The interaction of human and Epstein–Barr virus miRNAs with Multiple Sclerosis risk loci

Although the causes of Multiple Sclerosis (MS) still remain largely unknown, multiple lines of evidence suggest that Epstein–Barr virus (EBV) infection may contribute to the development of MS. Here, we aimed to identify the potential contribution of EBV-encoded and host cellular miRNAs to MS pathogenesis. We identified differentially expressed host miRNAs in EBV infected B cells (LCLs) and putative host/EBV miRNA interactions with MS risk loci. We estimated the genotype effect of MS risk loci on the identified putative miRNA:mRNA interactions in silico. We found that the protective allele of MS risk SNP rs4808760 reduces the expression of hsa-mir-3188-3p. In addition, our analysis suggests that hsa-let-7b-5p may interact with ZC3HAV1 differently in LCLs compared to B cells. In vitro assays indicated that the protective allele of MS risk SNP rs10271373 increases ZC3HAV1 expression in LCLs, but not in B cells. The higher expression for the protective allele in LCLs is consistent with increased IFN response via ZC3HAV1 and so decreased immune evasion by EBV. Taken together, this provides evidence that EBV infection dysregulates the B cell miRNA machinery, including MS risk miRNAs, which may contribute to MS pathogenesis via interaction with MS risk genes either directly or indirectly

Time course of banana phospholipid retention by buccal epithelial cells

Surface active phospholipids (SAPs) adhere to biological surfaces and produce biophysical actions that may potentially be useful in the treatment of obstructive sleep apnoea when applied to the pharyngeal mucosa. Ripe bananas contain clinically promising SAPs and may represent a cheap and palatable means of administering SAPs to the pharyngeal mucosa. However, little is known regarding how long administered SAPs are retained on biological surfaces

Retention of ingested phospholipids on the oral mucosa

Bananas contain surface active phospholipids (PL) and may potentially be a cheap and palatable means of administering exogenous PL to the pharyngeal mucosa for the treatment of obstructive sleep apnoea. Method: Eight healthy women (20.1 ± 1.4 years of age) were studied to determine how long banana PL are retained on oral epithelial surfaces. Epithelial cells were gently scraped from the inside of the subjects' cheeks immediately before, and 1, 2, 4 and 6 hours after, subjects slowly drank 200 ml of an aqueous suspension containing 130 grams of ripe Cavendish banana. Fifty epithelial cells per cheek scraping sample were examined with epi-fluorescent microscopy after staining with the lipophilic fluorescent dye Nile red. Results: Cells collected before banana ingestion (BI) showed no evidence of epi-fluorescence, but the large majority of cells after BI displayed red epi-fluorescence indicative of PL. The diagram (mean data from 8 subjects) shows that the intensity of epi-fluorescence, was largely retained 6 hours after BI. Conclusion: Retention of ingested PL on epithelial surfaces may enable PL to exert a pharyngeal patency promoting action throughout an entire night which may prove to be of value in the treatment of obstructive sleep apnoea

Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100

Most genetic defects that arrest B-cell development in the bone marrow present early in life with agammaglobulinemia, whereas incomplete antibody deficiency is usually associated with circulating B cells. We report 3 related individuals with a novel for

Immunomodulation of the natural killer cell phenotype and response during HCV infection

Hepatitis C virus (HCV) infection develops into chronic hepatitis in over two-thirds of acute infections. While current treatments with direct-acting antivirals (DAAs) achieve HCV eradication in >95% of cases, no vaccine is available and re-infection can readily occur. Natural killer (NK) cells represent a key cellular component of the innate immune system, participating in early defence against infectious diseases, viruses, and cancers. When acute infection becomes chronic, however, NK cell function is altered. This has been well studied in the context of HCV, where changes in frequency and distribution of NK cell populations have been reported. While activating receptors are downregulated on NK cells in both acute and chronic infection, NK cell inhibiting receptors are upregulated in chronic HCV infection, leading to altered NK cell responsiveness. Furthermore, chronic activation of NK cells following HCV infection contributes to liver inflammation and disease progression through enhanced cytotoxicity. Consequently, the NK immune response is a double-edged sword that is a significant component of the innate immune antiviral response, but persistent activation can drive tissue damage during chronic infection. This review will summarise the role of NK cells in HCV infection, and the changes that occur during HCV therapy

Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100

Most genetic defects that arrest B-cell development in the bone marrow present early in life with agammaglobulinemia, whereas incomplete antibody deficiency is usually associated with circulating B cells. We report 3 related individuals with a novel form of severe B-cell deficiency associated with partial persistence of serum immunoglobulin arising from a missense mutation in NFKB2. Significantly, this point mutation results in a D865G substitution and causes a failure of p100 phosphorylation that blocks processing to p52. Severe B-cell deficiency affects mature and transitional cells, mimicking the action of rituximab. This phenotype appears to be due to disruption of canonical and noncanonical nuclear factor κB pathways by the mutant p100 molecule. These findings could be informative for therapeutics as well as immunodeficiency

