ESTIMATING AUTOANTIBODY SIGNATURES TO DETECT AUTOIMMUNE DISEASE PATIENT SUBSETS

Autoimmune diseases are characterized by highly specific immune responses against molecules in self-tissues. Different autoimmune diseases are characterized by distinct immune responses, making autoantibodies useful for diagnosis and prediction. In many diseases, the targets of autoantibodies are incompletely defined. Although the technologies for autoantibody discovery have advanced dramatically over the past decade, each of these techniques generates hundreds of possibilities, which are onerous and expensive to validate. We set out to establish a method to greatly simplify autoantibody discovery, using a pre-filtering step to define subgroups with similar specificities based on migration of labeled, immunoprecipitated proteins on sodium dodecyl sulfate (SDS) gels and autoradiography [Gel Electrophoresis and band detection on Autoradiograms (GEA)]. Human recognition of patterns is not optimal when the patterns are complex or scattered across many samples. Multiple sources of errors - including irrelevant intensity differences and warping of gels - have challenged automation of pattern discovery from autoradiograms. In this paper, we address these limitations using a Bayesian hierarchical model with shrinkage priors for pattern alignment and spatial dewarping. The Bayesian model combines information from multiple gel sets and corrects spatial warping for coherent estimation of autoantibody signatures defined by presence or absence of a grid of landmark proteins. We show the preprocessing creates better separated clusters and improves the accuracy of autoantibody subset detection via hierarchical clustering. Finally, we demonstrate the utility of the proposed methods with GEA data from scleroderma patients

PERK eIF2α kinase regulates neonatal growth by controlling the expression of circulating insulin-like growth factor-I derived from the liver

Humans afflicted with the Wolcott-Rallison syndrome and mice deficient for PERK (pancreatic endoplasmic reticulum eIF2α kinase) show severe postnatal growth retardation. In mice, growth retardation in Perk−/− mutants is manifested within the first few days of neonatal development. Growth parameters of Perk−/− mice, including comparison of body weight to length and organ weights, are consistent with proportional dwarfism. Tibia growth plates exhibited a reduction in proliferative and hypertrophic chondrocytes underlying the longitudinal growth retardation. Neonatal Perk−/− deficient mice show a 75% reduction in liver IGF-I mRNA and serum IGF-I within the first week, whereas the expression of IGF-I mRNA in most other tissues is normal. Injections of IGF-I partially reversed the growth retardation of the Perk−/− mice, whereas GH had no effect. Transgenic rescue of PERK activity in the insulin- secreting β-cells of the Perk−/− mice reversed the juvenile but not the neonatal growth retardation. We provide evidence that circulating IGF-I is derived from neonatal liver but is independent of GH at this stage. We propose that PERK is required to regulate the expression of IGF-I in the liver during the neonatal period, when IGF-I expression is GH-independent, and that the lack of this regulation results in severe neonatal growth retardation

Medication Complications in Extracorporeal Membrane Oxygenation.

The need for extracorporeal membrane oxygenation (ECMO) therapy is a marker of disease severity for which multiple medications are required. The therapy causes physiologic changes that impact drug pharmacokinetics. These changes can lead to exposure-driven decreases in efficacy or increased incidence of side effects. The pharmacokinetic changes are drug specific and largely undefined for most drugs. We review available drug dosing data and provide guidance for use in the ECMO patient population

A Multiancestral Genome-Wide Exome Array Study of Alzheimer Disease, Frontotemporal Dementia, and Progressive Supranuclear Palsy

Importance Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. Objective To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. Design, Setting, and Participants We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. Main Outcomes and Measures Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. Results Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P = .0049, European P = .041, African American P = .043, and Asian P = .027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P = 5.53 × 10−5) and PAXIP1 (P = 2.26 × 10−4), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. Conclusions and Relevance Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD

Nuclear Medicine in Pediatric Nephro-Urology: An Overview.

