IFN-beta pharmacogenomics in multiple sclerosis.

Multiple sclerosis (MS) is a condition of the CNS marked by inflammation and neurodegeneration. Interferon (IFN)-beta was the first, and still is the main, immunomodulatory treatment for MS. Its clinical efficacy is limited, and a proportion of patients, ranging between 20-55%, do not respond to the therapy.

Orchestrating innate immune responses in multiple sclerosis: molecular players.

Innate immunity is the body's first line of defense against foreign pathogens. Although adaptive immune responses have for long time been considered to play important roles in the etiopathogenesis of autoimmune disorders such as multiple sclerosis (MS), evidence exists that adaptive immunity is not acting in isolation but rather in conjunction with components of the innate immune system. In fact, innate immune responses influence the nature of adaptive immune responses, and many components of innate immunity are used by adaptive immunity as effectors.

The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis.

Genome-wide association studies (GWAS) have revealed that different diseases share susceptibility variants. Twelve single-nucleotide polymorphisms (SNPs) previously associated with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls. Three SNPs were found to be associated with MS: rs1678542 in KIF5A (P=0.

B cell expression of the inhibitory Fc gamma receptor is unchanged in early MS.

Expression of the inhibitory Fcgamma receptor IIB (FcgammaRIIB) has emerged as a late checkpoint during peripheral B cell development which prevents autoreactive memory B lymphocytes from becoming long-lived plasma cells. Decreased expression of FcgammaRIIB or non-functional FcgammaRIIB variants are associated with the development of autoimmune tissue inflammation. We determined the expression profile of FcgammaRIIB in peripheral blood cells in treatment-naïve patients with early MS.

Genetic association of CASP8 polymorphisms with primary progressive multiple sclerosis.

We investigated caspase 8 (CASP8) as a candidate gene for multiple sclerosis (MS) susceptibility. Three SNPs (rs2037815, rs12990906 and rs1035140) were genotyped in 546 MS patients and 547 controls. For SNP rs2037815, GG homozygosity was associated with primary progressive multiple sclerosis (PPMS) when compared with relapse-onset MS and controls.

Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis.

In most patients with multiple sclerosis, the disease initiates with a first attack or clinically isolated syndrome. At this phase, magnetic resonance imaging is an important predictor of conversion to multiple sclerosis. With the exception of oligoclonal bands, the role of other biomarkers in patients with clinically isolated syndrome is controversial.

Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis.

Objective: The aims of the study were to determine the immune responses to candidate viral triggers of multiple sclerosis (MS) in patients with clinically isolated syndromes (CISs), and to evaluate their potential value in predicting conversion to MS.

Methods: Immune responses to Epstein-Barr virus (EBV), human herpesvirus 6, cytomegalovirus (HCMV), and measles were determined in a cohort of 147 CIS patients with a mean follow-up of 7 years and compared with 50 demographically matched controls.

Results: Compared with controls, CIS patients showed increased humoral (p < 0.

Antiviral immune response in patients with multiple sclerosis and healthy siblings.

The objective of this study was to determine the immune responses to candidate viral triggers of multiple sclerosis in patients and healthy siblings raised in the same family household. Virus antigen-specific IgG responses to Epstein-Barr virus-derived gene products as well as to human herpersvirus-6, human cytomegalovirus, and measles virus were evaluated in 25 multiple sclerosis patients and compared with 49 healthy full-siblings. IgG responses to the latent Epstein-Barr virus-encoded nuclear antigen-1 (EBNA1) were selectively increased in individuals with multiple sclerosis compared with their unaffected siblings.

Do multimodal evoked potentials add information to MRI in clinically isolated syndromes?

The role of multimodal evoked potentials (MMEPs) in establishing multiple sclerosis (MS) diagnosis and prognosis has diminished nowadays. The objective of this article is to evaluate whether MMEPs add information to MRI in identifying patients with higher risk of relapse or development of disability after a clinically isolated syndrome (CIS). Patients who underwent visual, somato-sensory and brainstem auditory evoked potentials (EPs) were identified from a cohort of consecutive CIS.

A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking.

There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in CSF are being used in clinical practice. One of the most critical factors in CSF biomarker research is the inadequate powering of studies because of the lack of sufficient samples that can be obtained in single-center studies.

Clinical features of CIS of the brainstem/cerebellum of the kind seen in MS.

Recognition of multiple sclerosis (MS) attacks relies mostly on clinical assessment. However, their definition based on McDonald criteria refers mostly to timing and when dealing with clinical features is rather ambiguous: "..

Neurofilament ELISA validation.

Background: Neurofilament proteins (Nf) are highly specific biomarkers for neuronal death and axonal degeneration. As these markers become more widely used, an inter-laboratory validation study is required to identify assay criteria for high quality performance.

Methods: The UmanDiagnostics NF-light (R)enzyme-linked immunoabsorbent assays (ELISA) for the neurofilament light chain (NfL, 68kDa) was used to test the intra-assay and inter-laboratory coefficient of variation (CV) between 35 laboratories worldwide on 15 cerebrospinal fluid (CSF) samples.

Predicting responders to therapies for multiple sclerosis.

Therapies for relapsing-remitting multiple sclerosis (RRMS) are only partially effective, and, in most patients receiving such treatment, clinical activity persists. Accurately assessing the treatment response to disease-modifying agents enables non-responder patients to be identified at an early stage into therapy. Patients can then be switched to another, potentially more effective, therapy before too much neurological damage has occurred.

A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis.

