Role of the Human Endogenous Retrovirus HERV-K18 in Autoimmune Disease Susceptibility: Study in the Spanish Population and Meta-Analysis

Background

Human endogenous retroviruses (HERVs) are genomic sequences that resulted from ancestral germ-line infections by exogenous retroviruses and therefore are transmitted in a Mendelian fashion. Increased HERV expression and antibodies to HERV antigens have been found in various autoimmune diseases. HERV-K18 in chromosome 1 was previously associated with type one diabetes and multiple sclerosis (MS). The etiology of these complex conditions has not been completely elucidated even after the powerful genome wide association studies (GWAS) performed. Nonetheless, this approach does not scrutinize the repetitive sequences within the genome, and part of the missing heritability could lie behind these sequences. We aimed at evaluating the role of HERV-K18 in chromosome 1 on autoimmune disease susceptibility.

Methods

Two HERV-K18 SNPs (97Y/C and 154W/Stop substitutions) conforming three haplotypes were genotyped in Spanish cohorts of multiple sclerosis (n = 942), rheumatoid arthritis (n = 462) and ethnically matched controls (n = 601). Our findings were pooled in a meta-analysis including 5312 autoimmune patients and 4032 controls.

Results

Significant associations of both HERV-K18 polymorphisms in chromosome 1 with MS patients stratified by HLA-DRB1*15∶01 were observed [97Y/C p = 0.02; OR (95% CI) = 1.5 (1.04–2.17) and 154W/Stop: p = 0.001; OR (95% CI) = 1.6 (1.19–2.16)]. Combined meta-analysis of the previously published association studies of HERV-K18 with different autoimmune diseases, together with data derived from Spanish cohorts, yielded a significant association of the HERV-K18.3 haplotype [97Y–154W: p_M-H = 0.0008; OR_M-H (95% CI) = 1.22 (1.09–1.38)].

Conclusion

Association of the HERV-K18.3 haplotype in chromosome 1 with autoimmune-disease susceptibility was confirmed through meta-analysis.     

Down-regulated NOD2 by immunosuppressants in peripheral blood cells in patients with SLE reduces the muramyl dipeptide-induced IL-10 production

Background

Pattern recognition receptors (PRRs) such as Toll-like receptors are aberrantly expressed of peripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients, for playing immunopathological roles.

Methodology/Principal Findings

We investigated the expression and function of the PRR nucleotide-binding oligomerization domain (NOD2) in SLE. NOD2 expression in T, B lymphocytes, monocytes, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) was assessed in SLE patients and healthy controls (HCs) using flow cytometric analysis. Ex vivo production of cytokines from PBMCs upon NOD2 agonist muramyl dipeptide (MDP) stimulation was assessed using Cytometric Bead Array. Over-expression of NOD2 in monocytes was observed in immunosuppressant naïve SLE patients, and was positively associated with longer disease duration. Immunosuppressive therapy was an independent explanatory variable for downregulating NOD2 expression in CD8+ T, monocytes, mDCs and pDCs. Ex vivo basal productions of cytokines (IL-6, IL-8 and IL-10) were significantly increased in immunosuppressant naïve patients and patients with active disease despite immunosuppressants compared with HCs. Upon MDP stimulaiton, relative induction (%) of cytokines (IL-1β) from PBMC was significantly increased in immunosuppressant naïve patients with inactive disease, and patients with active disease despite immunosuppressant treatment compared with HCs. Immunosuppressant usage was associated with a decreased basal production and MDP induced relative induction (%) of IL-10 in patients with inactive disease compared with immunosuppressant naïve patients and HCs.

Conclusions/Significance

Bacterial exposure may increase the NOD2 expression in monocytes in immunosuppressant naïve SLE patients which can subsequently lead to aberrant activation of PBMCs to produce proinflammatory cytokines, implicating the innate immune response for extracellular pathogens in the immunopathological mechanisms in SLE. Immunosuppressant therapy may downregulate NOD2 expression in CD8+ T lymphocytes, monocytes, and DCs in SLE patients which subsequently IL-10 reduction, contributing towards the regulation of immunopathological mechanisms of SLE, at the expense of increasing risk of bacterial infection.     

Relationship of Glucocorticoid Receptor Expression in Peripheral Blood Mononuclear Cells and the Cochlea of Guinea Pigs and Effects of Dexamethasone Administration

Background

Glucocorticoids (GCs) are widely used to treat sudden sensorineural hearing loss (SSNHL) and significantly improve hearing. However, GC insensitivity has been observed in some patients of SSNHL.

