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. 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 (r(2) 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.

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. 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.

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). 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.

HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis.

The formation of antibodies to interferon-beta (IFN-beta), 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-beta. 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-beta. 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 break T cell tolerance and facilitate antibody development to IFN-beta. In summary, we identified genetic factors determining the immunogenicity of IFN-beta, a protein-based disease-modifying agent for the treatment of MS.

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. Immuno-phenotype of leukocyte subsets and cytokines IL-1ß, 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±3.11 pg/ml vs. 1.5±1.36 pg/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.

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. A fluorescence-based assay was designed that measures HIV infection by two parameters relating to the early and the late phases of HIV replication, respectively. Validation of the assay with a panel of nine reference inhibitors yielded effective inhibitory concentrations consistent with published data and allowed discrimination between inhibitors of early and late phases of HIV replication. Finer resolution of the effects of reference drugs on different steps of HIV replication was achieved in secondary time-of-addition assays. The EASY-HIT assay yielded high Z' scores (>0.9) and signal stabilities, confirming its robustness. Screening of the LOPAC(1280) library identified 10 compounds (0.8%), of which eight were known to inhibit HIV, validating the suitability of this assay for screening applications. Studies evaluating anti-HIV activities of natural products with the EASY-HIT technology led to the identification of three novel inhibitory compounds that apparently act at different steps of HIV-1 replication. Furthermore, we demonstrate successful evaluation of plant extracts for HIV-inhibitory activities, suggesting application of this technology for the surveillance of biological extracts with anti-HIV activities. We conclude that the EASY-HIT technology is a versatile tool for the discovery and characterization of HIV inhibitors.

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. 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.

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. VZV is not a disease-relevant antigen in MS.

Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis.

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.

Viral load determines the B-cell response in the cerebrospinal fluid during human immunodeficiency virus infection.

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.

CD8 T-cell subsets and viral load in the cerebrospinal fluid of therapy-naive HIV-infected individuals.

Central nervous system involvement is common in HIV infection. We determined the relationship between T-cell subsets and viral load in the cerebrospinal fluid (CSF) of therapy-naive, asymptomatic HIV-infected individuals. A shift from naive to effector-memory CD8 T cells was observed in the CSF of HIV-infected individuals compared with controls. The HIV load strongly correlated with CD8 T cells in CSF. Effector-memory CD8 T cells were positively and effector CD8 T cells were negatively associated with viral replication in CSF.

Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.

Understanding the mechanisms of immune cell migration to multiple sclerosis lesions offers significant therapeutic potential. This study focused on the chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1), both of which regulate B cell migration in lymphoid tissues. We report that immunohistologically CXCL12 was constitutively expressed in CNS parenchyma on blood vessel walls. In both active and chronic inactive multiple sclerosis lesions CXCL12 protein was elevated and detected on astrocytes and blood vessels. Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing-remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4+ cells and almost all B cells expressed the CXCL13 receptor CXCR5. In vitro, CXCL13 was produced by monocytes and at much higher levels by macrophages. CXCL13 mRNA and protein expression was induced by TNFalpha and IL-1beta but inhibited by IL-4 and IFNgamma. Together, CXCL12 and CXCL13 are elevated in active multiple sclerosis lesions and CXCL12 also in inactive lesions. The consequences of CXCL12 up-regulation could be manifold. CXCL12 localization on blood vessels indicates a possible role in leucocyte extravasation, and CXCL12 may contribute to plasma cell persistence since its receptor CXCR4 is retained during plasma cell differentiation. CXCL12 may contribute to axonal damage as it can become a neurotoxic mediator of cleavage by metalloproteases, which are present in multiple sclerosis lesions. The strong linkage of CXCL13 to immune cells and immunoglobulin levels in CSF suggests that this is one of the factors that attract and maintain B and T cells in inflamed CNS lesions. Therefore, both CXCL13 and CXCR5 may be promising therapeutic targets in multiple sclerosis.

Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis.

BACKGROUND: Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an alpha4beta(1) integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection. OBJECTIVE: To test the effect of natalizumab treatment on the CD4(+)/CD8(+) T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood. DESIGN: Prospective longitudinal study. SETTING: Academic and private multiple sclerosis centers. PATIENTS: Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus-infected patients. MAIN OUTCOME MEASURES: CD4(+) and CD8(+) T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound alpha4 integrin on peripheral blood CD4(+) and CD8(+) T cells was analyzed before and after natalizumab therapy. RESULTS: Natalizumab therapy decreased the CSF CD4(+)/CD8(+) ratio of patients with MS to levels similar to those of human immunodeficiency virus-infected patients. CD4(+)/CD8(+) ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4(+)/CD8(+) ratios normalized. The expression of unbound alpha4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4(+) vs CD8(+) T cells. CONCLUSIONS: Natalizumab treatment alters the CSF CD4(+)/CD8(+) ratio. Lower expression of unbound alpha4 integrin on CD4(+) T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.