Fungal inositol pyrophosphate IP7 is crucial for metabolic adaptation to the host environment and pathogenicity

Inositol pyrophosphates (PP-IPs) comprising inositol, phosphate, and pyrophosphate (PP) are essential for multiple functions in eukaryotes. Their role in fungal pathogens has never been addressed. Cryptococcus neoformans is a model pathogenic fungus causing life-threatening meningoencephalitis. We investigate the cryptococcal kinases responsible for the production of PP-IPs (IP7/IP8) and the hierarchy of PP-IP importance in pathogenicity. Using gene deletion and inositol polyphosphate profiling, we identified Kcs1 as the major IP6 kinase (producing IP7) and Asp1 as an IP7 kinase (producing IP8). We show that Kcs1-derived IP7 is the most crucial PP-IP for cryptococcal drug susceptibility and the production of virulence determinants. In particular, Kcs1 kinase activity is essential for cryptococcal infection of mouse lungs, as reduced fungal burdens were observed in the absence of Kcs1 or when Kcs1 was catalytically inactive. Transcriptome and carbon source utilization analysis suggested that compromised growth of the KCS1 deletion strain (Δkcs1 mutant) in the low-glucose environment of the host lung is due to its inability to utilize alternative carbon sources. Despite this metabolic defect, the Δkcs1 mutant established persistent, low-level asymptomatic pulmonary infection but failed to elicit a strong immune response in vivo and in vitro and was not readily phagocytosed by primary or immortalized monocytes. Reduced recognition of the Δkcs1 cells by monocytes correlated with reduced exposure of mannoproteins on the Δkcs1 mutant cell surface. We conclude that IP7 is essential for fungal metabolic adaptation to the host environment, immune recognition, and pathogenicity

Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility

Abstract Background Genome wide association studies have identified > 200 susceptibility loci accounting for much of the heritability of multiple sclerosis (MS). Epstein-Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS. The molecular and immunological basis for this has not been established. Infected B cell proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. Methods We have investigated transcriptomes of B cells and EBV-infected B cells at Latency III (LCLs) and identified MS risk genes with altered expression on infection and with expression levels associated with the MS risk genotype (LCLeQTLs). The association of LCLeQTL genomic burden with EBV phenotypes in vitro and in vivo was examined. The risk genotype effect on LCL proliferation with CD40 stimulation was assessed. Results These LCLeQTL MS risk SNP:gene pairs (47 identified) were over-represented in genes dysregulated between B and LCLs (p < 1.53 × 10−4), and as target loci of the EBV transcription factor EBNA2 (p < 3.17 × 10−16). Overall genetic burden of LCLeQTLs was associated with some EBV phenotypes but not others. Stimulation of the CD40 pathway by CD40L reduced LCL proliferation (p < 0.001), dependent on CD40 and TRAF3 MS risk genotypes. Both CD40 and TRAF3 risk SNPs are in binding sites for the EBV transcription factor EBNA2, with expression of each correlated with EBNA2 expression dependent on genotype. Conclusions These data indicate targeting EBV may be of therapeutic benefit in MS

Autoantibodies, routine and novel markers of neuroinflammation in people with atypical psychiatric disease

Background: Increasingly, the immune system is recognized as participating in the pathophysiology of psychiatric disease. There is renewed interest in biomarkers identifying immune activation. Methods: We measured serum and cerebral spinal fluid (CSF) autoantibodies with other routine and novel markers of neuroinflammation, including CSF cytokines in patients with atypical psychiatric (AP) disease who were referred by their psychiatrist. Their results were compared with cohorts of non-inflammatory (NI) controls, viral infectious controls and patients with autoimmune encephalitis. Results: Thirty-five AP patients were enrolled (29 females; 6 males), alongside 18 NI controls. Six AP patients had first episode psychosis, 7 had depression, 3 had schizophrenia. Others had a mix of both psychotic and mood disorder features, making their disease difficult to classify. Ten patients had a history of autoimmune disease and 11 a family history of autoimmunity.Low-mid titre (1:80-1:640) anti-nuclear antibodies (ANAs) without associated positive extractable nuclear antigen antibodies were noted in 20 patients. The predominant pattern was speckled (17/20, 85%); other patterns were mitotic spindle apparatus (2) or homogenous and speckled (2). One patient had a high titre 1:2560 speckled ANA associated anti-SSa/Ro60 antibodies and high thyroperoxidase antibodies (900IU/mL; normal 5 monocytes), 5 had raised CSF protein (>0.45g/L), 3 had CSF restricted oligoclonal bands and 13 had raised CSF neopterin (>20nm/L).CSF cytokines: granulocyte-macrophage colony-stimulating factor, and interferon gamma were associated with AP patients. A subset of patients (10) had at least one CSF cytokine beyond 4 standard deviations of the NI cohort.Our data supports more extensive investigation of patients presenting with psychiatric disease across a broad diagnostic spectrum. Further study is needed to validate these results