In the context of ante-natally diagnosed hydronephrosis, the vast majority of children with a dilated renal pelvis do not need any surgical treatment, as the dilatation resolves spontaneously with time. Slow drainage demonstrated at Tc-99m-mercaptoacetyltriglycine (MAG3) renography does not necessarily mean obstruction. Obstruction is defined as resistance to urinary outflow with urinary stasis at the level of the pelvic-ureteric junction (PUJ) which, if left untreated, will damage the kidney. Unfortunately this definition is retrospective and not clinically helpful. Therefore, the identification of the kidney at risk of losing function in an asymptomatic patient is a major research goal. In the context of renovascular hypertension a DMSA scan can be useful before and after revascularisation procedures (angioplasty or surgery) to assess for gain in kidney function. Renal calculi are increasingly frequent in children. Whilst the vast majority of patients with renal stones do not need functional imaging, DMSA scans with SPECT and a low dose limited CT can be very helpful in the case of complex renal calculi. Congenital renal anomalies such as duplex kidneys, horseshoe kidneys, crossed-fused kidneys and multi-cystic dysplastic kidneys greatly benefit from functional imaging to identify regional parenchymal function, thus directing further management. Positron emission tomography (PET) is being actively tested in genito-urinary malignancies. Encouraging initial reports suggest that F-18-fluorodeoxyglucose (FDG) PET is more sensitive than CT in the assessment of lymph nodal metastases in patients with genito-urinary sarcomas; an increased sensitivity in comparison to isotope bone scans for skeletal metastatic disease has also been reported. Further evaluation is necessary, especially with the promising advent of PET/MRI scanners. Nuclear Medicine in paediatric nephro-urology has stood the test of time and is opening up to new exciting developments

Molecular Subsetting of Interferon Pathways in Sjögren's Syndrome

ObjectiveSjögren's syndrome (SS) is an autoimmune disease that targets the salivary and lacrimal glands. While all patients demonstrate inflammatory infiltration and abnormal secretory function in the target tissues, the disease features, pathology, and clinical course can vary. Activation of distinct inflammatory pathways may drive disease heterogeneity. The purpose of this study was to investigate whether activation of the interferon (IFN) pathway correlates with key phenotypic features.MethodsClinical data and 1 labial salivary gland (stored frozen) were obtained from each of 82 participants (53 patients with primary SS and 29 control subjects) in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Salivary gland lysates were immunoblotted with markers of type I or type II IFN, and patterns of IFN activity were determined by hierarchical clustering. Correlations between SS phenotypic features and IFN activity in the salivary gland were performed.ResultsA total of 58% of the SS participants had high IFN activity and differed significantly from those with low IFN activity (higher prevalence of abnormal findings on sialometry, leukopenia, hyperglobulinemia, high-titer antinuclear antibody, anti-SSA, and high focus score on labial salivary gland [LSG] biopsy). Three distinct patterns of IFN were evident: type I-predominant, type II-predominant, and type I/II mixed IFN. These groups were clinically indistinguishable except for the LSG focus score, which was highest in those with type II-predominant IFN.ConclusionThe SS phenotype includes distinct molecular subtypes, which are segregated by the magnitude and pattern of IFN responses. Associations between IFN pathways and disease activity suggest that IFNs are relevant therapeutic targets in SS. Patients with distinct patterns of high IFN activity are clinically similar, demonstrating that IFN-targeting therapies must be selected according to the specific pathway(s) that is active in vivo in the individual patient

Patient experiences of receiving a diagnosis of hypermobile Ehlers-Danlos syndrome

Hypermobile Ehlers-Danlos syndrome (hEDS) presents with a wide range of clinical symptoms and comorbidities that impact quality of life. The diagnosis is challenging and often delayed due to the heterogeneity of the disease and lack of diagnostic biomarkers, which adds to the disease burden by affecting patients' psychosocial adaptation and overall well-being. Previous studies have revealed that healthcare professionals and the public have a limited understanding and familiarity with the condition, which leads to disapproval and skepticism that greatly impact patients' social spheres and welfare. While physical manifestations have been widely discussed, the psychosocial impact and the importance of receiving a diagnosis have not been fully studied in the current literature. This survey study investigated the impact of diagnosis in hEDS patients, selected from the University of Miami's hEDS registry. Survey questions were formulated based on clinical expertise and literature review. Descriptive statistics, Mann-Whitney test, and Spearman's correlation were used for data analysis. The median age at symptom presentation was 10 years, with a median gap of 4 years before the initial medical evaluation. On average, it took 10 years to receive a diagnosis of hEDS. Nearly all participants (95.2%) expressed receiving a diagnosis as "important" or "highly important," with 81.9% agreeing that it helped them cope with their condition better, 76.8% could better manage their symptoms, and felt more in control of their long-term care. Participants mostly had a positive emotional reaction and experienced an improvement in the support they were receiving from their caregivers and healthcare providers after receiving a diagnosis of hEDS. This study demonstrates that receiving a diagnosis could positively impact the patient's support, quality of care, and overall well-being

Autoantibodies targeting telomere-associated proteins in systemic sclerosis.

