Sex differences in the genetics of sarcoidosis across European and African ancestry populations

BackgroundSex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren’s syndrome (LS) and non-Löfgren’s syndrome (non-LS).MethodsA meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by an SNP lookup in the UK Biobank (UKB, n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex.ResultsWe identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and ANXA11. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified.ConclusionOur findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis

On age related changes in axons and glia of the central nervous system

A growing body of evidence shows that phenotypic changes including axon aberrations, rather than loss of neurons, account for behavioral impairments during aging. The present thesis was undertaken to investigate the occurrence of axon aberrations in relation to transmitter identity, glial reaction and sensorimotor disturbances. To shed light on possible underlying mechanisms, signs of oxidative stress and inflammation were also examined. The studies were performed on behaviorally defined aged (30 months old) and young adult (2-3 months old) Sprague Dawley rats, by using electron microscopy, immunohistochemistry, in situ hybridization and reverse transcriptase-polymerase chain reaction. The results show that many aged motoneurons lose a significant portion of their bouton covering, due to a decreased number of apposing boutons. Consistent with the more pronounced sensorimotor disturbances observed in the hind- in comparison with the forelimbs, lumbar motoneurons appeared more severely affected than cervical motoneurons. In the neuropil of the motor nucleus, aberrant axons were encountered. Ultrastructural analysis of aberrant axons in relation to content of amino acid neurotransmitters and the free radical scavenger glutathione (GSH) revealed that many of the aberrant axons contained high levels of glutamate-immunoreactivity (-IR) and were often enriched with GSH-IR. Increased levels of GSH-IR were also encountered in glutamate-IR terminals with a preserved ultrastructure, suggesting that a changed redox status may be mechanistic in the development of axon aberrations. GABA- and glycine-IR terminals were more rarely affected, suggesting that excitatory and inhibitory pathways are differentially affected. In the aged rats, immunohistochemistry showed a reduced fiber density and axon aberrations of cholinergic and monoaminergic axons in both the spinal cord and the hippocampus. In contrast, the innervation of alpha-motonearons by C boutons was preserved in senescence. However, the C boutons showed a decreased labeling for cholinergic markers. Regions disclosing axon terminal loss and aberrations showed increased expression of glial fibrillary acidic protein (GFAP, the main intermediate filament of astrocytes). Using Marchi staining on spinal cord sections, the outer parts of the white matter showed signs of a changed myelin metabolism and/or dysmyelination in aged rats. hi the same regions, astro- and microglial cells showed conspicuous signs of activation, most pronounced in rats disclosing the most severe sensorimotor disturbances. The glial reaction appeared less pronounced in brain white matter compared to the spinal cord white matter. The spinal cord white matter of aged rats also disclosed a changed expression of several cytokines, while the majority of investigated cytokines were unaltered in the hippocampus. One of the most prominent changes was an upregulation of the proinflammatory cytokine IFN-gamma, encountered in both the hippocampus and the spinal cord. There was a robust upregulation of TGFbeta-1 and IL1-beta in astroglia of spinal cord white matter, while no change was evident in the hippocampus. CNTF levels were unaltered in aged rats, however, IR appeared reduced in oligodendroglia-like cells, while it seemed increased in astroglia of the spinal cord white matter. IGF-1, a molecule with similar effects as CNTF, was upregulated in hippocampus but not in die spinal cord

A superconducting gravimeter for evaluation of groundwater changes in the field

textThe Superconducting Gravimeter (SG) is an extremely sensitive instrument that measures relative changes in gravity. It is based on the movement of a superconducting sphere levitated in a magnetic field created by current in superconducting coils. It is capable of detecting gravity variations as small as 10⁻¹¹ ms⁻². Because early production SG's lost helium at a steady rate, a large capacity dewar was required for reasonable periods of uninterrupted operation. In the late 1990's, Sumitomo Heavy Industries (SHI) developed a compact refrigeration system able to achieve liquid helium temperatures near 4K. It eliminates helium loss and allows a much smaller dewar to provide long intervals of continuous operation. These technical advances led us to develop an SG configured as a transportable field instrument. The goals were: 1) to package the entire SG system in two containers; 2) to test transport feasibility while the sensor remained in a superconducting levitated state; 3) to verify operability in field conditions; and 4) to determine the value of a transportable SG in groundwater and aquifer studies. We integrated the SG with a full weather station (measuring barometric pressure, rainfall, soil moisture etc.) and a geodetic GPS receiver (measuring vertical movement and atmospheric water vapor). All components were contained within enclosures constructed from angle and sheet aluminum. Each has dimensions ~1.5 x 0.8 x 1 m, total mass ~250 kg (including equipment) and can be transported easily by a medium truck while the sensor remained in a superconducting levitated state. Temporal gravity variations measured by the SG include solid Earth tides, pole-tide, atmospheric pressure effect, ocean loading effect, and terrestrial water storage variations. Most of these can be well modeled, except the last term. We developed a standard procedure for SG data processing. The first field deployment of the SG system was for the study of the Edwards aquifer, a Karst aquifer system that provides water resources in Central Texas, and was operated by a monitoring well equipped with transducer to measure water level changes. The residual gravity changes measured by the SG were only sensitive to the water storage changes underground. With well level measurements, it can be used to estimate aquifer's specific yield.Geological Science

