HHV-6 IN MULTIPLE SCLEROSIS: A POSSIBLE TRIGGER OF AUTOIMMUNE DISEASE

Background. Multiple sclerosis (MS) is predominantly regarded as an autoimmune disease in which viral infections could represent a trigger in genetically susceptible individuals. There is a growing evidence about an involvement of Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) in MS aethiopatogenesis. Previous studies failed to give a definitive answer to this question mainly because they fell short in patient’s selection, timing, volume and source (blood and/or CFS) of the biological sample collected for the analysis. In addition, none of them utilized a fully controlled system of highly sensitive calibrated quantitative real-time PCR (cQPCR) applied separately to both biological fluids (plasma and CFS) and their cellular component (PBMC and CSF-derived cellular pellet) to discriminate between active or latent infection and therefore between a direct or indirect role of these viruses in the MS. Objective. To elucidate the role of HHV-6 and EBV in MS Methods. Paired samples of plasma and cerebral spinal fluid (CSF) from patients with clinically active MS (n=55) and from patients with heterogeneous set of inflammatory and non inflammatory neurological diseases (OND/OIND) were examined for HHV-6 and EBV DNA load; a control group of was examined. Furthermore, in a subgroup of 11 patients affected from active MS at disease, the presence of HHV-6 and EBV DNA was measured in the fluidic fraction (CSF supernatant and centrifuged plasma) and in their cellular counterpart (CSF-derived cellular pellets and PBMCs). Finally, plasma viremia was also analyzed in samples derived from four cohorts of healthy (n=111) and patients controls including subjects affected by Autoimmune connective tissue diseases (ACTD, n=115), patients suffering of Chronic Fatigue Syndrome (CFS, n=63), and HIV-seropositive subjects. By a complete panel of calibrated quantitative real-time PCR (cQPCR) assays for plasma viral load measurements and of the parallel QPCR assay for the determination of human genomic DNA content (CCR5 assay) were excluded potential errors introduced by contamination of plasma by bystander cell lysis and/or by the presence of chromosomally integrated HHV-6 (CIHHV-6). Results. Overall, 25/55 MS CSFs (45%) contained HHV-6 (20 samples; 36%) or EBV DNA (5 samples; 9%); by contrast, only 2/33 OND/OIND CSFs (6%) resulted positive for HHV-6 and none for EBV-DNA. Plasmatic levels of HHV-6 and EBV DNA resulted significantly increased in patients affected by MS when compared to a heterogeneous set of OID/OIND. Both findings are not easily explainable with an accidental contamination due to breakage of latently infected cells or by the presence of ciHHV-6 carriers. Therefore, the presence of HHV-6 DNA in CSF and in plasma of MS patients is most likely due to viral reactivation or to a destruction of infected cells occurring in the brain tissue. The significant increase in HHV-6 detection and viral load observed in plasma of a relevant proportion of OND/OIND (33%) and (ACTD, 27%) patients deserve further investigation. Interestingly, the presence of HHV-6 DNA was detected in 5/11 clarified CSF supernatants. In one instances CSF viremia was accompanied also by cell-associated DNAemia in the absence of both plasma and PBMCs detectable viral load, suggesting the occurrence of a selective accumulation in the brain of HHV-6 infected cell. In other 4 patients the concomitant finding of HHV-6 DNA load in clarified CSF and plasma cell-free samples in the absence of detectable PBMCs (except for one with only 20 GEq/106 cells) and CSF-cellular load suggests the possibility of a sistemic infection as pathogenetic mechanism. Conversely, the concomitant presence of EBV in CSF derived cellular pellets associated to absence of plasma viremia suggest the EBV bystander damage hypothesis to CNS. Conclusions. These data are compatible with the hypothesis that HHV-6 may act as a pathogenic factor predisposing patients to the development of MS

Possible role of human herpesvirus 6 as a trigger of autoimmune disease

Human herpesvirus 6 (HHV-6) infection is common and has a worldwide distribution. Recently, HHV-6A and HHV-6B have been reclassified into two distinct species based on different biological features (genetic, antigenic, and cell tropism) and disease associations. A role for HHV-6A/B has been proposed in several autoimmune disorders (AD), including multiple sclerosis (MS), autoimmune connective tissue diseases, and Hashimoto's thyroiditis. The focus of this review is to discuss the above-mentioned AD associated with HHV-6 and the mechanisms proposed for HHV-6A/B-induced autoimmunity. HHV-6A/B could trigger autoimmunity by exposing high amounts of normally sequestered cell antigens, through lysis of infected cells. Another potential trigger is represented by molecular mimicry, with the synthesis of viral proteins that resemble cellular molecules, as a mechanism of immune escape. The virus could also induce aberrant expression of histocompatibility molecules thereby promoting the presentation of autoantigens. CD46-HHV-6A/B interaction is a new attractive mechanism proposed: HHV-6A/B (especially HHV-6A) could participate in neuroinflammation in the context of MS by promoting inflammatory processes through CD46 binding. Although HHV-6A/B has the ability to trigger all the above-mentioned mechanisms, more studies are required to fully elucidate the possible role of HHV-6A/B as a trigger of AD. © 2013 Francesco Broccolo et al