Objective

To study the correlation between GR expression in peripheral blood mononuclear cells (PBMCs) and in the cochlea of guinea pigs at mRNA and protein levels.

Methods

One group of guinea pigs received dexamethasone (10 mg/kg/day) intraperitoneally for 7 consecutive days (dexamethasone group), and another group of guinea pigs received normal saline (control group). Real time PCR and Western blotting were used to detect the expression of GR mRNA and GR protein in PBMCs and the cochleae.

Results

The GR mRNA and GR protein were detected in both PBMCs and the cochlear tissue of guinea pigs. GR mRNA and GR protein levels in PBMCs were positively correlated with those in the cochlea. The expression of GR mRNA and GR protein was significantly increased in the dexamethasone group compared to the control group.

Conclusions

Levels of GR mRNA and GR protein in the PBMCs were positively correlated with those in the cochlea of guinea pigs. Systemic dexamethasone treatment can significantly up-regulate GR expression in PBMCs and in the cochlea. Measurement of the GR level in PBMCs could be used as an indicator of GR level in the cochlea.     

Frequency of Human Endogenous Retroviral Sequences (HERV) K113 and K115 in the Polish Population,and Their Effect on HIV Infection

Background

The human genome contains about 8% of endogenous retroviral sequences originated from germ cell infections by exogenous retroviruses during evolution. Most of those sequences are inactive because of accumulation of mutations but some of them are still capable to be transcribed and translated. The latter are insertionally polymorphic HERV-K113 and HERV-K115. It has been suggested that their presence and expression was connected with several human diseases. It is also believed that they could interfere with the replication cycle of exogenous retroviruses, including HIV.

Results

Prevalence of endogenous retroviral sequences HERV-K113 and HERV-K115 was determined in the Polish population. The frequencies were found as 11.8% for HERV-K113 and 7.92% for HERV-K115. To verify the hypothesis that the presence of these HERVs sequences could affect susceptibility to HIV infection, comparison of a control group (HIV-negative, not exposed to HIV; n = 303) with HIV-positive patients (n = 470) and exposed but uninfected (EU) individuals (n = 121) was performed. Prevalence of HERV-K113 and HERV-K115 in the EU group was 8.26% and 5.71%, respectively. In the HIV(+) group we detected HERV-K113 sequences in 12.98% of the individuals and HERV-K115 sequences in 7.23% of the individuals. There were no statistically significant differences between groups studied.

Conclusion

The frequency of HERV-K113 and HERV-K115 sequences in Poland were found to be higher than usually shown for European populations. No relation between presence of the HERVs and HIV infection was detected.     

Atrioventricular Block Subsequent to Intraoperative Device Closure Atrial Septal Defect with Transthoracic Minimal Invasion; A Rare and Serious Complication

Objectives

Atrioventricular block (AVB) is a infrequent and serious complication after percutaneous ASD closure. In this study, we report on the incidence of AVB associated with intraoperative device closure of the ASD with transthoracic minimal invasion, and the outcomes of this complication in our center.

Methods

Between May 2006 and January 2011, a total of 213 secundum-type ASD patients were accepted in our hospital for intraoperative and transthoracic device closure with a domestic occluder. All patients were assessed by real-time transthoracic echocardiography (TTE) and electrocardiograph (ECG).

Results

All patients were occluded successfully under this approach. Immediate postprocedure third-degree AVB was observed in two patients. Since heart rates were in the range of about 50 to 55 beats per minute, no intervention was needed except for close observation for one patient. Another patient who recovered sinus rhythm intermittently during the operation was fitted with a temporary pacemaker. Approximately one week following glucocorticoid treatment, the AVB resolved spontaneously in these two patients. Mobitz type II AVB occurred in three patients during the procedure. Two patients developed post-operative cardiac arrest and were rescued successfully with cardiopulmonary resuscitation. One other patient changed to Mobitz type I AVB after three days. During the follow-up period, which ranged from six months to five years, no further occurrence of AVB was found.

Conclusions

Intraoperative and transthoracic device closure of secundum ASDs with domestic occluder resulted in excellent closure rate. AVB is an infrequent but serious complication during and after device closure of a secundum ASD. AVB is a complication that warrants greater attention and long-term follow-up.     

Gamma activation in young people with autism spectrum disorders and typically-developing controls when viewing emotions on faces

Background

Behavioural studies have highlighted irregularities in recognition of facial affect in children and young people with autism spectrum disorders (ASDs). Recent findings from studies utilising electroencephalography (EEG) and magnetoencephalography (MEG) have identified abnormal activation and irregular maintenance of gamma (>30 Hz) range oscillations when ASD individuals attempt basic visual and auditory tasks.

