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Abstract: 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. In accordance with findings in other autoimmune disorders decreased sCD21 levels were found in MS patients. On ß-IFN treatment serum sCD21 concentrations further decreased. To explore the role of the CD21 gene for MS susceptibility and the altered CD21 levels in MS patients we performed exon sequencing of the CD21 gene. While we identified new single nucleotide polymorphism (SNP) and confirmed previously reported SNPs, none of the SNPs was associated with MS. Our findings demonstrate that sCD21 expression is altered in MS patients similar to other autoimmune diseases although no evidence was found for a specific role of the CD21 gene in MS. [Copyright &y& Elsevier]

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 noninflammatory 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). Albumin, IgG, IgA and IgM were measured by nephelometry. CSF immune cell subsets were determined by seven-color flow cytometry. Results: CXCL13 was significantly elevated in the CSF of all patient groups with inflammatory diseases. BAFF levels were significantly increased in patients with LNB and OIND. CXCL12 was significantly elevated in patients with LNB. B cells and plasmablasts were significantly elevated in the CSF of all patients with inflammatory diseases. CXCL13 showed the most consistent correlation with CSF B cells, plasmablasts and intrathecal Ig synthesis. Conclusions: CXCL13 seems to be the major determinant for B cell recruitment to the CNS compartment in different neuroinflammatory diseases. Thus, elevated CSF CXCL13 levels rather reflect a strong humoral immune response in the CNS compartment than being specific for a particular disease entity. [ABSTRACT FROM AUTHOR]

Abstract: 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. AQP4 antibody positive CNS autoimmunity cases most frequently had IgG responses to four viruses (38.5%), while presence of antibodies to three herpes viruses was most common in MS and controls (41.8% and 35.7%, respectively). Compared to MS, AQP4 positive cases had a significantly higher CMV seropositivity rate (P =0.003) and a lower prevalence of EBV antibodies (P =0.01). The analysis of immunoreactivity of samples above the diagnostic threshold revealed that in AQP4 positive CNS autoimmunity the IgG response to EBV (P <0.001) and VZV (P <0.01) was lower than in MS, whereas immununoreactivity to HSV-1 was higher than in controls (P <0.01). The distinct pattern of seroprevalence and immunoreactivity against herpes viruses in AQP4 positive CNS autoimmunity and MS provide further insights to the pathogenetical heterogeneity. Whether these findings reflect an epi-phenomenon of autoimmune disorders or indicate a disease-specific deregulated virus–host interaction needs to be examined in further studies. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Summary: 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-1β, IL-6 and TNFα in patients with well-defined temporal lobe epilepsy (TLE) and determined modifying factors. Serum levels of IL-1β, IL-6 and TNFα were quantified by ELISA at baseline as well as immediately, 1h and 24h after a complex partial (CPS) or secondary generalized tonic–clonic seizure (GTCS) during video-EEG monitoring in 25 patients suffering from temporal epilepsy. IL-6 increased by 51% immediately after the seizure (p <0.01) and remained elevated for 24h. This increase lacked in patients with hippocampal sclerosis (HS; n =16, mean increase 28%, p >0.5, vs. 112%, p <0.01 in patients without HS). IL-6 levels were higher after right-sided seizures as compared to left-sided seizures 24h after the seizure (8.7pg/mL vs. 3.4pg/mL, p <0.05). In patients taking valproate (VPA, n =9), the levels of IL-1β were higher as compared to patients not treated with VPA. The results suggest a relationship between the cytokine system and characteristics of TLE such as side and pathology. [Copyright &y& Elsevier]

The formation of antibodies to interferon-beta (IFN-β), a protein-based disease-modifying agent for multiple sclerosis (MS), is a problem in clinical practice. These antibodies may neutralize the biological effects of the protein drug, potentially decreasing its therapeutic effects. By high-resolution HLA class I and II typing we identified two HLA class II alleles associated with the development of antibodies to IFN-β. In two independent continuous and binary-trait association studies, HLA-DRB1 *0401 and HLA-DRB1 *0408 (odds ratio: 5.15)—but not other HLA alleles—were strongly associated with the development of binding and neutralizing antibodies to IFN-β. The associated HLA-DRB1 *04 alleles differ from nonassociated HLA-DRB1 *04 alleles by a glycine-to-valine substitution in position 86 of the epitope-binding alpha-helix of the HLA class II molecule. The peptide-binding motif of HLA-DRB1 *0401 and *0408 might promote binding and presentation of an immunogenic peptide, which may eventually breakTcell tolerance and facilitate antibody development to IFN-β. In summary, we identified genetic factors determining the immunogenicity of IFN-β, a protein-based disease-modifying agent for the treatment of MS. [ABSTRACT FROM AUTHOR]