Reproductive and hormonal risk factors for sarcoidosis : a nested case–control study

Background: Sarcoidosis incidence peaks in females around the fifth decade of life, which coincides with menopause, suggesting hormonal factors play a role in disease development. We investigated whether longer exposure to reproductive and hormonal factors is associated with reduced sarcoidosis risk. Methods: We conducted a matched case–control study nested within the Mammography Screening Project. Incident sarcoidosis cases were identified via medical records and matched to controls on birth and questionnaire date (1:4). Information on hormonal factors was obtained through questionnaires prior to sarcoidosis diagnosis. Multilevel modelling was used to estimate adjusted odds ratios with 95% credible intervals (OR; 95% CI). Results: In total, 32 sarcoidosis cases and 124 controls were included. Higher sarcoidosis odds were associated with older age at menarche (OR 1.19: 95% CI 0.92–1.55), natural menopause versus non-natural (OR 1.53: 95% CI 0.80–2.93), later age at first pregnancy (OR 1.11: 95% CI 0.76–1.63) and ever hormone replacement therapy (HRT) use (OR 1.40: 95% CI 0.76–2.59). Lower odds were associated with older age at menopause (OR 0.90: 95% CI 0.52–1.55), longer duration of oral contraceptive use (OR 0.70: 95% CI 0.45–1.07), longer duration of HRT use (OR 0.61: 95% CI 0.22–1.70), ever local estrogen therapy (LET) use (OR 0.83: 95% CI 0.34–2.04) and longer duration of LET use (OR 0.78: 95% CI 0.21–2.81). However, the CIs could not rule out null associations. Conclusion: Given the inconsistency and modest magnitude in our estimates, and that the 95% credible intervals included one, it still remains unclear whether longer estrogen exposure is associated with reduced sarcoidosis risk

Distinctive Regulatory T Cells and Altered Cytokine Profile Locally in the Airways of Young Smokers with Normal Lung Function.

Smoking influences the immune system in different ways and, hypothetically, effects on pulmonary effector and regulatory T cells emerge as potentially detrimental. Therefore, we characterized the frequencies and characteristics of CD4+ and CD8+ T cell subsets in the blood and lungs of young tobacco smokers. Bronchoalveolar lavage (BAL) and peripheral blood were obtained from healthy moderate smokers (n = 18; 2-24 pack-years) and never-smokers (n = 15), all with normal lung function. Cells were stimulated ex vivo and key intracellular cytokines (IFNγ, IL-17, IL-10 and TNFα) and transcription factors (Foxp3, T-bet and Helios) were analyzed using flow cytometry. Our results indicate that smoking is associated with a decline in lung IL-17+ CD4+ T cells, increased IFNγ+ CD8+ T cells and these alterations relate to the history of daily cigarette consumption. There is an increased fraction of Foxp3+ regulatory T cells being Helios- in the lungs of smokers. Cytokine production is mainly confined to the Helios- T cells, both in regulatory and effector subsets. Moreover, we detected a decline of Helios+Foxp3- postulated regulatory CD8+ T cells in smokers. These alterations in the immune system are likely to increase risk for infection and may have implications for autoimmune processes initiated in the lungs among tobacco smokers

Common variants of T-cells contribute differently to phenotypic variation in sarcoidosis

The involvement of the immune system, particularly the role of T-cells, in sarcoidosis is unclear. The existence of higher CD4+ T-cells and increased CD4/CD8 ratio may indicate a pathogenic role of T-cells in the disease. In this study, we quantified the contribution of T-cells associated variants and of CD4/CD8 ratio in sarcoidosis phenotypes, Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS). We employed a polygenic-based approach using genome-wide association studies results on relative levels of T-cells in healthy individuals to measure the genetic contribution of T-cells in sarcoidosis entities. Results revealed that the genetic architecture of LS is highly influenced by genetic variants associated with CD8+ T-cells and CD4/CD8 ratio, explaining up to 7.94% and 6.49% of LS variation, respectively; whereas, the genetic architecture of non-LS is minimally influenced by T-cells, explaining a phenotypic variation o

