scholarly journals Novel TREM2 splicing isoform that lacks the V-set immunoglobulin domain is abundant in the human brain

2020 ◽  
Author(s):  
Kostantin Kiianitsa ◽  
Irina Kurtz ◽  
Neal Beeman ◽  
Mark Matsushita ◽  
Wei-Ming Chien ◽  
...  
Keyword(s):  
Human Brain ◽  
Late Onset ◽  
Adaptor Protein ◽  
Full Length ◽  
Type I ◽  
Phagocytic Capacity ◽  
Exon 2 ◽  
Increased Risk ◽  
Immunoglobulin Domain ◽  
Full Length Transcript

AbstractTREM2 is an immunoglobulin-like receptor expressed by certain myeloid cells, such as macrophages, dendritic cells, osteoclasts and microglia. In the brain, TREM2 plays an important role in the immune function of microglia, and its dysfunction is linked to various neurodegenerative conditions in humans. Ablation of TREM2 or its adaptor protein TYROBP causes Polycystic Lipo-Membranous Osteodysplasia with Sclerosing Leukoencephalopathy (also known as Nasu-Hakola disorder) with early onset of dementia, while some missense variants in TREM2 are associated with an increased risk of late-onset Alzheimer’s disease. Human TREM2 gene is a subject to alternative splicing, and its major, full-length canonical transcript encompasses 5 exons. Herein, we report a novel alternatively spliced TREM2 isoform without exon 2 (Δe2), which constitutes a sizable fraction of TREM2 transcripts and has highly variable inter-individual expression in the human brain (average frequency 10%; range 3.7-35%). The protein encoded by Δe2 lacks a V-set immunoglobulin domain from its extracellular part but retains its transmembrane and cytoplasmic domains. We demonstrated Δe2 protein expression in TREM2-positive THP-1 cells, in which the expression of full-length transcript was precluded by CRISPR/Cas9 disruption of the exon 2 coding frame. In “add-back” experiments, overexpression of full-length, but not Δe2 TREM2, restored phagocytic capacity and promoted interferon type I response in the knockout cells. Our findings suggest that expression of a Δe2 splice isoform may modify the dosage of full-length transcript potentially weakening some TREM2 receptor functions in the human brain.

scholarly journals SRSF1 and PTBP1 Aretrans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer’s Disease Risk

2019 ◽  
Vol 39 (18) ◽  
Author(s):  
Petra van Bergeijk ◽  
Uthpala Seneviratne ◽  
Estel Aparicio-Prat ◽  
Robert Stanton ◽  
Samuel A. Hasson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Late Onset ◽  
Splice Junction ◽  
Full Length ◽  
Receptor Expression ◽  
Genetic Associations ◽  
Rna Sequences ◽  
Exon 2

ABSTRACTA single nucleotide polymorphism (SNP) in exon 2 of the CD33 gene is associated with reduced susceptibility to late-onset Alzheimer’s disease (AD) and causal for elevated mRNA lacking exon 2. In contrast to full-length CD33, transcripts lacking exon 2 result in CD33 protein unable to suppress activation responses in myeloid cells, including microglia. Currently, little is known about the regulation of CD33 exon 2 splicing. Using functional genomics and proteomic approaches, we found that SRSF1 and PTBP1 act as splicing enhancers to increase CD33 exon 2 inclusion in mRNA. Binding of PTBP1 to RNA sequences proximal to the intron 1-exon 2 splice junction is altered by the SNP and represents a potential mechanism behind the SNP-genotype dependent alternative splicing. Our studies also reveal that binding of SRSF1 to the CD33 RNA is not altered by the SNP genotype. Instead, a putative SRSF1 binding sequence at the 3′ end of exon 2 directs CD33 exon 2 inclusion into the mRNA, indicating that PTBP1 and SRSF1 promote full-length isoform expression through different mechanisms. Our findings shed light on molecular interactions that regulate CD33 exon 2 splicing, ultimately impacting receptor expression on the cell surface. These data aid in the understanding of CD33’s regulation of microglial signaling underpinning the AD genetic associations.

scholarly journals Immunological Aspects Related to Viral Infections in Severe Asthma and the Role of Omalizumab

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 348
Author(s):  
Francesco Menzella ◽  
Giulia Ghidoni ◽  
Carla Galeone ◽  
Silvia Capobelli ◽  
Chiara Scelfo ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Severe Asthma ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Antiviral Effect ◽  
Point Of View ◽  
Type I ◽  
Effector Cells ◽  
Viral Spread ◽  
Increased Risk

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although extremely limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which can stabilize the effector cells, and is becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allow a great improvement in the management of asthma.