The effect of interferon-beta in multiple sclerosis is modest and many patients do not respond to treatment. To date, no single biomarker reliably correlates with responsiveness to interferon-beta in multiple sclerosis. In the present study, genome-wide expression profiling was performed in peripheral blood mononuclear cells from 47 multiple sclerosis patients treated with interferon-beta for a minimum of 2 years and classified as responders and non-responders based on clinical criteria.

Differential susceptibility to apoptosis of CD4+T cells expressing CCR5 and CXCR3 in patients with MS.

We aimed to evaluate differences in the susceptibility to apoptosis of CD4+CCR5+ and CD4+CXCR3+T cells between MS patients (N=41) and controls (N=15) 6 days after activation of peripheral blood cells with anti-CD3 antibodies and 24 h following stimulation with anti-Fas antibodies. Susceptibility to anti-CD3 induced activation-induced cell death (AICD) and Fas-mediated apoptosis was selectively increased in CD4+CCR5+T cells compared with CD4+CCR5- and CD4+CXCR3-/+T cells. Compared with controls, CD4+CCR5+T cells from patients with primary progressive MS (PPMS) were more resistant to anti-CD3-induced AICD and anti-Fas-induced apoptosis determined with the mitochondrial probe DiOC(6) (3-3'-dihexyloxacarboyanine iodide).

Genome-wide scan of 500,000 single-nucleotide polymorphisms among responders and nonresponders to interferon beta therapy in multiple sclerosis.

Background: Interferon beta is 1 of 2 first-line treatments for relapsing-remitting multiple sclerosis (MS). However, not all patients respond to interferon beta therapy, and to date there is a lack of surrogate markers that reliably correlate with responsiveness to interferon beta therapy in MS.

Objective: To identify allelic variants that influence response to interferon beta therapy in patients with MS.

Measures in the first year of therapy predict the response to interferon beta in MS.

Background And Objective: Several criteria for treatment response to interferon beta (IFNbeta) have been proposed, although there is no consensus among different investigators. Hence, the aim of this study was to investigate magnetic resonance imaging (MRI) and clinical predictors of response during the first 12 months of therapy.

Methods: This is a prospective and longitudinal study of relapsing-remitting multiple sclerosis (RRMS) patients treated with IFNbeta.

Plasma levels of 15d-PGJ are not altered in multiple sclerosis.

Background: The 15-deoxi delta prostaglandin J(2) (15d-PGJ(2)) is a peroxisome proliferator-activated receptor-gamma agonist with potent anti-inflammatory properties. It has been suggested that 15d-PGJ(2) may modulate multiple sclerosis (MS).

Methods: Here, we investigated the plasma levels of 15d-PGJ(2) by enzyme-linked immunoassay in 28 healthy controls and 140 MS patients [30 patients with primary-progressive MS, 28 patients with secondary-progressive MS, and 82 patients with relapsing-remitting MS (28 patients during clinical remission, 25 patients during relapse, and 29 treated with interferon-beta - IFN-beta)].

Genetic association between polymorphisms in the BTG1 gene and multiple sclerosis.

In the present study, we investigated the B-cell translocation gene 1 (BTG1) as a candidate for multiple sclerosis (MS) susceptibility. BTG1 is a member of a family of genes involved in the apoptotic process. We genotyped two SNPs of the BTG1 gene (rs731652 and rs12694) in 550 MS patients and 548 controls.

United Europeans for development of pharmacogenomics in multiple sclerosis network.

Multiple sclerosis (MS) is a chronic inflammatory, disabling disease of the CNS. A recent study has estimated the annual cost of MS in Europe at euro12.5 billion.

HLA class I and II alleles and response to treatment with interferon-beta in relapsing-remitting multiple sclerosis.

In the present study, we investigated the influence of HLA class I and class II genes in the response to interferon-beta (IFNbeta) in multiple sclerosis (MS) patients. HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 DNA typing was performed by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) in a cohort of 149 relapsing-remitting MS patients classified into IFNbeta responders (n=74) and non-responders (n=75) based on stringent clinical criteria. Distribution of HLA class I and class II alleles individually and the HLA-DR2 haplotype was similar between responders and non-responders to treatment.

Plasma chitotriosidase activity in multiple sclerosis.

A recent study has shown that chitotriosidase (Chit) may play a role in the pathogenesis of multiple sclerosis (MS). Plasma Chit activity was investigated in 219 untreated MS patients and 160 healthy controls (HC) by means of a fluorometric enzyme activity assay. Chit activity was also measured in a subgroup of 46 patients following treatment with interferon-beta (IFNbeta).

Changes in matrix metalloproteinases and their inhibitors during interferon-beta treatment in multiple sclerosis.

Matrix metalloproteinases (MMPs) and tissue inhibitors (TIMPs) play a key role in the pathogenesis of multiple sclerosis (MS) and have been proposed as biomarkers of response to therapy. We investigated serum levels of several MMPs and TIMPs in 43 relapsing-remitting MS (RRMS) patients undergoing interferon-beta (IFN-b) treatment and classified as responders and non-responders based on clinical criteria. Levels of MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-2 were determined by ELISA before treatment and after 3, 6, 12, and 24 months of therapy.

Identification of a novel risk locus for multiple sclerosis at 13q31.3 by a pooled genome-wide scan of 500,000 single nucleotide polymorphisms.

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with an important genetic component and strongest association driven by the HLA genes. We performed a pooling-based genome-wide association study of 500,000 SNPs in order to find new loci associated with the disease. After applying several criteria, 320 SNPs were selected from the microarrays and individually genotyped in a first and independent Spanish Caucasian replication cohort.