Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis.

Objective: Intrathecal synthesis of immunoglobulin gamma (IgG) synthesis is frequently observed in patients with multiple sclerosis (MS). Whereas the extent of intrathecal IgG synthesis varies largely between patients, it remains rather constant in the individual patient over time. The aim of this study was to identify common genetic variants associated with the IgG index as a marker of intrathecal IgG synthesis in MS.

CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation.

Background: The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS) compartment during neuroinflammation. To determine which chemokines/cytokines show the strongest association with a humoral immune response in the cerebrospinal fluid (CSF), we measured their concentrations in the CSF and correlated them with immune cell subsets and antibody levels.

Methods: Cytokine/chemokine concentrations were measured in CSF and serum by ELISA in patients with non-inflammatory neurological diseases (NIND, n = 20), clinically isolated syndrome (CIS, n = 30), multiple sclerosis (MS, n = 20), Lyme neuroborreliosis (LNB, n = 8) and patients with other inflammatory neurological diseases (OIND, n = 30).

The role of the Epstein-Barr virus receptor CD21 in multiple sclerosis.

Multiple Sclerosis (MS) is characterised by a chronic inflammation and demyelination of brain and spinal cord with a yet unknown aetiology. Based on multiple epidemiological and immunological studies, which suggest a role of Epstein-Barr virus (EBV) infection in the pathogenesis of MS, we investigated CD21 (CR2, complement receptor type 2), which serves as the EBV receptor. Serum concentrations of soluble CD21 receptor (sCD21) were determined in MS patients and controls.

Single-nucleotide polymorphisms in HLA- and non-HLA genes associated with the development of antibodies to interferon-β therapy in multiple sclerosis patients.

Interferons-β (IFN-β) are the most widely used immunomodulatory drugs for treatment of multiple sclerosis (MS). The development of neutralizing antibodies (NABs) against IFN-β is one of the main reasons for treatment failure. While formulation of the drug has a proven impact on the development of NABs, the genetic predisposition to develop antibodies is poorly understood.

Influence of the HLA-DRB1 genotype on antibody development to interferon beta in multiple sclerosis.

Objective: To determine relevant HLA-DRB1 alleles associated with the susceptibility of anti-interferon beta antibody development in a large patient cohort.

Design: In a case-control study, HLA-DRB1 genotyping was performed in a discovery cohort (n = 268) and a validation cohort (n = 825).

Setting: Patients were recruited in Germany by primary care physicians and neurologists and were mainly of Northern European heritage.

Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS.

Background: The oral immunomodulator fingolimod (FTY720) has recently been shown to be highly effective in relapsing-remitting multiple sclerosis (MS). Fingolimod is a functional antagonist of the sphingosine-1-phosphate receptor 1 and thereby inhibits sphingosine-1-phosphate-dependent lymphocyte egress from secondary lymphoid tissues, resulting in a pronounced lymphopenia in the peripheral blood. The effects of fingolimod treatment on the CSF of patients with MS have not been studied so far.

Population structure and HLA DRB1 1501 in the response of subjects with multiple sclerosis to first-line treatments.

Using retrospectively collected outcome data for treatment naïve subjects treated with either glatiramer acetate (GA) (n=332) or interferon beta (IFN β) (n=424), we replicated the lack of a significant difference in efficacy between these treatments. Further, for both treatments, we observed a decline in the hazard of a relapse over time, which may suggest the existence of subsets of subjects with differential responses to each treatment. The HLA DRB1 1501 allele explained some of this variation in event-free survival while on GA, and we found suggestive evidence that an IRF8 polymorphism influences event-free survival in IFN β treated subjects.

Interictal alterations of cytokines and leukocytes in patients with active epilepsy.

Background: Involvement of the innate immune system in the pathogenesis of epilepsies has been suggested but possible interactions between the immune system and human epilepsy remain unclear. We analyzed the interictal immuno-phenotype of leukocyte subsets and proinflammatory cytokine profiles in epileptic patients and correlated them with the epilepsy syndrome.

Methods: 101 patients with active focal or generalized epilepsy were prospectively included and compared to 36 healthy controls.

EASY-HIT: HIV full-replication technology for broad discovery of multiple classes of HIV inhibitors.

HIV replication assays are important tools for HIV drug discovery efforts. Here, we present a full HIV replication system (EASY-HIT) for the identification and analysis of HIV inhibitors. This technology is based on adherently growing HIV-susceptible cells, with a stable fluorescent reporter gene activated by HIV Tat and Rev.

More CLEC16A gene variants associated with multiple sclerosis.

Objectives: Recently, associations of several single-nucleotide polymorphisms (SNPs) within the CLEC16A gene with multiple sclerosis (MS), type-I diabetes, and primary adrenal insufficiency were reported.

Methods: We performed linkage disequilibrium (LD) fine mapping with 31 SNPs from this gene, searching for the region of highest association with MS in a German sample consisting of 603 patients and 825 controls.

Results: Four SNPs located in intron 19 of the CLEC16A gene were found associated.

Aquaporin 4 antibody positive central nervous system autoimmunity and multiple sclerosis are characterized by a distinct profile of antibodies to herpes viruses.

