Cumulative Roles for Epstein-Barr Virus, Human Endogenous Retroviruses, and Human Herpes Virus-6 in Driving an Inflammatory Cascade Underlying MS Pathogenesis.

Roles for viral infections and aberrant immune responses in driving localized neuroinflammation and neurodegeneration in multiple sclerosis (MS) are the focus of intense research. Epstein-Barr virus (EBV), as a persistent and frequently reactivating virus with major immunogenic influences and a near 100% epidemiological association with MS, is considered to play a leading role in MS pathogenesis, triggering localized inflammation near or within the central nervous system (CNS). This triggering may occur directly via viral products (RNA and protein) and/or indirectly via antigenic mimicry involving B-cells, T-cells and cytokine-activated astrocytes and microglia cells damaging the myelin sheath of neurons. The genetic MS-risk factor HLA-DR2b (DRB1*1501ß, DRA1*0101α) may contribute to aberrant EBV antigen-presentation and anti-EBV reactivity but also to mimicry-induced autoimmune responses characteristic of MS. A central role is proposed for inflammatory EBER1, EBV-miRNA and LMP1 containing exosomes secreted by viable reactivating EBV+ B-cells and repetitive release of EBNA1-DNA complexes from apoptotic EBV+ B-cells, forming reactive immune complexes with EBNA1-IgG and complement. This may be accompanied by cytokine- or EBV-induced expression of human endogenous retrovirus-W/-K (HERV-W/-K) elements and possibly by activation of human herpesvirus-6A (HHV-6A) in early-stage CNS lesions, each contributing to an inflammatory cascade causing the relapsing-remitting neuro-inflammatory and/or progressive features characteristic of MS. Elimination of EBV-carrying B-cells by antibody- and EBV-specific T-cell therapy may hold the promise of reducing EBV activity in the CNS, thereby limiting CNS inflammation, MS symptoms and possibly reversing disease. Other approaches targeting HHV-6 and HERV-W and limiting inflammatory kinase-signaling to treat MS are also being tested with promising results. This article presents an overview of the evidence that EBV, HHV-6, and HERV-W may have a pathogenic role in initiating and promoting MS and possible approaches to mitigate development of the disease.

Seasonal temperature is associated with Parkinson's disease prescriptions: an ecological study.

The aim of this study is to test what effect the weather may have on medications prescribed to treat Parkinson's disease. Twenty-three years of monthly time, series data was sourced from the Pharmaceutical Benefits Scheme (PBS) and the Bureau of Meteorology (BOM). Data were available for eight states and territories and their corresponding capital cities. The dependent variable was the aggregate levodopa equivalent dose (LED) for 51 Parkinson's medications identified on the PBS. Two explanatory variables of interest, temperature and solar exposure, were identified in the BOM data set. Linear and cosinor models were estimated with fixed and random effects, respectively. The prescribed LED was 4.2% greater in January and 4.5% lower in July. Statistical analysis showed that temperature was associated with the prescription of Parkinson medications. Our results suggest seasonality exists in Parkinson's disease symptoms and this may be related to temperature. Further work is needed to confirm these findings and understand the underlying mechanisms as a better understanding of the causes of any seasonal variation in Parkinson's disease may help clinicians and patients manage the disease more effectively.

Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort.

Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.

Th1 polarization of CD4+ T cells by Toll-like receptor 3-activated human microglia.

Toll-like receptors (TLRs) are expressed by human microglia and translate environmental cues into distinct activation programs. We addressed the impact of TLR ligation on the capacity of human microglia to activate and polarize CD4 T cell responses. As microglia exist under distinct states of activation, we examined both ramified and ameboid microglia isolated from adult and fetal CNS, respectively. In vitro, ligation of TLR3 significantly increased major histocompatibility complex and costimulatory molecule expression on adult microglia and induced high levels of interferon-alpha, interleukin-12p40, and interleukin-23. TLR4 and, in particular, TLR2 had a more limited capacity to induce such responses. Coculturing allogeneic CD4 T cells with microglia preactivated with TLR3 did not increase T cell proliferation above basal levels but consistently led to elevated levels of interferon-gamma secretion and Th1 polarization. Fetal microglial TLR3 responses were comparable; in contrast, TLR2 and TLR4 decreased major histocompatibility complex class II expression on fetal cells and reduced CD4 T cell proliferation to levels below those found in untreated cocultures. All 3 TLRs induced comparable interleukin-6 secretion by microglia. Our findings illustrate how activation of human microglia via TLRs, particularly TLR3, can change the profile of local CNS immune responses by translating Th1 polarizing signals to CD4 T cells.

Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections.

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) cause clinically important persistent infections. The effects of virus persistence on innate immunity, including NK cell responses, and the underlying mechanisms are not fully understood. We examined the frequency, phenotype, and function of peripheral blood CD3- CD56+ NK subsets in HIV+ and HCV+ patients and identified significantly reduced numbers of total NK cells and a striking shift in NK subsets, with a marked decrease in the CD56(dim) cell fraction compared to CD56(bright) cells, in both infections. This shift influenced the phenotype and functional capacity (gamma interferon production, killing) of the total NK pool. In addition, abnormalities in the functional capacity of the CD56(dim) NK subset were observed in HIV+ patients. The shared NK alterations were found to be associated with a significant reduction in serum levels of the innate cytokine interleukin 15 (IL-15). In vitro stimulation with IL-15 rescued NK cells of HIV+ and HCV+ patients from apoptosis and enhanced proliferation and functional activity. We hypothesize that the reduced levels of IL-15 present in the serum during HIV and HCV infections might impact NK cell homeostasis, contributing to the common alterations of the NK pool observed in these unrelated infections.