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Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2+APC+ oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.

In multiple sclerosis (MS) lymphoid follicle-like aggregates have been reported in the meninges of patients. Here we investigated the functional relevance of B cell infiltration into the central nervous system (CNS) in MP4-induced experimental autoimmune encephalomyelitis (EAE), a B cell-dependent mouse model of MS. In chronic EAE, B cell aggregates were characterized by the presence of CXCL13 + and germinal center CD10 + B cells. Germline transcripts were expressed in the CNS and particularly related to T H 17-associated isotypes. We also observed B cells with restricted VH gene usage that differed from clones found in the spleen. Finally, we detected CNS-restricted spreading of the antigen-specific B cell response towards a myelin and a neuronal autoantigen. These data imply the development of autonomous B cell-mediated autoimmunity in the CNS in EAE — a concept that might also apply to MS itself. [ABSTRACT FROM AUTHOR]

Abstract: The concept of TH17 stemness is attracting increasing attention in the field of tumor immunology. The expression of stem cell-like properties and the promotion of long-term immunity by TH17 cells are also of outmost relevance for autoimmunity. Studying two mouse models of multiple sclerosis (MS), we show that CNS antigen-specific TH17 cells occur in high frequencies in the individual mice. However, there was no preferential shift towards a TH17 response over time. These data suggest that there is no evidence for a differential apoptosis rate in TH1 versus TH17 cells in EAE. Apparently the selective enrichment of TH17 cells that can occur under certain conditions such as cancer does not result from an intrinsic property of TH17 cells, but rather from selective pressure present in the microenvironment. [Copyright &y& Elsevier]

The authors discuss the glial potassium channel, KIR4.1 antibodies, as biomarkers in multiple sclerosis. They argue that a clarification of the pathogenicity of KIR4.1 antibodies is necessary. The posibility of a serum immunoglobulin G (IgG) reactivity against KIR4.1 presenting an epiphenomenon and the presence of an additional target for autoreactive B cells beyond the central nervous system (CNS) is also explored.