Viral infections are implicated in the onset and promotion of autoimmunity in genetically predisposed individuals. In this study, immune response patterns to herpes viruses were compared in aquaporin 4 (AQP4) antibody positive central nervous system (CNS) autoimmunity and multiple sclerosis (MS). Serum samples of patients with AQP4 antibody positive CNS autoimmunity (n=52), relapsing-remitting MS (n=55) and controls including non-autoimmune neurological disorders and healthy individuals (n=56) were tested for IgG antibodies to herpes viruses 1-6 (HSV-1, HSV-2, VZV, EBV, CMV, HHV-6) using commercial ELISA kits.

The role of antibodies in multiple sclerosis.

B cells, plasma cells, and antibodies are commonly found in active central nervous system (CNS) lesions in patients with multiple sclerosis (MS). B cells isolated from CNS lesions as well as from the cerebrospinal fluid (CSF) show signs of clonal expansion and hypermutation, suggesting their local activation. Plasma blasts and plasma cells maturating from these B cells were recently identified to contribute to the development of oligoclonal antibodies produced within the CSF, which remain a diagnostic hallmark finding in MS.

Evidence for VAV2 and ZNF433 as susceptibility genes for multiple sclerosis.

In a genome wide association study consisting of 592 German multiple sclerosis (MS) patients and 825 controls we were able to replicate the association of the HLA region with MS independently of previous case control studies. No SNPs outside the HLA region reached a genome wide level of significance. Nevertheless, we found suggestive evidence for an association of MS with variants in two new genes, the VAV2 gene and the gene for ZNF433.

Antibody responses to EBV and native MOG in pediatric inflammatory demyelinating CNS diseases.

Background: Epstein-Barr virus (EBV) has been discussed as a possible causative agent in inflammatory demyelinating diseases of the CNS. Cross-reactivity between EBV and myelin proteins has been proposed as a potential mechanism by which EBV could elicit an autoimmune response targeting the CNS. Recently, high antibody titers to native myelin oligodendrocyte glycoprotein (nMOG) were found in children affected by the first inflammatory demyelinating event.

The antibody response to oligodendrocyte specific protein in multiple sclerosis.

The role of autoantibody responses in pathogenesis or progression of multiple sclerosis (MS) remains controversial. This is partly because the methods that can distinctly identify pathogenic antibody reactivities targeting native membrane proteins from the reactivities that originate as an epiphenomenon in such disease are just emerging. Oligodendrocyte specific protein (OSP or claudin-11) is a candidate autoantigen in MS and CSF reactivity towards OSP has been reported in MS patients.

Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease.

Objective: Myelin oligodendrocyte glycoprotein (MOG) is a candidate target antigen in demyelinating diseases of the central nervous system (CNS). Although MOG is encephalitogenic in different animal models, the relevance of this antigen in human autoimmune diseases of the CNS is still controversial.

Methods: We investigated the occurrence and biological activity of antibodies to native MOG (nMOG) in 47 children during a first episode of CNS demyelination (acute disseminated encephalomyelitis [ADEM], n = 19 and clinical isolated syndrome [CIS], n = 28) by a cell-based bioassay.

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.

Depletion of B lymphocytes from cerebral perivascular spaces by rituximab.

Background: Rituximab is a recombinant chimeric monoclonal antibody against CD20, a molecule expressed on cells of the B-cell lineage. A phase 2 clinical trial recently provided strong evidence of the beneficial effects of rituximab in patients with relapsing-remitting multiple sclerosis. We and other investigators previously demonstrated that rituximab therapy depletes B lymphocytes from peripheral blood and cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis.

Enhancement of chemokine expression by interferon beta therapy in patients with multiple sclerosis.

Background: Interferon beta has been approved for the treatment of multiple sclerosis (MS). It is believed that immunomodulatory rather than antiviral activity of interferon beta is responsible for disease amelioration. The impact of interferon beta on the chemoattraction of immune cells has not been fully addressed.

Etiology and site of temporal lobe epilepsy influence postictal cytokine release.

Inflammatory mechanisms are involved in the pathogenesis of epilepsy. Vice versa, immune functions are regulated by the brain. We measured postictal changes in serum levels of the immuno-modulating cytokines IL-1beta, IL-6 and TNFalpha in patients with well-defined temporal lobe epilepsy (TLE) and determined modifying factors.

Varicella zoster virus is not a disease-relevant antigen in multiple sclerosis.

Herpesvirions and varicella zoster virus (VZV) DNA were recently reported in all 15 cerebrospinal fluid (CSF) samples from patients with relapsing-remitting multiple sclerosis (MS) obtained within 1 week of exacerbation. Using identical electron microscopic and polymerase chain reaction techniques, including additional primer sets representing different regions of the VZV genome, we found no herpesvirions or VZV DNA in MS CSF or acute MS plaques. Although enzyme-linked immunosorbent assay analysis demonstrated a higher titer of VZV antibody in MS CSF than in inflammatory control samples, recombinant antibodies prepared from clonally expanded MS CSF plasma cells did not bind to VZV.

Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy.

Objective: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy.