Gene microarray analysis of multiple sclerosis lesions

Multiple sclerosis (MS) is an autoimmune disease affecting central nervous system white matter. The cause is unknown. It is thought that environmental factors trigger an immune response against myelin antigens in a genetically susceptible individual. The characteristic lesion of MS seen in the brain is a plaque, an area of inflammation, demyelination and glial reaction or ‘sclerosis’. Several recent studies have examined gene expression in MS plaques on a large scale using microarray technology. The involvement of immune-related genes has been confirmed, and many new genes not previously associated with MS lesions have been identified. Microarray studies are significant in identifying potential new targets for therapy.     

Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis

Multiple sclerosis (MS) is an inflammatory central nervous system (CNS) disorder characterized by T cell mediated demyelination. In MS, prolonged T cell survival and increased T cell proliferation have been linked to disease relapse and progression. Recently, the autophagy related gene 5 (Atg5) has been shown to modulate T cell survival. In this study, we examined the expression of Atg5 using both a mouse model of autoimmune demyelination as well as blood and brain tissues from MS cases. Quantitative real-time PCR analysis of RNA isolated from blood samples of experimental autoimmune encephalomyelitis (EAE) mice revealed a strong correlation between Atg5 expression and clinical disability. Analysis of protein extracted from these cells confirmed both upregulation and post-translational modification of Atg5 the latter of which was positively correlated with EAE severity. Analysis of RNA extracted from T cells isolated by negative selection, indicated that Atg5 expression was significantly elevated in individuals with active relapsing-remitting MS compared to non-diseased controls. Brain tissue sections from relapsing-remitting MS cases examined by immunofluorescent histochemistry suggested that encephalitogenic T cells are a source of Atg5 expression in MS brain samples. Together these data suggest that increased T cell expression of Atg5 may contribute to inflammatory demyelination in MS.     

Genome-wide association studies in multiple sclerosis: lessons and future prospects

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease with complex aetiology. A haplotype within the major histocompatibility region is the major risk factor for MS, but despite clear evidence for a genetic component additional risk variants were not identified until the recent advent of genome-wide association studies (GWAS). At present, 10 GWAS have been conducted in MS, and together with follow-up studies these have confirmed 16 loci with genome-wide significance. Many of these common risk variants are located at or near genes with central immunological functions and the majority are associated with other autoimmune diseases. However, evidence from pathway analyses on more modestly associated variants also supports the involvement of neurological genes. Although the mechanisms by which the associated variants exert their effects are still poorly understood, some have been shown to correlate with expression of nearby genes. Further studies are required to define the functionally relevant variants in the identified regions and to investigate their effects at the molecular and cellular level. Finally, many genetic risk variants for MS remain to be identified. In order to expose some of the loci with more modest effects, a GWAS in nearly 10,000 MS patients has recently been completed.     

Insight from genome-wide association studies in rheumatoid arthritis and multiple sclerosis

Autoimmune diseases are caused by multiple genes and environmental effects. In addition, genetic contributions and the number of associated genes differ among different diseases and ethnic populations. Genome-wide association studies (GWAS) on rheumatoid arthritis (RA) and multiple sclerosis (MS) show that these diseases share many genetic factors. Recently, in addition to the major histocompatibility complex (MHC) gene, other genetic loci have been found to be associated with the risk for autoimmune diseases. This review focuses on the search for genetic variants that influence the susceptibility to RA and MS as typical autoimmune diseases and discusses the future of GWAS.     

Apoptosis in multiple sclerosis

Several recent studies have provided evidence that apoptosis is an important feature in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. Apoptosis presumably plays a role in the immunoregulation via activation-induced T-cell death (AICD) and in local processes of tissue damage. In this review the dual role of apoptosis in the MS pathogenesis and its relevance regarding therapeutic concepts is discussed.     

Glatiramer acetate treatment normalizes deregulated microRNA expression in relapsing remitting multiple sclerosis

The expression of selected microRNAs (miRNAs) known to be involved in the regulation of immune responses was analyzed in 74 patients with relapsing remitting multiple sclerosis (RRMS) and 32 healthy controls. Four miRNAs (miR-326, miR-155, miR-146a, miR-142-3p) were aberrantly expressed in peripheral blood mononuclear cells from RRMS patients compared to controls. Although expression of these selected miRNAs did not differ between treatment-naïve (n = 36) and interferon-beta treated RRMS patients (n = 18), expression of miR-146a and miR-142-3p was significantly lower in glatiramer acetate (GA) treated RRMS patients (n = 20) suggesting that GA, at least in part, restores the expression of deregulated miRNAs in MS.     