Methodology/Principal Fndings

The pilot study reported here is the first study to use spatial filtering techniques in MEG to explore face processing in children with ASD. We set out to examine theoretical suggestions that gamma activation underlying face processing may be different in a group of children and young people with ASD (n = 13) compared to typically developing (TD) age, gender and IQ matched controls. Beamforming and virtual electrode techniques were used to assess spatially localised induced and evoked activity. While lower-band (3–30 Hz) responses to faces were similar between groups, the ASD gamma response in occipital areas was observed to be largely absent when viewing emotions on faces. Virtual electrode analysis indicated the presence of intact evoked responses but abnormal induced activity in ASD participants.

Conclusions/Significance

These findings lend weight to previous suggestions that specific components of the early visual response to emotional faces is abnormal in ASD. Elucidation of the nature and specificity of these findings is worthy of further research.     

The Cost of Autism Spectrum Disorders

Objective

A diagnosis of an autism spectrum disorders is usually associated with substantial lifetime costs to an individual, their family and the community. However, there remains an elusive factor in any cost-benefit analysis of ASD diagnosis, namely the cost of not obtaining a diagnosis. Given the infeasibility of estimating the costs of a population that, by its nature, is inaccessible, the current study compares expenses between families whose children received a formal ASD diagnosis immediately upon suspecting developmental atypicality and seeking advice, with families that experienced a delay between first suspicion and formal diagnosis.

Design

A register based questionnaire study covering all families with a child with ASD in Western Australia.

Participants

Families with one or more children diagnosed with an ASD, totalling 521 children diagnosed with an ASD; 317 records were able to be included in the final analysis.

Results

The median family cost of ASD was estimated to be AUD $34,900 per annum with almost 90% of the sum ($29,200) due to loss of income from employment. For each additional symptom reported, approximately $1,400 cost for the family per annum was added. While there was little direct influence on costs associated with a delay in the diagnosis, the delay was associated with a modest increase in the number of ASD symptoms, indirectly impacting the cost of ASD.

Conclusions

A delay in diagnosis was associated with an indirect increased financial burden to families. Early and appropriate access to early intervention is known to improve a child''s long-term outcomes and reduce lifetime costs to the individual, family and society. Consequently, a per symptom dollar value may assist in allocation of individualised funding amounts for interventions rather than a nominal amount allocated to all children below a certain age, regardless of symptom presentation, as is the case in Western Australia.     

Paternal Age and Risk of Autism in an Ethnically Diverse, Non-Industrialized Setting: Aruba

Objective

The aim of this study was to examine paternal age in relation to risk of autism spectrum disorders (ASDs) in a setting other than the industrialized west.

Design

A case-control study of Aruban-born children (1990–2003). Cases (N = 95) were identified at the Child and Adolescent Psychiatry Clinic, the only such clinic in Aruba; gender and age matched controls (N = 347) were gathered from public health records. Parental age was defined categorically (≤29, 30–39, 40–49, ≥50y). The analysis was made, using conditional logistic regression.

Results

Advanced paternal age was associated with increased risk of ASDs in offspring. In comparison to the youngest paternal age group (≤29y), risk of autism increased 2.18 times for children born from fathers in their thirties, 2.71 times for fathers in their forties, and 3.22 thereafter.

Conclusion

This study, part of the first epidemiologic study of autism in the Caribbean, contributes additional evidence, from a distinctive sociocultural setting, of the risk of ASD associated with increased paternal age.     

Impaired Prefrontal Hemodynamic Maturation in Autism and Unaffected Siblings

Background

Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed.

Methodology/Principal Findings

Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs.

Conclusion/Significance

Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.     

Autism spectrum disorders and schizophrenia: meta-analysis of the neural correlates of social cognition

Context

Impaired social cognition is a cardinal feature of Autism Spectrum Disorders (ASD) and Schizophrenia (SZ). However, the functional neuroanatomy of social cognition in either disorder remains unclear due to variability in primary literature. Additionally, it is not known whether deficits in ASD and SZ arise from similar or disease-specific disruption of the social cognition network.

Objective

To identify regions most robustly implicated in social cognition processing in SZ and ASD.

Data Sources

Systematic review of English language articles using MEDLINE (1995–2010) and reference lists.

Study Selection

Studies were required to use fMRI to compare ASD or SZ subjects to a matched healthy control group, provide coordinates in standard stereotactic space, and employ standardized facial emotion recognition (FER) or theory of mind (TOM) paradigms.

