Publications by authors named "Stacey R Rose"

9 Publications

  • Page 1 of 1

APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort.

Hepatology 2021 Mar;73(3):1088-1104

Translational, Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

Background And Aims: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas.

Approach And Results: Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH.

Conclusions: APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31421DOI Listing
March 2021

Host immune status-specific production of gliotoxin and bis-methyl-gliotoxin during invasive aspergillosis in mice.

Sci Rep 2017 09 8;7(1):10977. Epub 2017 Sep 8.

Fungal Pathogenesis Unit, LCIM, NIAID, NIH, Bethesda, MD, USA.

Delayed diagnosis in invasive aspergillosis (IA) contributes to its high mortality. Gliotoxin (GT) and bis-methyl-gliotoxin (bmGT) are secondary metabolites produced by Aspergillus during invasive, hyphal growth and may prove diagnostically useful. Because IA pathophysiology and GT's role in virulence vary depending on the underlying host immune status, we hypothesized that GT and bmGT production in vivo may differ in three mouse models of IA that mimic human disease. We defined temporal kinetics of GT and bmGT in serum, bronchoalveolar lavage fluid (BALF) and lungs of A. fumigatus-infected chronic granulomatous disease (CGD), hydrocortisone-treated, and neutropenic mice. We harvested lungs for assessment of fungal burden, histology and GT/bmGT biosynthetic genes' mRNA induction. GT levels were higher in neutropenic versus CGD or steroid-treated lungs. bmGT was persistently detected only in CGD lungs. GT, but not bmGT, was detected in 71% of sera and 50% of BALF of neutropenic mice; neither was detected in serum/BALF of CGD or steroid-treated mice. Enrichment of GT in Aspergillus-infected neutropenic lung correlated with fungal burden and hyphal length but not induction of GT biosynthetic genes. In summary, GT is detectable in mouse lungs, serum and BALF during neutropenic IA, suggesting that GT may be useful to diagnose IA in neutropenic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-10888-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591180PMC
September 2017

Novel signal transducer and activator of transcription 1 mutation disrupts small ubiquitin-related modifier conjugation causing gain of function.

J Allergy Clin Immunol 2018 05 30;141(5):1844-1853.e2. Epub 2017 Aug 30.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md.

Background: Sumoylation is a posttranslational reversible modification of cellular proteins through the conjugation of small ubiquitin-related modifier (SUMO) and comprises an important regulator of protein function.

Objective: We sought to characterize the molecular mechanism of a novel mutation at the SUMO motif on signal transducer and activator of transcription 1 (STAT1).

Methods: STAT1 sequencing and functional characterization were performed in transfection experiments by using immunoblotting and immunoprecipitation in STAT1-deficient cell lines. Transcriptional response and target gene activation were also investigated in PBMCs.

Results: We identified a novel STAT1 mutation (c.2114A>T, p.E705V) within the SUMO motif (IKTE) in a patient with disseminated Rhodococcus species infection, Norwegian scabies, chronic mucocutaneous candidiasis, hypothyroidism, and esophageal squamous cell carcinoma. The mutation is located in the tail segment and is predicted to disrupt STAT1 sumoylation. Immunoprecipitation experiments performed in transfected cells confirmed absent STAT1 sumoylation for E705V, whereas it was present in wild-type (WT) STAT1 cells, as well as the loss-of-function mutants L706S and Y701C. Furthermore, stimulation with IFN-γ led to enhanced STAT1 phosphorylation, enhanced transcriptional activity, and target gene expression in the E705V-transfected compared with WT-transfected cells. Computer modeling of WT and mutant STAT1 molecules showed variations in the accessibility of the phosphorylation site Y701, which corresponded to the loss-of-function and gain-of-function variants.

Conclusion: This is the first report of a mutation in the STAT1 sumoylation motif associated with clinical disease. These data reinforce sumoylation as a key posttranslational regulatory modification of STAT1 and identify a novel mechanism for gain-of-function STAT1 disease in human subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2017.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832513PMC
May 2018

Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

JCI Insight 2016 Aug;1(13)

Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common mutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4 T cells and CD21CD38 B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.88782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004733PMC
August 2016

CARD9-Dependent Neutrophil Recruitment Protects against Fungal Invasion of the Central Nervous System.

PLoS Pathog 2015 Dec 17;11(12):e1005293. Epub 2015 Dec 17.

Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.