scholarly journals Epilepsy in Down Syndrome: A Highly Prevalent Comorbidity

2021 ◽  
Vol 10 (13) ◽  
pp. 2776
Author(s):  
Miren Altuna ◽  
Sandra Giménez ◽  
Juan Fortea
Keyword(s):  
Down Syndrome ◽  
Functional Outcomes ◽  
Clinical Presentation ◽  
Late Onset ◽  
Current Knowledge ◽  
Epileptic Seizures ◽  
Myoclonic Epilepsy ◽  
Increased Risk ◽  
Number Of Individuals

Individuals with Down syndrome (DS) have an increased risk for epilepsy during the whole lifespan, but especially after age 40 years. The increase in the number of individuals with DS living into late middle age due to improved health care is resulting in an increase in epilepsy prevalence in this population. However, these epileptic seizures are probably underdiagnosed and inadequately treated. This late onset epilepsy is linked to the development of symptomatic Alzheimer’s disease (AD), which is the main comorbidity in adults with DS with a cumulative incidence of more than 90% of adults by the seventh decade. More than 50% of patients with DS and AD dementia will most likely develop epilepsy, which in this context has a specific clinical presentation in the form of generalized myoclonic epilepsy. This epilepsy, named late onset myoclonic epilepsy (LOMEDS) affects the quality of life, might be associated with worse cognitive and functional outcomes in patients with AD dementia and has an impact on mortality. This review aims to summarize the current knowledge about the clinical and electrophysiological characteristics, diagnosis and treatment of epileptic seizures in the DS population, with a special emphasis on LOMEDS. Raised awareness and a better understanding of epilepsy in DS from families, caregivers and clinicians could enable earlier diagnoses and better treatments for individuals with DS.

Association between digoxin use and sudden cardiac death in individuals with the rs10494366 variant of the NOS1AP gene

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N Soroush ◽  
A Aarnoudse ◽  
F Shokri ◽  
M Van Den Berg ◽  
F Ahmadizar ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Smoking Status ◽  
Adaptor Protein ◽  
Therapeutic Window ◽  
P Value ◽  
Qtc Interval ◽  
Total Study Population ◽  
Increased Risk

Abstract Background Digoxin is one of the oldest cardiovascular medications still used to treat heart failure and atrial fibrillation. Due to its narrow therapeutic window, it is associated with life threatening intoxication and arrhythmias, and with QTc-shortening. Common genetic variation in the nitric oxide synthase-1 adaptor protein (NOS1AP) has been associated with QTc interval prolongation. Purpose We investigated whether the rs10494366 variant of the NOS1AP gene modified the risk of SCD in patients using digoxin. Methods In a prospective population-based cohort study, we included data of the three cohorts, started as of January 1st, 1991 until January 1st 2014. Digoxin current use on the date of cardiac death in cases and the same day of follow-up in the remainder of the cohort was a time-dependent exposure. The main outcome was SCD defined as sudden and unexpected death as a result of cardiac causes, according to international criteria. Identification and adjudication of SCD was performed independently, before the start of this study. We used Cox proportional hazard regression analysis to investigate the associations between NOS1AP rs10494366 variant and incident SCD among digoxin users compared to non-users. Associations were adjusted for age, sex (model 1) in addition to BMI, prevalent diabetes, myocardial infarction, baseline hypertension and smoking status (past, current, never) (model 2). Results We included 14,594 individuals, with a mean age of 65.3 (SD 10.3) years. Almost 59% were female. The cumulative incidence of SCD was 9.5% (609 cases) by the end of follow up. Among them, 98 (16%) individuals were exposed to digoxin at the time of death. In model 1, NOS1AP rs10494366 variant was not associated with SCD in the total study population. However, an interaction term of the gene with the daily dose of digoxin was significantly associated with increased risk of SCD (p-value 0.0001). In model 2, the risk of SCD in current users of digoxin was 4.2 [95% CI 1.3–13.8] for the GG genotype; 2.1 [95% CI 1.1–4.2] for the GT genotype, and 1.5 [95% CI 0.7–3.2] for the TT genotype. Conclusion NOS1AP rs10494366 variant modified the risk of sudden cardiac death in users of digoxin. Our study suggests that individuals with the homozygous minor GG allele have a fourfold increased risk of sudden cardiac death. Funding Acknowledgement Type of funding source: None

scholarly journals Association between early bronchiolitis and the development of childhood asthma: a meta-analysis

BMJ Open ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. e043956
Author(s):  
Guizuo Wang ◽  
Dong Han ◽  
Zhengdong Jiang ◽  
Manxiang Li ◽  
Shumei Yang ◽  
...  
Keyword(s):  
Early Life ◽  
Fixed Effects ◽  
Late Onset ◽  
Meta Analysis ◽  
Later Life ◽  
Analysis Data ◽  
Fixed Effects Model ◽  
Case Control Studies ◽  
Increased Risk ◽  
Registration Number

