Background. Human bocavirus (HBoV) is a recently discovered parvovirus associated with respiratory tract infections in children. We conducted the first systematic prospective clinical and molecular ...study using nasopharyngeal aspirates (NPAs) and fecal samples. Methods. NPAs negative for influenza virus, parainfluenza virus, respiratory syncytial virus, adenovirus, and coronavirus and fecal samples from patients with acute gastroenteritis were included. On the basis of results from a pilot study using 400 NPAs from all age groups, a prospective 12-month study was conducted to detect HBoV in 1200 NPAs and 1435 fecal samples from patients <18 years old by polymerase chain reaction. The complete genome sequences of HBoVs from 12 NPAs and 12 fecal samples were determined. Results. Of the 400 NPAs collected in the pilot study, 20 (5.0%) were found to contain HBoV, all from children <5 years old. In the subsequent prospective study of pediatric patients, HBoV was detected in 83 (6.9%) of 1200 NPAs. Upper and lower respiratory tract infections were equally common. HBoV was detected in 30 (2.1%) of 1435 fecal samples. Fever and watery diarrhea were the most common symptoms. The seasonality of HBoV in NPAs and fecal samples was similar. Codetection with other pathogens occurred in 33% and 56% of NPAs and fecal samples, respectively, from patients with HBoV infection. Genomes of HBoVs from NPAs and fecal samples displayed minimal sequence variations. Conclusions. HBoV was detected in fecal specimens in children with acute gastroenteritis. A single lineage of HBoV was associated with both respiratory tract and enteric infections.
Epigenetic variants have been shown in recent studies to be important contributors to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report a 2-step study of discovery followed by ...replication to identify DNA methylation alterations associated with SLE in a Chinese population. Using a genome-wide DNA methylation microarray, the Illumina Infinium HumanMethylation450 BeadChip, we compared the methylation levels of CpG sites in DNA extracted from white blood cells from 12 female Chinese SLE patients and 10 healthy female controls.
We identified 36 CpG sites with differential loss of DNA methylation and 8 CpG sites with differential gain of DNA methylation, representing 25 genes and 7 genes, respectively. Surprisingly, 42% of the hypomethylated CpG sites were located in CpG shores, which indicated the functional importance of the loss of DNA methylation. Microarray results were replicated in another cohort of 100 SLE patients and 100 healthy controls by performing bisulfite pyrosequencing of four hypomethylated genes, MX1, IFI44L, NLRC5 and PLSCR1. In addition, loss of DNA methylation in these genes was associated with an increase in mRNA expression. Gene ontology analysis revealed that the hypomethylated genes identified in the microarray study were overrepresented in the type I interferon pathway, which has long been implicated in the pathogenesis of SLE.
Our epigenetic findings further support the importance of the type I interferon pathway in SLE pathogenesis. Moreover, we showed that the DNA methylation signatures of SLE can be defined in unfractionated white blood cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The global burden of fungal diseases has been increasing, as a result of the expanding number of susceptible individuals including people living with human immunodeficiency virus (HIV), hematopoietic ...stem cell or organ transplant recipients, patients with malignancies or immunological conditions receiving immunosuppressive treatment, premature neonates, and the elderly. Opportunistic fungal pathogens such as
, and
are distributed worldwide and constitute the majority of invasive fungal infections (IFIs). Dimorphic fungi such as
spp.,
spp.,
spp. are geographically restricted to their respective habitats and cause endemic mycoses. Disseminated histoplasmosis, coccidioidomycosis, and
infection are recognized as acquired immunodeficiency syndrome (AIDS)-defining conditions, while the rest also cause high rate of morbidities and mortalities in patients with HIV infection and other immunocompromised conditions. In the past decade, a growing number of monogenic immunodeficiency disorders causing increased susceptibility to fungal infections have been discovered. In particular, defects of the IL-12/IFN-γ pathway and T-helper 17-mediated response are associated with increased susceptibility to endemic mycoses. In this review, we put together the various forms of endemic mycoses on the map and take a journey around the world to examine how cellular and molecular defects of the immune system predispose to invasive endemic fungal infections, including primary immunodeficiencies, individuals with autoantibodies against interferon-γ, and those receiving biologic response modifiers. Though rare, these conditions provide importance insights to host defense mechanisms against endemic fungi, which can only be appreciated in unique climatic and geographical regions.
Objective
Human complement C4 is complex, with multiple layers of diversity. The aims of this study were to elucidate the copy number variations (CNVs) of C4A and C4B in relation to disease risk in ...systemic lupus erythematosus (SLE), and to compare the basis of race‐specific C4A deficiency between East Asians and individuals of European descent.
Methods
The East Asian study population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy numbers (GCNs) of total C4, C4A, and C4B, as well as C4‐Long and C4‐Short genes, were determined and validated using independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein occurring concurrently with C4A deficiency.
Results
In East Asians, high GCNs of total C4 and C4A were strongly protective against SLE, whereas low and medium GCNs of total C4 and C4A, and the absence of C4‐Short genes, were risk factors for SLE. Homozygous C4A deficiency was infrequent in East Asian subjects, but had an odds ratio (OR) of 12.4 (P = 0.0015) for SLE disease susceptibility. Low serum complement levels were strongly associated with low GCNs of total C4 (OR 3.19, P = 7.3 × 10−7) and C4B (OR 2.53, P = 2.5 × 10−5). Patients with low serum complement levels had high frequencies of anti–double‐stranded DNA antibodies (OR 4.96, P = 9.7 × 10−17), hemolytic anemia (OR 3.89, P = 3.6 × 10−10), and renal disease (OR 2.18, P = 8.5 × 10−6). The monomodular‐Short haplotype found to be prevalent in European Americans with C4A deficiency, which was in linkage disequilibrium with HLA–DRB1*0301, was scarce in East Asians. Instead, most East Asian subjects with C4A deficiency were found to have a recombinant haplotype with bimodular C4‐Long and C4‐Short genes, encoding C4B1 and C4B96, which was linked to HLA–DRB1*1501. DNA sequencing revealed an E920K polymorphism in C4B96.
Conclusion
C4 CNVs and deficiency of C4A both play an important role in the risk and manifestations of SLE in East Asian and European populations.
Pulmonary fibrosis is a chronic progressive lung disease with few treatments. Human mesenchymal stem cells (MSCs) have been shown to be beneficial in pulmonary fibrosis because they have ...immunomodulatory capacity. However, there is no reliable model to test the therapeutic effect of human MSCs in vivo. To mimic pulmonary fibrosis in humans, we established a novel bleomycin-induced pulmonary fibrosis model in humanized mice. With this model, the benefit of human MSCs in pulmonary fibrosis and the underlying mechanisms were investigated. In addition, the relevant parameters in patients with pulmonary fibrosis were examined. We demonstrate that human CD8
T cells were critical for the induction of pulmonary fibrosis in humanized mice. Human MSCs could alleviate pulmonary fibrosis and improve lung function by suppressing bleomycin-induced human T-cell infiltration and proinflammatory cytokine production in the lungs of humanized mice. Importantly, alleviation of pulmonary fibrosis by human MSCs was mediated by the PD-1/programmed death-ligand 1 pathway. Moreover, abnormal PD-1 expression was found in circulating T cells and lung tissues of patients with pulmonary fibrosis. Our study supports the potential benefit of targeting the PD-1/programmed death-ligand 1 pathway in the treatment of pulmonary fibrosis.
Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating ...inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention.
Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous ...genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.
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