Expression Profile of Six RNA-Binding Proteins in Pulmonary Sarcoidosis

<div><p>Background</p><p>Sarcoidosis is characterised by up-regulation of cytokines and chemokine ligands/receptors and proteolytic enzymes. This pro-inflammatory profile is regulated post-transcriptionally by RNA-binding proteins (RBPs). We investigated <i>in vivo</i> expression of six RBPs (AUF1, HuR, NCL, TIA, TIAR, PCBP2) and two inhibitors of proteolytic enzymes (RECK, PTEN) in pulmonary sarcoidosis and compared it to the expression in four control groups of healthy individuals and patients with other respiratory diseases: chronic obstructive pulmonary disease (COPD), asthma and idiopathic interstitial pneumonias (IIPs).</p><p>Methods</p><p>RT-PCR was used to quantify the mRNAs in bronchoalveolar (BA) cells obtained from 50 sarcoidosis patients, 23 healthy controls, 30 COPD, 19 asthmatic and 19 IIPs patients. Flow cytometry was used to assess intracellular protein expression of AUF1 and HuR in peripheral blood T lymphocytes (PBTLs) obtained from 9 sarcoidosis patients and 6 healthy controls.</p><p>Results</p><p>Taking the stringent conditions for multiple comparisons into consideration, we consistently observed in the primary analysis including all patients regardless of smoking status as well as in the subsequent sub-analysis limited for never smokers that the BA mRNA expression of AUF1 (<i>p</i><0.001), TIA (<i>p</i><0.001), NCL (<i>p</i><0.01) and RECK (<i>p</i><0.05) was decreased in sarcoidosis compared to healthy controls. TIA mRNA was also decreased in sarcoidosis compared to both obstructive pulmonary diseases (COPD and asthma; <i>p</i><0.001) but not compared to IIPs. There were several positive correlations between RECK mRNA and RBP mRNAs in BA cells. Also sarcoidosis CD3+, CD4+ and CD8+ PBTLs displayed lower mean fluorescence intensity of AUF1 (<i>p≤</i>0.02) and HuR (<i>p≤</i>0.03) proteins than control healthy PBTLs.</p><p>Conclusion</p><p>mRNA expressions of three RBPs (AUF1, TIA and NCL) and their potential target mRNA encoding RECK in BA cells and additionally protein expression of AUF1 and HuR in PBTLs were down-regulated in our sarcoidosis patients compared to healthy individuals. Its significance, e.g. for stability of mRNAs encoding pro-inflammatory factors, should be further explored in sarcoidosis.</p></div

Clinical Outcomes and Predictors of Long‐Term Survival in Patients With and Without Previously Known Extracardiac Sarcoidosis Using Machine Learning: A Swedish Multicenter Study

Background Cardiac involvement can be an initial manifestation in sarcoidosis. However, little is known about the association between various clinical phenotypes of cardiac sarcoidosis (CS) and outcomes. We aimed to analyze the relation of different clinical manifestations with outcomes of CS and to investigate the relative importance of clinical features influencing overall survival. Methods and Results A retrospective cohort of 141 patients with CS enrolled at 2 Swedish university hospitals was studied. Presentation, imaging studies, and outcomes of de novo CS and previously known extracardiac sarcoidosis were compared. Survival free of primary composite outcome (ventricular arrhythmias, heart transplantation, or death) was assessed. Machine learning algorithm was used to study the relative importance of clinical features in predicting outcome. Sixty‐two patients with de novo CS and 79 with previously known extracardiac sarcoidosis were included. De novo CS showed more advanced New York Heart Association class (P=0.02), higher circulating levels of NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) (P<0.001), and troponins (P<0.001), as well as a higher prevalence of right ventricular dysfunction (P<0.001). During a median (interquartile range) follow‐up of 61 (44–77) months, event‐free survival was shorter in patients with de novo CS (P<0.001). The top 5 features predicting worse event‐free survival in order of importance were as follows: impaired tricuspid annular plane systolic excursion, de novo CS, reduced right ventricular ejection fraction, absence of β‐blockers, and lower left ventricular ejection fraction. Conclusions Patients with de novo CS displayed more severe disease and worse outcomes compared with patients with previously known extracardiac sarcoidosis. Using machine learning, right ventricular dysfunction and de novo CS stand out as strong overall predictors of impaired survival