Data Extraction

Activation foci from studies meeting inclusion criteria (n = 33) were subjected to a quantitative voxel-based meta-analysis using activation likelihood estimation, and encompassed 146 subjects with ASD, 336 SZ patients and 492 healthy controls.

Results

Both SZ and ASD showed medial prefrontal hypoactivation, which was more pronounced in ASD, while ventrolateral prefrontal dysfunction was associated mostly with SZ. Amygdala hypoactivation was observed in SZ patients during FER and in ASD during more complex ToM tasks. Both disorders were associated with hypoactivation within the Superior Temporal Sulcus (STS) during ToM tasks, but activation in these regions was increased in ASD during affect processing. Disease-specific differences were noted in somatosensory engagement, which was increased in SZ and decreased in ASD. Reduced thalamic activation was uniquely seen in SZ.

Conclusions

Reduced frontolimbic and STS engagement emerged as a shared feature of social cognition deficits in SZ and ASD. However, there were disease- and stimulus-specific differences. These findings may aid future studies on SZ and ASD and facilitate the formulation of new hypotheses regarding their pathophysiology.     

First-Episode Medication-Naive Major Depressive Disorder Is Associated with Altered Resting Brain Function in the Affective Network

Background

Major depressive disorder (MDD) has been associated with abnormal structure and function of the brain''s affective network, including the amygdala and orbitofrontal cortex (OFC). However, it is unclear if alterations of resting-state function in this affective network are present at the initial onset of MDD.

Aims

To examine resting-state function of the brain''s affective network in first-episode, medication-naive patients with MDD compared to healthy controls (HCs).

Methods

Resting-state functional magnetic resonance imaging (rs-fMRI) was performed on 32 first-episode, medication-naive young adult patients with MDD and 35 matched HCs. The amplitude of low-frequency fluctuations (ALFF) of the blood oxygen level-dependent (BOLD) signal and amygdala-seeded functional connectivity (FC) were investigated.

Results

Compared to HC, MDD patients showed reduced ALFF in the bilateral OFC and increased ALFF in the bilateral temporal lobe extending to the insular and left fusiform cortices. Enhanced anti-correlation of activity between the left amygdala seed and the left OFC was found in MDD patients but not in HCs.

Conclusions

Reduced ALFF in the OFC suggests hypo-functioning of emotion regulation in the affective network. Enhanced anti-correlation of activity between the amygdala and OFC may reflect dysfunction of the amygdala-OFC network and additionally represent a pathological process of MDD.     

High copy number in human endogenous retrovirus families is associated with copying mechanisms in addition to reinfection

There are at least 31 families of human endogenous retroviruses (HERVs), each derived from an independent infection by an exogenous virus. Using evidence of purifying selection on HERV genes, we have shown previously that reinfection by replication-competent elements was the predominant mechanism of copying in some families. Here we analyze the evolution of 17 HERV families using d(N)/d(S) ratios and find a positive relationship between copy number and the use of additional copying mechanisms. All families with more than 200 elements have also used one or more of the following mechanisms: (1) complementation in trans (elements copied by other elements of the same family; HERV-H and ERV-9), (2) retrotransposition in cis (elements copying themselves) within germ-line cells (HERV-K(HML3)), and (3) being copied by non-HERV machinery (HERV-W). We discuss why these other mechanisms are rare in most families and suggest why complementation in trans is significant only in the larger families.     

Participation in social activities among adolescents with an autism spectrum disorder

Background

Little is known about patterns of participation in social activities among adolescents with an autism spectrum disorder (ASD). The objectives were to report nationally representative (U.S.) estimates of participation in social activities among adolescents with an ASD, to compare these estimates to other groups of adolescents with disabilities, and examine correlates of limited social participation.

Methods and Findings

We analyzed data from wave 1 of the National Longitudinal Transition Study 2, a large cohort study of adolescents enrolled in special education. Three comparison groups included adolescents with learning disabilities, mental retardation, and speech/language impairments. Adolescents with an ASD were significantly more likely never to see friends out of school (43.3%), never to get called by friends (54.4%), and never to be invited to social activities (50.4%) when compared with adolescents from all the other groups. Correlates of limited social participation included low family income and having impairments in conversational ability, social communication, and functional cognitive skills.

Conclusions

Compared with prior research, our study significantly expands inquiry in this area by broadening the range of social participation indicators examined, increasing the external validity of findings, focusing on the under-studied developmental stage of adolescence, and taking an ecological approach that included many potential correlates of social participation. There were notable differences in social participation by income, a dimension of social context seldom examined in research on ASDs.