Objective Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is frequently associated with intrathecal immunoglobulin synthesis and cerebrospinal fluid (CSF) pleocytosis, but little is known about the B-cell response in the CSF of these patients. In this study, we investigated the relation between virus load and the frequency and phenotype of B cells in the CSF of HIV-infected patients. Methods The distribution of T cells, B cells, short-lived plasmablasts, and long-lived plasma cells was analyzed by flow cytometry in CSF and peripheral blood of 33 patients with HIV infection compared with 12 patients with noninfectious CNS diseases. HIV RNA copy number in CSF and serum was quantified by kinetic polymerase chain reaction. Results B-cell and plasmablast levels were increased in the CSF of HIV-infected patients compared with patients with noninfectious CNS diseases. Whereas CSF B cells were found at similar frequency during early and late stages of HIV infection, plasmablasts were more prevalent in the CSF during early infection. Plasmablasts in the CSF correlated with intrathecal IgG synthesis and even stronger with HIV RNA copy numbers in CSF, in particular, in untreated, early HIV-infected individuals. Initiation of antiviral treatment in therapy-naive patients strongly decreased HIV copy numbers and plasmablasts in CSF. Interpretation Our findings demonstrate that HIV infection of the CNS triggers an early profound B-cell response, with plasmablasts serving as the main virus-related B-cell subset in the CSF. Ann Neurol 2007 [ABSTRACT FROM AUTHOR]

Abstract: Inflammatory diseases of the central nervous system (CNS) are characterized by cerebrospinal fluid (CSF) pleocytosis often involving the recruitment of B cells. Little is still known about B cells that are found in the CSF during neuroinflammation. To address the phenotype of these B cells, we studied the distribution of the major B cell subsets in peripheral blood (PB) and CSF of 25 patients with inflammatory diseases of the nervous system by flow cytometry. Six different B cell subsets were identified in PB and CSF according to the surface expression of IgM, IgD, CD27 and CD19. In all patients analysed, memory B cells outnumbered naïve B cells in the CSF, whereas naïve B cells were more prevalent in PB. The accumulation of memory B cells in the CSF was largely due to the recruitment of IgM−IgD− class switched memory B cells. The distribution of IgM+IgD+, IgM−IgD+, IgM+IgD− memory cells and immature cells did not differ significantly between CSF and PB. These findings demonstrate a selective recruitment of IgM−IgD− memory B cells to the CSF suggesting a specific role of these cells during neuroinflammation. [Copyright &y& Elsevier]

MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology. A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins. Also, CD8+ T cell responses to latent EBV proteins were higher in MS patients than in controls. In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS). Although the cause of MS is still uncertain, it is well accepted that both genetic and environmental factors are important for the development of disease. In this study, we focused on the Polio Virus Receptor (PVR) and Herpesvirus entry mediator B (HVEB) receptor genes, which are located on chromosome 19q13, a region previously linked to MS. Both receptors are expressed in the brain and immune system and play an important role for inter-cellular adhesion and entry of neurotropic viruses to the brain. We identified four new polymorphisms in the PVR gene, which were located in the promoter region and three different exons. All exonic polymorphisms altered the amino acid sequence of the receptor. No new polymorphisms were found in the HVEB gene, but we confirmed a previously identified intronic polymorphism. We analyzed the frequency of the polymorphisms by RFLP analysis in sporadic MS patients, MS families, and healthy controls and determined the surface expression of HVEB and PVR on peripheral blood monocytes. We did not find differences in the frequency of the polymorphisms or surface expression between MS patients and controls. Overall, our findings do not support a role of HVEB and PVR genes in the development of MS. [Copyright &y& Elsevier]

Sleeping sites are a potentially important resource for grey mouse lemurs since they are confronted with high daily temperature fluctuations and a high predation pressure. In order to determine the existence and degree of resource competition, sleeping site characteristics, locations, and usage patterns as well as sleeping group compositions were investigated in a 3 month field study in a dry deciduous forest of northwestern Madagascar. The daily sleeping sites of females were on average better insulated and safer than those of males. Males used more sleeping sites and changed the site more often than females. During the whole study, males slept alone, whereas the females formed stable sleeping groups in on average 83.7% of the days. Sex-specific differences in usage patterns might be explained by intersexual resource competition and female dominance and could possibly be related to differential parental investment of the sexes. The underlying study indicates that sleeping sites may be a restricted and defendable resource for grey mouse lemurs. The investigation gives new insights into the distribution patterns and social organization of this species. Am. J. Primatol. 46:77–84, 1998. © 1998 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

A correction to the article "HLA-DRBJ *Q4Q7 and HLA-DRBJ *0408 Are Strongly Associated with the Development of Antibodies against lnterferon-? Therapy in Multiple Sclerosis" that was published in July 2008 issue is presented.