Possible Role of Human Herpesvirus 6 as a Trigger of Autoimmune Disease

Human herpesvirus 6 (HHV-6) infection is common and has a worldwide distribution. Recently, HHV-6A and HHV-6B have been reclassified into two distinct species based on different biological features (genetic, antigenic, and cell tropism) and disease associations. A role for HHV-6A/B has been proposed in several autoimmune disorders (AD), including multiple sclerosis (MS), autoimmune connective tissue diseases, and Hashimoto's thyroiditis. The focus of this review is to discuss the above-mentioned AD associated with HHV-6 and the mechanisms proposed for HHV-6A/B-induced autoimmunity. HHV-6A/B could trigger autoimmunity by exposing high amounts of normally sequestered cell antigens, through lysis of infected cells. Another potential trigger is represented by molecular mimicry, with the synthesis of viral proteins that resemble cellular molecules, as a mechanism of immune escape. The virus could also induce aberrant expression of histocompatibility molecules thereby promoting the presentation of autoantigens. CD46-HHV-6A/B interaction is a new attractive mechanism proposed: HHV-6A/B (especially HHV-6A) could participate in neuroinflammation in the context of MS by promoting inflammatory processes through CD46 binding. Although HHV-6A/B has the ability to trigger all the above-mentioned mechanisms, more studies are required to fully elucidate the possible role of HHV-6A/B as a trigger of AD

Possible Role of Human Herpesvirus 6 as a Trigger of Autoimmune Disease

Human herpesvirus 6 (HHV-6) infection is common and has a worldwide distribution. Recently, HHV-6A and HHV-6B have been reclassified into two distinct species based on different biological features (genetic, antigenic, and cell tropism) and disease associations. A role for HHV-6A/B has been proposed in several autoimmune disorders (AD), including multiple sclerosis (MS), autoimmune connective tissue diseases, and Hashimoto's thyroiditis. The focus of this review is to discuss the above-mentioned AD associated with HHV-6 and the mechanisms proposed for HHV-6A/B-induced autoimmunity. HHV-6A/B could trigger autoimmunity by exposing high amounts of normally sequestered cell antigens, through lysis of infected cells. Another potential trigger is represented by molecular mimicry, with the synthesis of viral proteins that resemble cellular molecules, as a mechanism of immune escape. The virus could also induce aberrant expression of histocompatibility molecules thereby promoting the presentation of autoantigens. CD46-HHV-6A/B interaction is a new attractive mechanism proposed: HHV-6A/B (especially HHV-6A) could participate in neuroinflammation in the context of MS by promoting inflammatory processes through CD46 binding. Although HHV-6A/B has the ability to trigger all the above-mentioned mechanisms, more studies are required to fully elucidate the possible role of HHV-6A/B as a trigger of AD

Modulation of gene expression in Kaposi's sarcoma-associated herpesvirus-infected lymphoid and epithelial cells

Aim: To evaluate the gene expression changes that occur soon after the active infection of two susceptible cell types with human herpesvirus 8 (HHV-8). Materials & methods: The expression profile of 282 human genes involved in the inflammatory process was investigated in HHV-8 A1 or C3 subtype-infected and mock-infected human epithelial cells and lymphoid cells. Results: The HHV-8-induced transcriptional profiles in the epithelial and lymphoid cells were very different. A robust increase in the expression was found in genes belonging to different categories, especially the categories of inflammation response and signal transduction. Conclusion: These results indicate that during early infection, HHV-8 induces a variety of cell type-specific processes, thus providing infection signatures useful as potential targets for therapeutic intervention

Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases

Background: Little is known about the involvement of human herpesviruses 6 and 7 (HHV-6 and HHV-7) in autoimmune connective tissue diseases (ACTD). Objective: To determine the prevalence of active infection with HHV-6 and HHV-7 in patients with ACTD. Study design: The presence and quantity of HHV-6 DNA was determined by quantitative real-time PCR in a cross-sectional study of serum, peripheral blood mononuclear cells, and tissues obtained from 58 ACTD patients and 38 healthy subjects (HS). Specific anti-HHV-6 antibody titer was also measured. Results: HHV-6 serum viremia occurred in a significantly higher proportion of ACTD patients compared to HS [26/58 (44.8%) vs. 1/38 (2.6%), p = 0.001] with the highest reactivation frequency [7/10 (70%)] observed in patients with scleroderma. Moreover, HHV-6 in serum was associated with ACTD activity (22/38 vs. 4/20, p < 0.05). Higher titers of HHV-6 antibodies were found in ACTD patients than in HS, although HHV-6 seroprevalence among patients with ACTD and HS was similar. HHV-7 viremia was not detected in any patients or HS controls. Conclusion: The frequent reactivation of HHV-6 in scleroderma and other ACTD, especially when active, suggests that HHV-6 may play a role in the pathogenesis of these diseases. \ua9 2009 Elsevier B.V. All rights reserved

Efficacy and safety of capsule endoscopy in octogenarian patients: a retrospective study

Background: Life expectancy and the number of ultra-octogenarians increased significantly, thus making crucial the appropriateness of several endoscopic procedures in elderly patients. The aim of our study was to provide a retrospective analysis of the efficacy and safety of capsule endoscopy in patients aged over 80 years. Methods: In this single-centre study, 900 patients underwent capsule endoscopy between 2002 and 2015 for different indications; of these 106 patients aged ≥80 years (group A) and 99 patients aged 40-60 years (control group B) were retrospectively selected. Results: Occult gastrointestinal bleeding accounted for 62.1% of all indications for capsule endoscopy in group B, compared to 95.2% in group A (p&lt;0.001). Although not statistically significant, the diagnostic yield was higher in group A (71%) vs. group B (62%). The percentages of reaching the cecum and the median gastric transit time were uniform within the two groups. In contrast, small bowel transit time was longer in group A vs. B. Small bowel preparation was similar in the two groups. The exam was generally well tolerated in both groups, with capsule aspiration being one of the main adverse events, which occurred in two elderly patients. Conclusions: Our data expand previous findings confirming that capsule endoscopy can be performed safely even in very old patients and show that the diagnostic yield is similar to that of younger patients