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.

Significance: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). B cells play a key role in MS immunopathology, as demonstrated by the success of B cell-directed therapies; however, the target antigen of MS remains unknown. Using a combination of ELISpot-based prescreening of peripheral blood mononuclear cells followed by investigation of antibody specificity with a CNS antigen array, we identified a population of MS patients characterized by a highly active B cell response. These individuals with MS, who have active B cell responses, exhibited heterogeneous interindividual anti-CNS antibody responses, although the antigenic specificity of the antibodies remained stable over time for each individual.

Detection of antigen-specific memory B cells for immune monitoring requires their activation, and is commonly accomplished through stimulation with the TLR7/8 agonist R848 and IL-2. To this end, we evaluated whether addition of IL-21 would further enhance this TLR-driven stimulation approach; which it did not. More importantly, as most antigen-specific B cell responses are T cell-driven, we sought to devise a polyclonal B cell stimulation protocol that closely mimics T cell help. Herein, we report that the combination of agonistic anti-CD40, IL-4 and IL-21 affords polyclonal B cell stimulation that was comparable to R848 and IL-2 for detection of influenza-specific memory B cells. An additional advantage of anti-CD40, IL-4 and IL-21 stimulation is the selective activation of IgM⁺ memory B cells, as well as the elicitation of IgE⁺ ASC, which the former fails to do. Thereby, we introduce a protocol that mimics physiological B cell activation through helper T cells, including induction of all Ig classes, for immune monitoring of antigen-specific B cell memory.

Summary: The role of fibroblast growth factor‐2 (FGF‐2) in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis is discussed. This study is the first to use FGF‐2^−/− mice to further address the involvement of FGF‐2 in the disease process. We demonstrate that immunization with myelin oligodendrocyte glycoprotein peptide 35–55 induces more severe experimental autoimmune encephalomyelitis in FGF‐2^−/− mice compared with FGF‐2^+/+ mice. The antigen‐specific cytokine response to myelin oligodendrocyte glycoprotein peptide and the degree of central nervous system inflammation was similar in both groups. However, FGF‐2^−/− mice displayed increased infiltration of CD8⁺ T cells and macrophages/microglia. In addition, nerve fibre degeneration and axonal loss were augmented, whereas the extent of remyelination in central nervous system lesions was reduced. FGF‐2 has been associated with the induction of demyelination and the inhibition of myelin production by oligodendrocytes. Our study supports the opposing notion that FGF‐2 can also assert a neuroprotective function. This may be particularly appealing when it comes to targeting the neurodegenerative aspect of multiple sclerosis.