Guilherme Sciascia do Olival

Genomic analysis of ERVWE2 locus in patients with multiple sclerosis: absence of genetic association but potential role of human endogenous retrovirus type W elements in molecular mimicry with myelin antigen

Human endogenous retroviruses (HERVs) arise from ancient infections of the host germline cells by exogenous retroviruses, constituting 8% of the human genome. Elevated level of envelope transcripts from HERVs-W has been detected in CSF, plasma and brain tissues from patients with Multiple Sclerosis (MS), most of them from Xq22.3, 15q21.3, and 6q21 chromosomes. However, since the locus Xq22.3 (ERVWE2) lack the 5′ LTR promoter and the putative protein should be truncated due to a stop codon, we investigated the ERVWE2 genomic loci from 84 individuals, including MS patients with active HERV-W expression detected in PBMC. In addition, an automated search for promoter sequences in 20 kb nearby region of ERVWE2 reference sequence was performed. Several putative binding sites for cellular cofactors and enhancers were found, suggesting that transcription may occur via alternative promoters. However, ERVWE2 DNA sequencing of MS and healthy individuals revealed that all of them harbor a stop codon at site 39, undermining the expression of a full-length protein. Finally, since plaque formation in central nervous system (CNS) of MS patients is attributed to immunological mechanisms triggered by autoimmune attack against myelin, we also investigated the level of similarity between envelope protein and myelin oligodendrocyte glycoprotein (MOG). Comparison of the MOG to the envelope identified five retroviral regions similar to the Ig-like domain of MOG. Interestingly, one of them includes T and B cell epitopes, capable to induce T effector functions and circulating Abs in rats. In sum, although no DNA substitutions that would link ERVWE2 to the MS pathogeny was found, the similarity between the envelope protein to MOG extends the idea that ERVEW2 may be involved on the immunopathogenesis of MS, maybe facilitating the MOG recognizing by the immune system. Although awaiting experimental evidences, the data presented here may expand the scope of the endogenous retroviruses involvement on MS pathogenesis.

Multiple sclerosis and herpesvirus interaction

Multiple sclerosis is the most common autoimmune inflammatory demyelinating disease of the central nervous system, and its etiology is believed to have both genetic and environmental components. Several viruses have already been implicated as triggers and there are several studies that implicate members of the Herpesviridae family in the pathogenesis of MS. The most important characteristic of these viruses is that they have periods of latency and exacerbations within their biological sanctuary, the central nervous system. The Epstein-Barr, cytomegalovirus, human herpesvirus 6 and human herpesvirus 7 viruses are the members that are most studied as being possible triggers of multiple sclerosis. According to evidence in the literature, the herpesvirus family is strongly involved in the pathogenesis of this disease, but it is unlikely that they are the only component responsible for its development. There are probably multiple triggers and more studies are necessary to investigate and define these interactions.

Medication withdrawal may be an option for a select group of patients in relapsing-remitting multiple sclerosis

This article describes the clinical and radiological evolution of a stable group of patients with relapsing-remitting multiple sclerosis that had their disease-modifying therapy (DMT) withdrawn. Forty patients, which had made continuous use of one immunomodulator and had remained free of disease for at least 5 years, had their DMT withdrawn and were observed from 13 to 86 months. Out of the followed patients, 4 (10%) patients presented with new attacks. In addition to these patients, 2 (5%) patients had new lesions revealed by magnetic resonance imaging that did not correspond to clinical attacks. Despite these results, the difficult decision to withdraw medication requires careful analysis. Withdrawal, however, should not be viewed as simply the suspension of treatment because these patients should be evaluated periodically, and the immunomodulators should be readily reintroduced if new attacks occur. Nonetheless, medication withdrawal is an option for a select group of patients.

Clinical predictors of response to immunomodulators for multiple sclerosis

OBJECTIVES To determine, based on clinical criteria, the proportion of multiple sclerosis (MS) patients responsive to immunomodulators (RI) and nonresponsive to immunomodulators (NRI), and to ascertain whether clinical and epidemiological data differs between RI and NRI patient groups. METHODS Patients were assessed on rate of exarcerbations per year, for the period before and after commencement of treatment. The RI and NRI groups were compared for several clinical and epidemiological characteristics. DISCUSSION AND CONCLUSION A total of 31.4% of the patients were nonresponders to the immunomodulatory treatment. The main predictors of immunomodulatory response were early diagnostic and commencement of therapy and high rate of annual exacerbations prior to treatment. Given the arsenal of medication options available for MS management, screening potential candidates for different therapeutic approaches are critical to optimize evolution of patients with the disease.

Validation and cross-cultural adaptation of sexual dysfunction modified scale in multiple sclerosis for Brazilian population

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). These patients suffer from various comorbidities, including sexual dysfunction (SD). The lesions of MS may affect regions of the CNS along the pathway of sexual response. The Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19) is a scale that assesses sexual dysfunction. Adapt and validate the MSISQ-19 to Brazilian patients with MS. 204 individuals were evaluated, 134 patients with MS and 70 healthy persons for the control group. It was determined reproducibility, validity, internal consistency and sensitivity of the MSISQ-19-BR. Among patients with MS, 54.3% of male and 71.7% of female presented some kind of SD. In the control group the results were 12.5% and 19.5%, respectively. The MSISQ-19-BR is reproducible, reliable and valid for the Brazilian population and may be used as a tool for assessing the impact of sexual dysfunction in patients with MS.

