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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. Patients: All patients had a diagnosis of multiple sclerosis and were receiving long-term interferon beta therapy. Main Outcome Measures: The antibody status to interferon beta was determined in all patients by capture enzyme-linked immunosorbent assay and in vivo myxovirus protein A assay and correlated with the HLADRB1 genotype. Results: In the discovery and validation cohorts, HLADRB1* 04:01, *04:08, *16:01 were identified as genetic markers that are associated with an increased risk of anti-interferon beta antibody development (P<.05). In addition, alleles with a protective potential were identified, including HLA-DRB1*03:01, *04:04, *11:04. However, after correction for multiple testing, protective alleles did not reach statistical significance. Conclusion: The HLA alleles identified in this study seem to be the major genetic determinant of antibody development, allowing the prediction of the individual risk of patients before initiation of therapy. [ABSTRACT FROM AUTHOR]

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. Objective: To address the influence of interferon beta on the expression of chemokines and their receptors in a standardized setting. Design: The expression of 14 chemokines and 14 chemokine receptor genes was determined by quantitative realtime polymerase chain reaction from fresh blood samples. Setting: Outpatient units in Germany. Patients: Untreated and interferon beta-treated patients with MS who tested positive and negative for neutralizing antibodies (NABs) were recruited from August 24, 2006, through December 15, 2006, for the initial study and from March 12, 2007, through April 2, 2007, for the validation study. Main Outcome Measures: Gene expression and serum chemokine protein levels. Results: CCL1, CCL2, CCL7, CXCL10, CXCL11, and CCR1 gene expression was strongly upregulated in interferon beta-treated, NAB-negative MS patients. In contrast, gene expression in interferon beta-treated, NABpositive MS patients did not differ from untreated control donor individuals. Antibody titers inversely correlated with chemokine and chemokine receptor gene expression. Accordingly, serum chemokine protein levels of interferon beta-treated, NAB-negative MS patients were significantly higher than in untreated or interferon beta- treated, NAB-positive MS patients. Conclusions: We demonstrate that interferon beta strongly upregulates a set of chemokines and CCR1 in peripheral immune cells. The peripheral upregulation of these chemokines may reduce the chemoattraction of immune cells to the central nervous system and thus add to the therapeutic effects of interferon beta. [ABSTRACT FROM AUTHOR]

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. Objective: To determine the effect of rituximab on the presence of B cells in cerebral perivascular spaces. Design, Setting, and Patients: Case report from a tertiary academic medical center. Cerebral white matter from autopsy material of a patient with gastrointestinal mantle-cell lymphoma who developed progressive multifocal leukoencephalopathy following rituximab therapy was evaluated by immunohistochemistry. Locationmatched brain sections of patients with multiple sclerosis not treated with rituximab, patients without central nervous system disease, and patients with progressive multifocal leukoencephalopathy not associated with rituximab were used as controls. Main Outcome Measures: Assessment of the number of B lymphocytes in cerebral perivascular spaces in a patient with gastrointestinal mantle-cell lymphoma treated with rituximab, patients with multiple sclerosis, patients with progressive multifocal leukoencephalopathy not associated with rituximab, and healthy control subjects. Results:Wewere unable to detect B cells in cerebral perivascular spaces of the patient who developed progressive multifocal leukoencephalopathy following rituximab therapy 8 months after her last dose. In contrast, B cells were detectable in all control brain tissues. Conclusions: To our knowledge, this is the first report to show B-lymphocyte depletion from brain tissue following rituximab therapy. A reduction in B-cell numbers may be an important contributing factor in the pathogenesis of central nervous system infections. [ABSTRACT FROM AUTHOR]

Background: Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an α4β1 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 a 4 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 a 4 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 α4 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]