Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease among the elderly. To understand pathogenesis and to test therapies, animal models that faithfully reproduce key pathological PD hallmarks are needed. As a prelude to developing a model of PD, we tested the tropism, efficacy, biodistribution, and transcriptional impact of canine adenovirus type 2 (CAV-2) vectors in the brain of Microcebus murinus, a nonhuman primate that naturally develops neurodegenerative lesions. We show that introducing helper-dependent (HD) CAV-2 vectors results in long-term, neuron-specific expression at the injection site and in afferent nuclei. Although HD CAV-2 vector injection induced a modest transcriptional response, no significant adaptive immune response was generated. We then generated and tested HD CAV-2 vectors expressing LRRK2 (leucine-rich repeat kinase 2) and LRRK2 carrying a G2019S mutation (LRRK2G2019S), which is linked to sporadic and familial autosomal dominant forms of PD. We show that HD-LRRK2G2019S expression induced parkinsonian-like motor symptoms and histological features in less than 4 months

Genetic Variations in IL28B and Allergic Disease in Children

Environmental changes affecting the relationship between the developing immune system and microbial exposure have been implicated in the epidemic rise of allergic disease in developed countries. While early developmental differences in T cell function are well-recognised, there is now emerging evidence that this is related to developmental differences in innate immune function. In this study we sought to examine if differences associated with innate immunity contribute to the altered immune programming recognised in allergic children. Here, we describe for the first time, the association of carriage of the T allele of the tagging single nucleotide polymorphism rs12979860 3 kb upstream of IL28B, encoding the potent innate immune modulator type III interferon lambda (IFN-λ3), and allergy in children (p = 0.004; OR 4.56). Strikingly, the association between rs12979860 genotype and allergic disease is enhanced in girls. Furthermore, carriage of the T allele at rs12979860 correlates with differences in the pro-inflammatory profile during the first five years of life suggesting this contributes to the key differences in subsequent innate immune development in children who develop allergic disease. In the context of rising rates of disease, these immunologic differences already present at birth imply very early interaction between genetic predisposition and prenatal environmental influences

IL28B genetic variations are associated with high sustained virological response (SVR) of interferon-α plus ribavirin therapy in Taiwanese chronic HCV infection

Chronic hepatitis C virus (HCV) infection patients exhibit different sustained virological responses (SVRs) following the treatment with pegylated interferon-α (IFN-α) and ribavirin. Genome-wide association studies consistently linked SVR of IFN-α-based therapy to the IL28B single-nucleotide polymorphisms (SNPs) on chromosome 19q.13 in various populations. This study was undertaken to investigate the association of IL28B SNPs with SVR in a cohort of Taiwanese chronic HCV patients. Ten SNPs of IL28B were genotyped in 728 chronic HCV patients and 960 healthy controls. Genotype distributions, allele frequencies and haplotypes were tested for SVR and susceptibility in Taiwanese chronic HCV patients. Non-genotype 1 infection (adjusted P=3.3 × 10−12, odds ratio (OR) 0.179; 95% confidence interval (CI): 0.110–0.290) and low HCV viral load (<400 000 IU ml–1) (adjusted P=3.5 × 10−9, OR 0.299; 95% CI: 0.200–0.446) were two major factors identified for high SVR. Notably, eight IL28B SNPs including previously described disease-associated SNPs (Trend test P=0.005) were significantly associated with SVR. Our data indicate that IL28B polymorphisms are the essential contributing factors for high SVR in Taiwanese chronic HCV patients. Combination of virus genotyping and host genetic data may be used to select the optimal treatment regimes in IFN-based therapy

The Cell Adhesion Molecule “CAR” and Sialic Acid on Human Erythrocytes Influence Adenovirus In Vivo Biodistribution

Although it has been known for 50 years that adenoviruses (Ads) interact with erythrocytes ex vivo, the molecular and structural basis for this interaction, which has been serendipitously exploited for diagnostic tests, is unknown. In this study, we characterized the interaction between erythrocytes and unrelated Ad serotypes, human 5 (HAd5) and 37 (HAd37), and canine 2 (CAV-2). While these serotypes agglutinate human erythrocytes, they use different receptors, have different tropisms and/or infect different species. Using molecular, biochemical, structural and transgenic animal-based analyses, we found that the primary erythrocyte interaction domain for HAd37 is its sialic acid binding site, while CAV-2 binding depends on at least three factors: electrostatic interactions, sialic acid binding and, unexpectedly, binding to the coxsackievirus and adenovirus receptor (CAR) on human erythrocytes. We show that the presence of CAR on erythrocytes leads to prolonged in vivo blood half-life and significantly reduced liver infection when a CAR-tropic Ad is injected intravenously. This study provides i) a molecular and structural rationale for Ad–erythrocyte interactions, ii) a basis to improve vector-mediated gene transfer and iii) a mechanism that may explain the biodistribution and pathogenic inconsistencies found between human and animal models

Interferon-α and -β differentially regulate osteoclastogenesis: Role of differential induction of chemokine CXCL11 expression

In humans, type I interferon (IFN) is a family of 17 cytokines, among which the α subtypes and the β subtype are differentially expressed. It has been suggested that IFN-β activates a specific signaling cascade in addition to those activated by all type I IFNs. Nevertheless, no true biological relevance for a differential activity of α and β IFN subtypes has been identified so far. Because type I IFNs are critical for the regulation of osteoclastogenesis in mice, we have compared the effect of IFN-α2 and IFN-β on the differentiation of human monocytes into osteoclasts. Primary monocytes undergoing osteoclastic differentiation are highly and equally sensitive to both α2 and β IFNs as determined by measuring the induction levels of several IFN-stimulated genes. However, IFN-β was 100-fold more potent than the α2 subtype at inhibiting osteoclastogenesis. Expression profiling of the genes differentially regulated by IFN-α2 and IFN-β in this cellular system revealed the chemokine CXCL11 as the only IFN-induced gene differentially up-regulated by IFN-β. We show that recombinant CXCL11 by itself inhibits osteoclastic differentiation. These results indicate that autocrine-acting CXCL11 mediates, at least in part, the regulations of osteoclastogenesis by type I IFNs

Mesenteric B cells centrally inhibit CD4(+) T cell colitis through interaction with regulatory T cell subsets

Inflammatory bowel disease reflects an aberrant mucosal CD4(+) T cell response to commensal enteric bacteria. In addition to regulatory T cell subsets, recent studies have revealed a protective role of B cells in murine CD4(+) T cell colitis, but the relationship of their action to T cell immunoregulation is unknown. Here we report that mesenteric lymph node (MLN) B cells protect mice from colitis induced by Gαi2(–/–) CD4(+) T cells. Protection required the transfer of both B cells and CD8α(+) T cells; neither cell type alone was sufficient to inhibit CD4(+) T cell-mediated colitis. Similar results were also observed in colitis induced by CD4(+)CD45RB(hi) T cells. Immunoregulation was associated with localization of B cells and expansion of CD4(–)CD8(–) CD3(+)NK1.1(+) T cells in the secondary lymphoid compartment, as well as expansion of CD4(+)CD8α(+) T cells in the intestinal intraepithelial compartment. MLN B cells from Gαi2(–/–) mice were deficient in a phenotypic subset and failed to provide cotransfer colitis protection. These findings indicate that protective action of B cells is a selective trait of MLN B cells acquired through a Gαi2-dependent developmental process and link B cells with the formation of regulatory T cells associated with mucosal immune homeostasis