprine (16.6%) or rituximab (16.6%). No patients had recurrences of PH. No survivors required supplemental oxygen nor developed interstitial lung disease (median follow‐up 2.6 years, range 1.5–5.0). Conclusion: In our review of pSLE patients with PH, the prevalence of this complication approximated that of adult SLE cohorts. However, in contrast to the adult population, PH presented earlier in the course of SLE in children. Additionally, outcomes were favorable with initiation of aggressive, multi‐modal immunosuppressive therapy with no recurrences. The mortality rate was much lower than described in adult cohorts.
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