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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. Within the CNS, antibody deposition is associated with complement activation and demyelination, indicating antigen recognition-associated effector function. While some studies indeed implied a disease-intrinsic and possibly pathogenic role of antibodies directed against components of the myelin sheath, no unequivocal results on a decisive target antigen within the CNS persisted to date. The notion of a pathogenic role for antibodies in MS is nevertheless empirically supported by the clinical benefit of plasma exchange in patients with histologic signs of antibody deposition within the CNS. Further, such evidence derives from the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In transgenic mice endogenously producing myelin-specific antibodies, EAE severity was substantially increased accompanied by enhanced CNS demyelination. Further, genetic engineering in mice adding T cells that recognize the same myelin antigen resulted in spontaneous EAE development, indicating that the coexistence of myelin-specific B cells, T cells, and antibodies was sufficient to trigger CNS autoimmune disease. In conclusion, various pathological, clinical, immunological, and experimental findings collectively indicate a pathogenic role of antibodies in MS, whereas several conceptual challenges, above all uncovering potential target antigens of the antibody response within the CNS, remain to be overcome. [Copyright &y& Elsevier]

Abstract: 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. We characterized the autoantibody response to OSP using sensitive cell based assays. In line with a previous report, higher antibody response to OSP 114–120 peptide and denatured protein was observed. However applying assays based on native OSP we did not observe any specific OSP response in MS patients. Our results demonstrate that anti-OSP antibodies do not recognise native glial OSP and may therefore rather represent an epiphenomenon in MS. [Copyright &y& Elsevier]

Abstract: Immunological phenomena may affect the course of focal epilepsy. We analyzed prospectively the pre- and postictal distribution of leukocyte subsets in epileptic patients. Methods: Twenty-two patients (age 36.6±10.8 years, 50% men) with temporal lobe epilepsy were included. Distribution of leukocyte subsets and serum levels of epinephrine were measured in peripheral blood immediately and 24 h after seizures and compared to baseline values. Results: In the immediate postictal state (10±6 min), we observed a significant relative increase of total leukocytes (42%, p =0.0004), neutrophil leukocytes (55%, p =0.0007), total lymphocytes (45%, p =0.0019), natural killer (NK) cells (104%, p =0.0017), and epinephrine (454%, p =0.0014). CD4+ T cells decreased by 13% (p =0.0113). These postictal changes remained significant considering only complex partial seizures (n =17). The alterations were more pronounced in patients with hippocampal sclerosis. Treatment with valproic acid (VPA) was accompanied by a greater postictal decrease of CD4+ T cells (25% compared to 5% in patients without VPA, p =0.041) while treatment with levetiracetam (LEV) correlated with a low postictal increase of NK-like T cells (4% versus 41%, p =0.016). Twenty-four hours after the seizures the alterations had resolved. Conclusion: Profound postictal changes in the immune cell composition of the peripheral blood may have been mediated by epinephrine release. The greater immune response in patients with mesial temporal lobe epilepsy due to hippocampal sclerosis may reflect a close relationship between mesial temporal structures and the sympathetic nerve system. VPA and LEV may have an impact on seizure induced immunological changes. [Copyright &y& Elsevier]

Borrelia burgdorferi may cause an acute infection of the central nervous system (CNS) that rarely leads to chronic disease. To characterize host immunity to B. burgdorferi in humans, we performed serial T cell receptor (TCR) variable β (TCRBV) chain analyses in blood and cerebrospinal fluid (CSF) samples from 10 patients with acute neuroborreliosis. In most patients, we found significant differences in TCRBV expression between CSF and peripheral blood T cells, predominantly involving CD8[sup +] T cells. T cells that accumulated in the CSF had a memory phenotype and expressed high levels of C-C chemokine receptor 5 and CD69. Serial studies demonstrated that CD8[sup +] T cell accumulation decreased continuously after resolution of the infection. In 2 patients, serial analysis of the TCR-α and -β chain sequences revealed that overexpression of TCRBV in CSF was caused by extensive clonal expansion of CD8[sup +] T cells. Our findings support the role of CD8[sup +] T cells during the early host defense against spirochete infection of the CNS. [ABSTRACT FROM AUTHOR]

A letters to the editor is presented which discusses the study on the prevalence of thyroid peroxidase (TPO) and serum thyroglobulin (TG) antibodies in aquaporin-4 antibody positive central nervous system (CNS) autoimmune disorders (AQP4 CNS AI) and multiple sclerosis (MS).