Accumulation of class switched IgD-IgM- memory B cells in the cerebrospinal fluid during neuroinflammation.

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.

Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis.

Multiple sclerosis is a chronic inflammatory and demyelinating disorder of the CNS with an unknown aetiology. Although intrathecal immunoglobulin G (IgG) synthesis is a key feature of the disease, little is still known about the B cell response in the CNS of multiple sclerosis patients. We analysed the phenotype and kinetics of different B cell subsets in patients with multiple sclerosis, infectious disease (IND) and non-inflammatory neurological disease (NIND). B cells were detected in the CSF of multiple sclerosis and IND patients, but were largely absent in NIND patients. In the CSF, the majority of B cells had a phenotype of memory B cells and short-lived plasma blasts (PB); plasma cells were absent from the compartment. The proportion of PB was highest in multiple sclerosis patients and patients with acute CNS infection. While PB disappeared rapidly from the CSF after resolution of infection in IND patients, these cells were present at high numbers throughout the disease course in multiple sclerosis patients. CSF PB numbers in multiple sclerosis patients strongly correlated with intrathecal IgG synthesis and inflammatory parenchymal disease activity as disclosed by MRI. This study identifies short-lived plasma blasts as the main effector B cell population involved in ongoing active inflammation in multiple sclerosis patients.

Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis.

BACKGROUND: The anti-CD20 monoclonal antibody rituximab effectively depletes B lymphocytes and has been successfully used in the therapy of immune-mediated disorders of the peripheral nervous system. A limited effect of rituximab on B lymphocytes in the cerebrospinal fluid compartment of patients with primary progressive multiple sclerosis (MS) was recently reported. OBJECTIVE: To determine the effect of rituximab on clinical, magnetic resonance imaging, and immunological variables in a patient with relapsing-remitting MS. DESIGN: A patient with relapsing-remitting MS was treated with rituximab. The patient was repeatedly examined clinically and by magnetic resonance imaging. The frequency of peripheral blood and cerebrospinal fluid B lymphocytes was assessed by flow cytometry before, during, and after rituximab therapy. RESULTS: Rituximab monotherapy resulted in significant clinical improvement. Inflammatory surrogate markers on magnetic resonance imaging were also reduced. B lymphocytes were depleted in the cerebrospinal fluid and peripheral blood. CONCLUSIONS: Our data demonstrate beneficial clinical effects of rituximab in relapsing-remitting MS, mediated through modulation of humoral systemic and central nervous system intrinsic immune responses. Clinical trials should determine optimal therapeutic strategies for patients with relapsing-remitting MS.

The immune response at onset and during recovery from Borrelia burgdorferi meningoradiculitis.

BACKGROUND: Borrelia burgdorferi causes a wide range of neurologic syndromes. In Europe, acute meningoradiculitis is the most common manifestation. OBJECTIVE: To address the nature of the immune response during the course of B burgdorferi meningoradiculitis, with special respect to the early and late changes in cerebrospinal fluid (CSF). METHODS: Serial immunophenotyping was performed and cytokine measurements were obtained in the peripheral blood and CSF of 12 European patients with definite B burgdorferi meningoradiculitis. RESULTS: Early during infection and before initiation of treatment, we observed high levels of interleukin (IL) 10, IL-6, and IL-8, and large numbers of B cells and plasma cells in the CSF of most patients. At the same time, we found a mainly unspecific intrathecal antibody synthesis. During resolution of the infection, cytokine levels normalized rapidly and plasma cells disappeared from the CSF. In parallel, the percentage of B cells in the CSF increased over several months, accompanied by rising levels of intrathecally produced B burgdorferi-specific antibodies. CONCLUSIONS: Our findings demonstrate that the early phase of B burgdorferi meningoradiculitis is characterized by a well-coordinated immune response involving specific cytokine release and plasma cell recruitment, followed by a long-lasting, antigen-specific B-cell response in the central nervous system.

The role of the polio virus receptor and the herpesvirus entry mediator B genes for the development of MS.

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.

Multiple sclerosis -- a coordinated immune attack across the blood brain barrier.

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS). The acquired immune system plays a central role in the pathogenesis of MS although target antigens and effector mechanisms are still poorly defined. Studies in animal models of infectious or autoimmune encephalomyelitis suggest that the acquired immune response targeting the CNS in MS originates from the periphery. Both T and B cells undergo activation and maturation in the lymphoid system allowing them to cross the blood brain barrier and infiltrate CNS tissue. Within the CNS, they require a local proinflammatory milieu contributed by macrophages and microglia to mediate their effector function which ultimately leads to damage of myelin sheath, oligodendrocytes, and neurons. In the current review, we elucidate the role of the immune system in MS with particular emphasis on activation and migration of immune cells to the CNS, the role of CNS cells in the inflammatory process and the contribution of the immune system to damage and repair. Based on these considerations we discuss new strategies to investigate pathogenetic pathways in multiple sclerosis.