ObjectiveEarly life bronchiolitis has been hypothesised to be associated with the subsequent risk of persistent wheezing or asthma. However, the link remains controversial. The objective of our study was to evaluate the association between bronchiolitis before 2 years of age and the late-onset wheezing/asthma.DesignSystematic review and meta-analysis.MethodsPubMed, Embase and Web of Science databases were systematically searched for studies published between 1955 and January 2020. Meanwhile, we also checked through the reference lists of relevant articles to see whether these references included reports of other studies that might be eligible for the review. Cohort and case–control studies assessing the association between early-life bronchiolitis and late-onset wheezing/asthma were included in this meta-analysis. Data were extracted by two independent reviewers. Results were pooled using a random-effects model or fixed-effects model according to the heterogeneity among studies.Results32 original articles with 292 844 participants, which met the criteria, were included in this meta-analysis. Bronchiolitis before 2 years of age was associated with an increased risk of subsequent wheezing/asthma (relative risk=2.46, 95% CI 2.14 to 2.82, p<0.001). After categorising studies into different groups based on age at the end of follow-up, geographical region and study quality, the association still remained significant.ConclusionsThe meta-analysis indicates an association between bronchiolitis before 2 years of age and the wheezing/asthma in later life. Well-designed and highly standardised prospective studies that better address bias due to potential confounding factors are needed to validate the risk identified in our meta-analysis.PROSPERO registration numberCRD42018089453.

scholarly journals 1110. Very Late Onset Infections Amongst Long Term Survivors of Kidney Transplantation

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S585-S585
Author(s):  
Harry Cheung ◽  
Marwan M Azar ◽  
Geliang Gan ◽  
Yanhong Deng ◽  
Elizabeth A Cohen ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Data ◽  
Opportunistic Infections ◽  
Late Onset ◽  
Retrospective Chart Review ◽  
Kidney Transplant Recipients ◽  
Increased Risk ◽  
Simple Logistic ◽  
Long Term Survivors

Abstract Background Kidney transplant recipients (KTR) are at increased risk for infections immediately post-transplant due to intense immunosuppression. However, this risk decreases over time as immunosuppression is tapered. The incidence of infection in KTR many years after transplant is not well characterized. The aim of this study was to describe these “very-late onset infections” (VLIs) ≥ 10 years after KT. Methods We performed a retrospective chart review of patients age ≥ 18 years who underwent KT between 2003 and 2009 and who survived ≥ 10 years post-KT. VLIs included opportunistic infections (OIs) and non-OIs. Demographics, comorbidities, immunosuppression, and clinical data for VLIs ≥ 10 years from KT were collected. Simple logistic regression was performed to determine characteristics associated with risk for VLIs. Results Of 332 KTR that met the inclusion criteria, the majority were male (62.0%), white (59.6%), and the largest proportion was transplanted between the ages of 50-59 (28.3%); 220 (67.9%) were on mycophenolate-based regimens. The mean Charlson Comorbidity Index (CCI) was 4.7 (S.D. 2.0). Of 332, 103 (31.0%) KTR experienced ≥ 1 VLI amounting to 187 episodes. Compared to those without VLI, KTR with VLI were more likely to have diabetes (p=0.005), cardiovascular disease (p=0.004), low ALC (p &lt; 0.001) and require dialysis (p=0.002). Of 103 KTR with VLI, 16 (15.5%) had OIs, while 87 KTR (84.5%) had non-OIs, most commonly urinary tract infection (n=85, 45.5%), pneumonia (n=35, 18.7%) and gastrointestinal infection (n=18, 9.6%). The most commonly isolated pathogens were E. coli (n=30, 16%), K. pneumoniae (n=16, 8.6%), MSSA (n=7, 3.7%), and P. aeruginosa (n=7, 3.7%). Higher CCI, diabetes, dialysis, cerebrovascular, cardiovascular disease and lower ALC were associated with increased risk for VLI (p &lt; 0.05), while living donor KTR was protective (p=0.04). Additionally, every 1 year after transplant was associated with an increased risk of VLI (OR=1.31, p &lt; 0.001). Table 1: Demographics, comorbidities, immunosuppression, and clinical data for all patients Conclusion VLIs were common in long-term survivors of KT and included both conventional and opportunistic pathogens. Every additional year from transplant incurred additional risk for VLI, particularly for those with multiple co-morbidities and lower ALC. Disclosures All Authors: No reported disclosures

scholarly journals Novel TREM2 splicing isoform that lacks the V‐set immunoglobulin domain is abundant in the human brain

2021 ◽  
Author(s):  
Kostantin Kiianitsa ◽  
Irina Kurtz ◽  
Neal Beeman ◽  
Mark Matsushita ◽  
Wei‐Ming Chien ◽  
...  
Keyword(s):  
Human Brain ◽  
Immunoglobulin Domain
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