ObjectivesSystemic sclerosis (SSc) is an autoimmune fibrotic disease affecting multiple tissues including the lung. A subset of patients with SSc with lung disease exhibit short telomeres in circulating lymphocytes, but the mechanisms underlying this observation are unclear.MethodsSera from the Johns Hopkins and University of California, San Francisco (UCSF) Scleroderma Centers were screened for autoantibodies targeting telomerase and the shelterin proteins using immunoprecipitation and ELISA. We determined the relationship between autoantibodies targeting the shelterin protein TERF1 and telomere length in peripheral leucocytes measured by qPCR and flow cytometry and fluorescent in situ hybridisation (Flow-FISH). We also explored clinical associations of these autoantibodies.ResultsIn a subset of patients with SSc, we identified autoantibodies targeting telomerase and the shelterin proteins that were rarely present in rheumatoid arthritis, myositis and healthy controls. TERF1 autoantibodies were present in 40/442 (9.0%) patients with SSc and were associated with severe lung disease (OR 2.4, p=0.04, Fisher's exact test) and short lymphocyte telomere length. 6/6 (100%) patients with TERF1 autoantibodies in the Hopkins cohort and 14/18 (78%) patients in the UCSF cohort had a shorter telomere length in lymphocytes or leukocytes, respectively, relative to the expected age-adjusted telomere length. TERF1 autoantibodies were present in 11/152 (7.2%) patients with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disease believed to be mediated by telomere dysfunction.ConclusionsAutoantibodies targeting telomere-associated proteins in a subset of patients with SSc are associated with short lymphocyte telomere length and lung disease. The specificity of these autoantibodies for SSc and IPF suggests that telomere dysfunction may have a distinct role in the pathogenesis of SSc and pulmonary fibrosis

Autoantibodies targeting telomere-associated proteins in systemic sclerosis.

ObjectivesSystemic sclerosis (SSc) is an autoimmune fibrotic disease affecting multiple tissues including the lung. A subset of patients with SSc with lung disease exhibit short telomeres in circulating lymphocytes, but the mechanisms underlying this observation are unclear.MethodsSera from the Johns Hopkins and University of California, San Francisco (UCSF) Scleroderma Centers were screened for autoantibodies targeting telomerase and the shelterin proteins using immunoprecipitation and ELISA. We determined the relationship between autoantibodies targeting the shelterin protein TERF1 and telomere length in peripheral leucocytes measured by qPCR and flow cytometry and fluorescent in situ hybridisation (Flow-FISH). We also explored clinical associations of these autoantibodies.ResultsIn a subset of patients with SSc, we identified autoantibodies targeting telomerase and the shelterin proteins that were rarely present in rheumatoid arthritis, myositis and healthy controls. TERF1 autoantibodies were present in 40/442 (9.0%) patients with SSc and were associated with severe lung disease (OR 2.4, p=0.04, Fisher's exact test) and short lymphocyte telomere length. 6/6 (100%) patients with TERF1 autoantibodies in the Hopkins cohort and 14/18 (78%) patients in the UCSF cohort had a shorter telomere length in lymphocytes or leukocytes, respectively, relative to the expected age-adjusted telomere length. TERF1 autoantibodies were present in 11/152 (7.2%) patients with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disease believed to be mediated by telomere dysfunction.ConclusionsAutoantibodies targeting telomere-associated proteins in a subset of patients with SSc are associated with short lymphocyte telomere length and lung disease. The specificity of these autoantibodies for SSc and IPF suggests that telomere dysfunction may have a distinct role in the pathogenesis of SSc and pulmonary fibrosis