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.

HLA DR2b-binding peptides from human endogenous retrovirus envelope, Epstein-Barr virus and brain proteins in the context of molecular mimicry in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is as yet poorly understood. Multiple mechanisms in different disease stages are responsible for immunopathology in MS. HLA Class II DR2b (DRB1*1501 ß, DRA1*0101 α) is the strongest genetic risk factor for MS. Remnants of ancient retroviruses in the human genome, termed human endogenous retroviruses (HERV), and Epstein-Barr virus (EBV) infection are also associated with MS. In silico analyses of human endogenous retroviral envelope (HERV env) proteins and three myelin proteins that are principal targets of an autoimmune response in MS showed sequence similarities between potential TH epitopes within pairs of viral and myelin peptides predicted to bind HLA DR2b. This led to the proposal that such molecular mimicry may potentially trigger MS. HLA DR2b binding characteristics of previously identified peptides from the three myelin proteins and HERV env proteins as well as additional in silico predicted peptides from other encephalitogenic brain proteins and EBV proteins were studied to further investigate molecular mimicry. Peptides containing potential TH epitopes from the myelin oligodendrocyte glycoprotein and HERV env previously predicted to bind HLA DR2b as well as other pertinent potential HLA DR2b-restricted TH epitopes were confirmed to bind HLA DR2b molecules. Molecular modelling of HLA DR2b in complex with high affinity peptides derived from MOG and HERV env proteins showed that their binding could occur in a similar manner to a HLA DR2b-binding peptide containing a known TH epitope. A structurally related pair of peptides predicted to bind HLA DR2b from the EBV protein EBNA1 and ß synuclein, a brain protein implicated in MS, were also shown to similarly bind HLA DR2b. The findings justify investigating CD4+ T cell responses to the identified peptides.

Potential molecular mimicry between the human endogenous retrovirus W family envelope proteins and myelin proteins in multiple sclerosis.

Multiple sclerosis is an autoimmune disease caused by the destruction of the myelin sheath in the central nervous system. The major target molecules for the immune response are the myelin basic protein, myelin oligodendrocyte glycoprotein and proteolipid protein but the aetiology of the disease is as yet poorly understood. The HLA Class II allele DRB1*1501 in particular as well as DRB5*0101 and the expression of human endogenous retroviral envelope proteins have been linked to multiple sclerosis but the molecular mechanisms relating these remain to be elucidated. We hypothesised that cross-reactive peptide epitopes in retroviral envelope proteins and myelin proteins that can be presented by the two Class II DR molecules may play a role in initiating multiple sclerosis. Sequence homologies between retroviral envelope and myelin proteins and in silico predictions of peptides derived from them that are able to bind to the two Class II alleles were examined to test the hypothesis. The results support the hypothesis that molecular mimicry in peptide epitopes from envelope proteins of the HERV-W family of endogenous retroviruses and myelin proteins is possible and could potentially trigger multiple sclerosis. Mimicry between syncytin-1, a HERV-W envelope protein that is expressed during placentation, and myelin proteins may also explain the higher prevalence of multiple sclerosis in women. Experiments to test the ability of the identified peptide epitopes to activate TH cells are required to confirm the present findings.

CD8+ lymphocytes and apoptosis in typical and atypical medullary carcinomas of the breast.

Medullary breast carcinoma (MBC) is a form of ductal invasive carcinoma (DIC) characterized by an abundant infiltration of the tumour by lymphocytes. MBC has been classified histologically into typical medullary carcinoma (TMC) and atypical medullary carcinoma (AMC), with TMC having a better prognosis than AMC and other DIC. The distribution of CD8+ lymphocytes within tumour nests and lymphocyte tracts, and apoptosis in lymphocytes and tumour cells within tumour nests, were studied in archived formalin fixed and paraffin embedded tissues of TMC and AMC. CD8+ lymphocytes tend to accumulate along the margins of lymphocyte tracts that adjoin tumour nests. There were significantly more CD8+ lymphocytes within tumour nests of TMC than AMC. TMC also tended to have more CD8+ lymphocytes within lymphocyte tracts than AMC. Apoptosis of lymphocytes in contact with tumour cells and of tumour cells in contact with lymphocytes was observed in both AMC and TMC within tumour nests but differences in the proportions of apoptotic tumour cells and lymphocytes between the two tumour types could not be established. The findings are consistent with CD8+ cytotoxic lymphocyte-mediated immunity contributing to the more favourable prognosis for TMC compared to AMC.

Cervical cancer in Brunei Darussalam.

INTRODUCTION: Cervical cancer caused by the human papilloma virus (HPV) is a common cancer in women. There is no published data on the recent incidence of cervical dysplasia, cervical cancer and genital warts caused by the different types of HPVs in Brunei Darussalam. METHODS: A cross-sectional, retrospective study was conducted utilising data from patients diagnosed with cervical cancer during the period 2005-2009 in Brunei Darussalam. The varying incidences of different types of cervical lesions among various ethnic and age groups, and in the overall population, were determined. RESULTS: The mean age-standardised incidence of invasive cervical cancer during the five-year period was 24.9 per 100,000 women per year (95% confidence interval [CI] 21.7, 28.1). Age-specific invasive cervical cancer incidence peaked in the age group 45-59 years. Chinese females tended to have a higher incidence of invasive cervical cancer (28.2 per 100,000 women per year; 95% CI 17.8, 38.7) than Malay females (20.6 per 100,000 women per year; 95% CI 17.1, 24.2), while other ethnic groups in Brunei Darussalam had a significantly lower incidence (6.5 per 100,000 women per year; 95% CI 3.0, 10.0). CONCLUSION: The results suggest that Brunei Darussalam has a relatively higher incidence of cervical cancer compared to its neighbouring countries. The findings support the need for more comprehensive screening, public education programmes and vaccination against HPV in the country.

Possible significance of differences in proportions of cytotoxic T cells and B-lineage cells in the tumour-infiltrating lymphocytes of typical and atypical medullary carcinomas of the breast.

Medullary carcinoma (MC) of the breast is a high grade carcinoma that has a relatively favourable prognosis compared to atypical medullary carcinoma (AMC) and other more common breast carcinomas. In a retrospective study in Brunei Darussalam of all available biopsy samples, we compared the nature of the tumour-infiltrating lymphocytes (TILs) in MC and AMC in relation to recorded tumour characteristics. CD4, CD8, CD20, CD25, CD45RO, and CD56 and common tumour biomarkers were detected immunohistochemically. The 11 cases of MC had no nodal metastases and survived without relapse, suggesting good tumour control. In contrast, 7 cases of nodal metastases and 1 relapse were observed in 12 AMCs. Although not statistically significant, there was a tendency for a greater proportion of AMCs to express the Her2/neu oncogene. Higher proportions of CD45RO+ and CD8+ cells, and lower levels of CD20+ cells, were characteristic of TILs in MC compared to AMC. The ratio of CTL to B-lineage cells in TILs in both tumours considered together was inversely related to the expression of HER2/neu and the presence of nodal metastases. The findings suggest that CTLs, rather than antibodies, may give better tumour control in MC relative to AMC. We propose that a comparison of the cellular, molecular and immunological characteristics of MC and AMC, as a paired model system, in a multi-centre investigation with a much larger number of samples will be valuable for better understanding mechanisms of tumour immunity.