Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

Myelin sheaths in the central nervous system (CNS) insulate axons and thereby allow saltatory nerve conduction, which is a prerequisite for complex brain function. Multiple sclerosis (MS), the most common inflammatory autoimmune disease of the CNS, leads to the destruction of myelin sheaths and the myelin-producing oligodendrocytes, thus leaving behind demyelinated axons prone to injury and degeneration. Clinically, this process manifests itself in significant neurological symptoms and disability. Resident oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) are present in the adult brain, and can differentiate into mature oligodendrocytes which then remyelinate the demyelinated axons. However, for multiple reasons, in MS the regenerative capacity of these cell populations diminishes significantly over time, ultimately leading to neurodegeneration, which currently remains untreatable. In addition, microglial cells, the resident innate immune cells of the CNS, can contribute further to inflammatory and degenerative axonal damage. Here, we review the molecular factors contributing to remyelination failure in MS by inhibiting OPC and NSC differentiation or modulating microglial behavior.

Background In the central nervous system (CNS) myelin sheaths stabilize, protect, and electrically insulate axons. However, in demyelinating autoimmune CNS diseases such as multiple sclerosis (MS) these sheaths are destroyed which ultimately leads to neurodegeneration. The currently available immunomodulatory drugs for MS effectively control the (auto)inflammatory facets of the disease but are unable to regenerate myelin by stimulating remyelination via oligodendroglial precursor cells (OPCs). Accordingly, there is broad consensus that the implementation of new regenerative approaches constitutes the prime goal for future MS pharmacotherapy. Main text Of note, recent years have seen several promising clinical studies investigating the potential of substances and monoclonal antibodies such as, for instance, clemastine, opicinumab, biotin, simvastatin, quetiapin and anti-GNbAC1. However, beyond these agents which have often been re-purposed from other medical indications there is a multitude of further molecules influencing OPC homeostasis. Here, we therefore discuss these possibly beneficial regulators of OPC differentiation and assess their potential as new pharmacological targets for myelin repair in MS. Conclusion Remyelination remains the most important therapeutic treatment goal in MS in order to improve clinical deficits and to avert neurodegeneration. The promising molecules presented in this review have the potential to promote remyelination and therefore warrant further translational and clinical research.

Background Fingolimod (Gilenya®), a first-in-class sphingosine-1-phosphate receptor modulator is approved for the treatment of relapsing-remitting multiple sclerosis. Fingolimod-induced selective immunosuppression leads to an increased risk of opportunistic infections such as cryptococcosis. So far, a total of 8 cases of fingolimod-related cryptococcal meningoencephalitis have been published. Case presentation A 49-year-old female with relapsing-remitting multiple sclerosis presented with cephalgia, fever, confusion and generalized weakness. She had been on fingolimod therapy for the past 5.5 years. Clinical examination suggested meningoencephalitis and laboratory findings showed an IgG2 deficiency. Initially no pathogen could be detected, but after 4 days Cryptococcus neoformans was found in the patient’s blood cultures leading to the diagnosis of cryptococcal meningoencephalitis. After antimycotic therapy, her symptoms improved and the patient was discharged. Conclusion MS patients on immunomodulatory  therapy are at constant risk for opportunistic infections. Cephalgia, fever and generalized weakness in combination with fingolimod-induced lymphopenia should be considered a red flag for cryptococcosis.

Neuromyotonia is a rare peripheral nerve hyperexcitability syndrome often associated with antibodies directed against contactin-associated protein-like 2 and leucine-rich, glioma inactivated 1. The quadrivalent human papilloma virus vaccine Gardasil®, first approved in 2006, is known to be a highly effective prophylaxis against papillomavirus types 6, 11, 16, and 18. Molecularly, this non-infectious recombinant vaccine is based on purified L1 proteins from the human papilloma virus capsid. Since the approval of this vaccine, several studies have investigated its safety regarding the occurrence of autoimmune conditions following application. Here, we present the first case of neuromyotonia with active Gadolinium enhancing demyelinating central nervous system lesions following vaccination with Gardasil®.