The clinical utility of JC virus antibody index measurements in the context of progressive multifocal leukoencephalopathy.

In natalizumab-treated patients without previous immunosuppressive treatment, the JCV antibody index is used to stratify PML risk. A high index value indicates that the risk to develop PML is significantly elevated, although probably about 99% of patients with this index value will not develop PML. This minireview aimed to provide an overview of the basic virology and immunology relevant to understanding JCV infections in MS patients, with a focus on what is presently known about antibodies to JCV and how they could be of use to predict and diagnose PML.

[Prognostic and predictively relevant factors for multiple sclerosis]. / Prognostische und prädiktiv relevante Faktoren bei der Multiplen Sklerose.

The immunotherapy of multiple sclerosis (MS) is currently one of the most dynamic fields in clinical neurology. The comprehensive number of well-established and new innovative treatment options are a challenge for an intensive preoccupation with the differential indications and an activity-driven treatment control. In this context this review summarizes the known predictors of the natural course of MS and gives a review of challenges to be expected in association with predictors of treatment control.

Fatal PML associated with efalizumab therapy: insights into integrin αLß2 in JC virus control.

OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. METHODS: We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLß2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients. RESULTS: Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE. CONCLUSIONS: From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.

CD8+ T-cell immunity in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: Chronic inflammatory demyelinating polyradiculopathy (CIDP) is a common, but often misdiagnosed disease of the peripheral nervous system with assumed autoimmune pathogenesis. While current concepts of CIDP postulate a pathogenetic role of B cells and (auto)antibodies, the relevance of CD8 T cells present in the biopsies is still elusive. Thus, we asked whether nervous tissue infiltrating and blood-derived lymphocytes in CIDP are clonally expanded to evaluate the involvement of T cells in the pathogenesis of the disease. METHODS: We characterized the clonal composition of the T-cell receptor repertoire in sural nerve biopsies (n = 25) and matching peripheral blood (n = 12) of patients with CIDP using PCR-based CDR3 spectratyping and subsequent DNA sequencing. As controls we used inflammatory myopathies (dermatomyositis, inclusion body myositis) and nonpathologic control biopsies. Immunohistochemistry was employed to visualize expanded CD8+ T-cell populations in sural nerve biopsies. RESULTS: In contrast to controls, T cells in CIDP biopsies showed strong monoclonal and oligoclonal restrictions in their T-cell receptor repertoire. Strikingly, clonal expansions found in the biopsies were reflected in the CD8+ T-cell pool of patients' peripheral blood. Clones overlapping between blood and biopsy could be confirmed by CDR3 sequencing. Finally, the predominance of expanded nerve-infiltrating CD8+ T-cell clones was visualized by immunohistochemistry. CONCLUSIONS: Together, these data provide strong evidence for an antigen-driven, major histocompatibility complex class I restricted, CD8+ T-cell-mediated attack against peripheral nerve tissue components contributing to the pathogenesis of CIDP.

Effects on capacitance by overexpression of membrane proteins.

Functional Channelrhodopsin-2 (ChR2) overexpression of about 10(4)channels/mum(2) in the plasma membrane of HEK293 cells was studied by patch-clamp and freeze-fracture electron microscopy. Simultaneous electrorotation measurements revealed that ChR2 expression was accompanied by a marked increase of the area-specific membrane capacitance (C(m)). The C(m) increase apparently resulted partly from an enlargement of the size and/or number of microvilli. This is suggested by a relatively large C(m) of 1.15+/-0.08 microF/cm(2) in ChR2-expressing cells measured under isotonic conditions. This value was much higher than that of the control HEK293 cells (0.79+/-0.02 microF/cm(2)). However, even after complete loss of microvilli under strong hypoosmolar conditions (100 mOsm), the ChR2-expressing cells still exhibited a significantly larger C(m) (0.85+/-0.07 microF/cm(2)) as compared to non-expressing control cells (0.70+/-0.03 microF/cm(2)). Therefore, a second mechanism of capacitance increase may involve changes in the membrane permittivity and/or thickness due to the embedded ChR2 proteins.