Modeling the distribution of new MRI cortical lesions in multiple sclerosis longitudinal studies

Objective

Recent studies have shown the relevance of the cerebral grey matter involvement in multiple sclerosis (MS). The number of new cortical lesions (CLs), detected by specific MRI sequences, has the potential to become a new research outcome in longitudinal MS studies. Aim of this study is to define the statistical model better describing the distribution of new CLs developed over 12 and 24 months in patients with relapsing-remitting (RR) MS.

Methods

Four different models were tested (the Poisson, the Negative Binomial, the zero-inflated Poisson and the zero-inflated Negative Binomial) on a group of 191 RRMS patients untreated or treated with 3 different disease modifying therapies. Sample size for clinical trials based on this new outcome measure were estimated by a bootstrap resampling technique.

Results

The zero-inflated Poisson model gave the best fit, according to the Akaike criterion to the observed distribution of new CLs developed over 12 and 24 months both in each treatment group and in the whole RRMS patients group adjusting for treatment effect.

Conclusions

The sample size calculations based on the zero-inflated Poisson model indicate that randomized clinical trials using this new MRI marker as an outcome are feasible.     

Insulin counter-regulation in multiple sclerosis

Fasting hypoglycemia is frequently observed in patients with Multiple Sclerosis (S.M.) showing orthostatic hypotension and defective thermoregulation, although they never complicate in hypoglycemic coma. The aim of this study was to evaluate glucose homeostasis in S.M. patients. Both insular and counter-insular regulating mechanisms were investigated by determination of glucose, insulin, C-peptide and cortisol plasmatic levels during OGTT, and subsequently by evaluating glucagon plasmatic levels after arginine administration (30 g., i.v.). Our results suggest that the increased susceptibility of S.M. patients to undergo fasting hypoglycemia could be related to some alterations in counter-insular mechanisms, generally included among neurovegetative modifications in S.M. patients and probably due to orthosympathetic function impairment.     

Antigen-specific therapies in multiple sclerosis

Multiple sclerosis is the major neurological disease of young adults in the western world, affecting about 1 per 1,000. It is characterised by chronic or recurrent lesions of inflammatory damage in the white matter of the central nervous system. Within such lesions, the protective myelin sheath is stripped off axons by infiltrated macrophages which leads to impaired conductivity. The inflammatory process most likely starts by activation of helper T cells directed against local myelin antigens. Currently, efforts are directed at specifically blocking such myelin-reactive helper T cells in order to control the disease. In this chapter, immunological features of multiple sclerosis and the experimental animal model for the disease, experimental allergic encephalomyelitis, are discussed. Next, an overview is presented on myelin antigens that have been suggested to play a role as target antigens in MS. Finally, strategies are discussed that are currently employed to selectively block the activation of T-cells reactive against myelin antigens.     

Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression

Reactive oxygen species (ROS) and subsequent oxidative damage may contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. ROS initiate lesion formation by inducing blood–brain barrier disruption, enhance leukocyte migration and myelin phagocytosis, and contribute to lesion persistence by mediating cellular damage to essential biological macromolecules of vulnerable CNS cells. Relatively little is known about which CNS cell types are affected by oxidative injury in MS lesions. Here, we show the presence of extensive oxidative damage to proteins, lipids, and nucleotides occurring in active demyelinating MS lesions, predominantly in reactive astrocytes and myelin-laden macrophages. Oxidative stress can be counteracted by endogenous antioxidant enzymes that confer protection against oxidative damage. Here, we show that antioxidant enzymes, including superoxide dismutase 1 and 2, catalase, and heme oxygenase 1, are markedly upregulated in active demyelinating MS lesions compared to normal-appearing white matter and white matter tissue from nonneurological control brains. Particularly, hypertrophic astrocytes and myelin-laden macrophages expressed an array of antioxidant enzymes. Enhanced antioxidant enzyme production in inflammatory MS lesions may reflect an adaptive defense mechanism to reduce ROS-induced cellular damage.     

Beta-interferon for multiple sclerosis

Interferon beta is widely used as first-line treatment for relapsing remitting multiple sclerosis (RRMS). Several products are marketed world-wide, and biosimilar products are emerging. Interferon beta reduces relapse rates by about 1/3, and reduces the appearance of new MRI lesions by about 2/3, and some studies have shown reduced disability progression, and reduced rates of brain atrophy. The mechanism of action of interferon beta in MS is poorly understood, partly due to the complex nature of the biological response to interferon injections. This mini-review succinctly summarizes clinical effects, possible mechanism of action, physiochemical properties of the different interferon products, issues related to immunogenicity, and biomarkers of the interferon beta response, and proposes important unresolved issues for future research.