Characterization of the first symptoms of multiple sclerosis in a Brazilian center: cross-sectional study

CONTEXT AND OBJECTIVE: Multiple sclerosis (MS) is a chronic, immune-mediated and degenerative central nervous system (CNS) disease with well-established diagnostic criteria. Treatment can modify the course of the disease. The objective of this study was to describe the initial symptoms of multiple sclerosis in a Brazilian medical center. DESIGN AND SETTING: Descriptive study, conducted in a Brazilian reference center for multiple sclerosis treatment. METHODS: Data on 299 patients with confirmed diagnoses of MS were included in the study. Their medical files were evaluated and the data were analyzed. RESULTS: The most common symptom involved the cranial nerves (50.83%) and unifocal manifestation was presented by the majority of this population (73.91%). The mean time between the first symptom and the diagnosis was 2.84 years. Unifocal symptoms correlated with longer time taken to establish the diagnosis, with an average of 3.20 years, while for multifocal symptoms the average time taken for the diagnosis was 1.85 years. Unifocal onset was related to greater diagnostic difficulty. CONCLUSIONS: MS is a heterogeneous disease and its initial clinical manifestation is very variable.

Central Nervous System Antiretroviral High Penetration Therapy

The use of highly effective antiretroviral therapy penetration into the central nervous system has indicators for input that can eradicate the viral load in cerebrospinal fluid, thereby helping to prevent the virus compartmentalization in CNS and hence probably preventing perpetuation of these cognitive disorders associated with HIV virus. However, more studies are necessary in order to demonstrate the real pathophysiological mechanisms associated with these effects and to prove that the side effects associated with the use of these medications are harmless than the benefits achieved on the neurocognitive disorders.

Validation survey of the impact of urinary incontinence (IIQ-7) and inventory of distress urogenital (UDI-6) – the short scales – in patients with multiple sclerosis

Cross-cultural adaptation and validation of the Impact Questionnaire of Urinary Incontinence (IIQ-7) and Urogenital Distress Inventory (UDI-6) - short scale - in the Brazilian population with multiple sclerosis. The IIQ-7 and UDI-6 were translated into Portuguese, called IIQ-7-BR and UDI-6-BR. The questionnaires were administered in 211 individuals selected randomly. Of these, 140 had MS according to McDonald criteria and 71 were included in the control group. In both questionnaires, the Cronbachs alpha coefficient was above 0.7. The IIQ-7-BR showed 94.31% concordance between the evaluated studies and UDI-6-BR, 93.33%. Thus, the instruments of this study were presented according to the standards proposed by the Instrument Review Criteria, reliability, validity and sensitivity, maintaining the original scales characteristics.

Neuropsychological assessment in HTLV-1 infection: Preliminary data of a comparative study among depression and neurocognitive impairments

The main goal of this present study was to investigate the presence of neurocognitive impairments in patients infected by HTLV-1 virus, associated with different levels of depression. 24 of the 150 patients regularly attending in the outpatient clinic of the HTLV at the Institute of Infectious Diseases Emilio Ribas, were evaluated by the team of neuropsychology and distributed into two groups, one with a degree of depression minimal / mild (n = 14) and another with moderate / severe (n = 10). 17 were female and 7 male, mean age 53.33 (SD = 11.9), average schooling 6.6 years (SD = 2.8), and 16 had HAM / TSP. The study delineation was observational and descriptive. The instruments used were the Beck Depression Inventory (BDI) to assess the depression state, plus a Neuropsychological Battery with the aim of assessing memory, language, and intellectual and motor functioning, attentional and executive functions. Data were analyzed by calculating averages, frequency and Spearman correlation (SPSS21v). The patients with higher levels of depression had worse performance on several cognitive domains. However, the neurocognitive deficits with statistical significance were found in tasks that assessed auditory memory post interference (p = 0.035) , sustained attention (p = 0.020) and motor speed (dominant hand = p = 0.02 / non-dominant hand p = 0.030). These preliminary data suggest that the neurocognitive performance may be related to the degree of depression and not solely the action of virus in the central nervous system.

Lack of evidence of ERVWE1/Xq22.3 involvement in MRSV transcripts detected in Multiple Sclerosis patients

HERV are viral ‘fossils’ that constitute 8% of the human genome and have been implicated in both health and disease conditions. HERV-W/MRSV (Multiple Sclerosis associated RetroVirus) RNA has been detected in patients with multiple sclerosis. MS is a chronic inflammatory disease of the central nervous system of unknown cause, resulting in demyelization and axonal degeneration. MSRV is defined by different transcripts, which vary in their source. Recently, it was described that most of MSRV/Env transcripts from MS patients derived from Xq22.3, 15q21.3 and 6q21. Although the genomic Xq22.3 MRSV/Env is truncated due to a stop codon (TGA) at position 39, the transcripts associated harbored a tryptophan (TGG) instead. Thus, to evaluate if a polymorphism at this position could be involved with full expression of this locus in MS patients we sequenced 1085bp of the ERVWE1/Xq22.3 from 15 MS patients of different ethnic origins and different clinical presentations and 14 health individuals. We found that all MS individuals harbor a stop codon at position 39, undermining the expression of a full-length ENV protein. No additional aminoacid substitution was found in both groups. Also, since there is no LTR flanking this gene, we performed an automated search for promoter sequences in 10kb nearby region. We found several putative binding sites for cellular co-factors and enhancers, suggesting that transcription may occur via alternative promoters. Altogether, the findings suggest that transcripts associated to ERVWE1/Xq22.3 previously detected may be artificially generated, possible due to in vitro recombination between this locus and other active ERVW/Env.