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. Methods: We performed a genome-wide association study of the IgG index in a discovery series of 229 patients. For confirmation we performed a replication in 2 independent series comprising 256 and 153 patients, respectively. The impact of associated single nucleotide polymorphisms (SNPs) on MS susceptibility was analyzed in an additional 1,854 cases and 5,175 controls. Results: Significant association between the IgG index and 5 SNPs was detected in the discovery and confirmed in both replication series reaching combined p values of p = 6.5 × 10−11 to p = 7.5 × 10−16. All identified SNPs are clustered around the immunoglobulin heavy chain (IGHC) locus on chromosome 14q32.33 and are in linkage disequilibrium ( r2 range, 0.71-0.95). The best associated SNP is located in an intronic region of the immunoglobulin gamma3 heavy chain gene. Additional sequencing identified the GM21* haplotype to be associated with a high IgG index. Further evaluation of the IGHC SNPs revealed no association with susceptibility to MS in our data set. Interpretation: The extent of intrathecal IgG in MS is influenced by the IGHC locus. No association with susceptibility to MS was found. Therefore GM haplotypes might affect intrathecal IgG synthesis independently of the underlying disease. ANN NEUROL 2013 [ABSTRACT FROM AUTHOR]

Abstract: 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. Immuno-phenotype of leukocyte subsets and cytokines IL-1β, IL-6 and tnfα were measured in peripheral blood. Multivariate analyses were performed to test group differences. Results: As compared to controls, the patients showed an elevated percentage of monocytes (18.06±7.08% vs. 12.68±4.55%, p <0.001), NK cells (14.88±7.08% vs. 11.43±5.41%, p =0.019) and IL-6 concentration (3.33±3.11pg/ml vs. 1.5±1.36pg/ml, p =0.002). This remained true when focal epilepsies or generalized epilepsies were compared separately to controls but only focal epilepsies showed additionally a decrease in B lymphocyts (8.16±3.76% vs. 11.54±4.2%, p <0.001). Treatment with lamotrigine was associated with a higher percentage of B lymphocytes and valproate with an increased percentage of CD4+ T lymphocytes. Therapy with levetiracetam showed a trend towards decreased CD8+ T cell counts. No significant differences were seen between focal and generalized epilepsies and between temporal and extratemporal lobe epilepsies. Conclusion: Patients with active epilepsy revealed interictal alterations of the immune system which varied among specific syndromes and were influenced by antiepileptic drug treatment. [Copyright &y& Elsevier]

Abstract: 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 ®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. Critical factors, such as sample transport and storage, analytical delays, reaction temperature and time, the laboratories'' accuracy and preparation of standards were documented and used for the statistical analyses. Results: The intra-laboratory CV averaged 3.3% and the inter-laboratory CV 59%. The results from the test laboratories correlated with those from the reference laboratory (R =0.60, p <0.0001). Correcting for critical factors improved the strength of the correlation. Differences in the accuracy of standard preparation were identified as the most critical factor. Correcting for the error introduced by variation in the protein standards improved the correlation to R =0.98, p <0.0001 with an averaged inter-laboratory CV of 14%. The corrected overall inter-rater agreement was subtantial (0.6) according to Fleiss'' multi-rater kappa and Gwet''s AC1 statistics. Conclusion: This multi-center validation study identified the lack of preparation of accurate and consistent protein standards as the main reason for a poor inter-laboratory CV. This issue is also relevant to other protein biomarkers based on this type of assay and will need to be solved in order to achieve an acceptable level of analytical accuracy. The raw data of this study is available online. [Copyright &y& Elsevier]

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. Results High serum immunoglobulin G (IgG) titers to nMOG were detected in 40% of children with CIS/ADEM but 0% of the control children affected by other neurological diseases, healthy children, or adults with inflammatory demyelinating diseases, respectively. By contrast, IgM antibodies to nMOG occurred in only 3 children affected by ADEM. Children with high anti-nMOG IgG titer were significantly younger than those with low IgG titer. Anti-nMOG IgG titers did not differ between the ADEM and CIS group, and did not predict conversion from CIS to MS during a mean 2-year follow-up. However, intrathecal IgG anti-MOG antibody synthesis was only seen in CIS children. IgG antibodies to nMOG not only bound to the extracellular domain of nMOG, but also induced natural killer cell-mediated killing of nMOG-expressing cells in vitro. Interpretation Overall, these findings suggest nMOG as a major target of the humoral immune response in a subgroup of children affected by inflammatory demyelinating diseases of the CNS. Children may provide valuable insight into the earliest immune mechanisms of CNS demyelination. Ann Neurol 2009;66:833-842 [ABSTRACT FROM AUTHOR]

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. VZV is not a disease-relevant antigen in MS. Ann Neurol 2009;65:474-479 [ABSTRACT FROM AUTHOR]