Candida is the most common human fungal pathogen and causes systemic infections that require neutrophils for effective host defense. Humans deficient in the C-type lectin pathway adaptor protein CARD9 develop spontaneous fungal disease that targets the central nervous system (CNS). However, how CARD9 promotes protective antifungal immunity in the CNS remains unclear. Here, we show that a patient with CARD9 deficiency had impaired neutrophil accumulation and induction of neutrophil-recruiting CXC chemokines in the cerebrospinal fluid despite uncontrolled CNS Candida infection. We phenocopied the human susceptibility in Card9-/- mice, which develop uncontrolled brain candidiasis with diminished neutrophil accumulation. The induction of neutrophil-recruiting CXC chemokines is significantly impaired in infected Card9-/- brains, from both myeloid and resident glial cellular sources, whereas cell-intrinsic neutrophil chemotaxis is Card9-independent. Taken together, our data highlight the critical role of CARD9-dependent neutrophil trafficking into the CNS and provide novel insight into the CNS fungal susceptibility of CARD9-deficient humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1005293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683065PMC
December 2015

Changing the culture around cultures.

Hosp Pediatr 2014 Nov;4(6):405-7

Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/hpeds.2014-0064DOI Listing
November 2014

The utility of bronchoalveolar lavage beta-D-glucan testing for the diagnosis of invasive fungal infections.

J Infect 2014 Sep 4;69(3):278-83. Epub 2014 May 4.

Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), 9000 Rockville Pike, Building 10 CRC, Room 11C 102, Bethesda, MD 20892, USA. Electronic address:

Objectives: To investigate the utility of beta-D-glucan (BDG) testing in bronchoalveolar lavage (BAL) fluid for the diagnosis of invasive fungal infection (IFI), as compared to BAL galactomannan (GM).

Methods: We retrospectively reviewed medical records of 132 consecutive patients at the National Institutes of Health (NIH) in whom BAL BDG testing was performed for diagnosis of pneumonia. Using the European Organization for Research and Treatment of Cancer/Mycoses Study Group guidelines, we determined which patients had proven or probable IFI, and assessed the diagnostic performance of BAL BDG testing, relative to BAL GM. We also determined the reproducibility of the BDG assay in BAL via repeat testing of patient samples.

Results: Ten patients had Pneumocystis pneumonia, and 34 patients had proven/probable IFI, including 14 with invasive aspergillosis (IA). BAL BDG was 100% sensitive for Pneumocystis. Although BAL BDG had similar sensitivity to BAL GM for the diagnosis of IA and IFI, it exhibited inferior specificity. Repeat testing demonstrated poor reproducibility of the BDG assay in BAL but not in serum.

Conclusions: BDG testing exhibits poor specificity and reproducibility in BAL. Identification of the BAL-specific factors that may interfere with the performance of the assay could improve the clinical usefulness of BAL BDG testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinf.2014.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127351PMC
September 2014

Etiology of thrombocytosis in a general medicine population: analysis of 801 cases with emphasis on infectious causes.

J Clin Med Res 2012 Dec 11;4(6):415-23. Epub 2012 Nov 11.

National Institutes of Health, National Institute of Allergy and Infectious Diseases, 10 Center Drive, Bethesda, MD 20892, USA.

Background: The clinical importance of an elevated platelet count is often overlooked, particularly as a diagnostic clue to the presence of an underlying infection. We sought to better describe the relationship between thrombocytosis and inflammatory conditions, with a focus on infectious causes.

Methods: We retrospectively reviewed 801 sequential cases of thrombocytosis (platelet count > 500 × 10(9)/L) at a tertiary care hospital.

Results: Essential thrombocythemia was the most common cause of primary thrombocytosis, and these patients were more likely to have extreme (> 800 × 10(9)/L) and prolonged (> 1 month) thrombocytosis. Secondary thrombocytosis was more common than primary, with infectious causes accounting for nearly half the cases. Demographic factors associated with an infectious etiology included inpatient status, quadriplegia/paraplegia, an indwelling prosthesis, dementia and diabetes. Clinical and laboratory characteristics associated with an infectious cause of thrombocytosis included fever, tachycardia, weight loss, hypoalbuminemia, neutrophilia, leukocytosis and anemia. Patients with thrombocytosis secondary to infection had a more rapid normalization of platelet count, but higher risk of dying, than those with secondary, non-infectious causes.

Conclusions: Infection is a common cause of thrombocytosis and should be considered in patients with comorbidities that increase risk of infection and when clinical and/or laboratory data support an infectious etiology. Thrombocytosis may have prognostic implications as a clinical parameter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4021/jocmr1125wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513424PMC
December 2012

Gastrointestinal basidiobolomycosis treated with posaconazole.

Med Mycol Case Rep 2012 Nov 15;2:11-4. Epub 2012 Nov 15.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, Bethesda 20892, USA.

A 67 year-old Caucasian male from Arizona presented with indolent symptoms of intestinal obstruction and hydronephrosis, found at surgery to be caused by a mass involving the terminal ileum and cecum, extending into the posterior abdominal wall and obstructing the right ureter. Histopathology was diagnostic of basidiobolomycosis. PCR of tissue and sequencing identified the fungus as, Basidiobolus ranarum. During one year of posaconazole treatment, the residual mass shrank, hydronephrosis was relieved and peripheral eosinophilia resolved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mmcr.2012.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885966PMC
November 2012