Multiple sclerosis is a chronic inflammatory disease of the CNS. Although progressive axonal injury and diffuse inflammatory damage has been shown in the chronic phase of the disease, little is known about the molecular mechanisms underlying these pathological processes. In order to identify these mechanisms, we have studied the gene expression profile in non-lesion containing tissue, the so-called normal-appearing white matter (NAWM). We performed differential gene expression analysis and quantitative RT-PCR on subcortical white matter from 11 multiple sclerosis and 8 control cases. Differentially expressed genes were further analysed in detail by in situ hybridization and immunofluorescence studies. We show that genes known to be involved in anti-inflammatory and protective mechanisms such as STAT6, JAK1, IL-4R, IL-10, Chromogranin C and Hif-1alpha are consistently upregulated in the multiple sclerosis NAWM. On the other hand, genes involved in pro-inflammatory mechanisms, such as STAT4, IL-1beta and MCSF, were also upregulated but less regularly. Immunofluorescence colocalization analysis revealed expression of STAT6, JAK1, IL-4R and IL-13R mainly in oligodendrocytes, whereas STAT4 expression was detected predominantly in microglia. In line with these data, in situ hybridization analysis showed an increased expression in multiple sclerosis NAWM of HIF-1alpha in oligodendrocytes and HLA-DRalpha in microglia cells. The consistency of the expression levels of STAT6, JAK1, JAK3 and IL-4R between the multiple sclerosis cases suggests an overall activation of the STAT6-signalling pathway in oligodendrocytes, whereas the expression of STAT4 and HLA-DRalpha indicates the activation of pro-inflammatory pathways in microglia. The upregulation of genes involved in anti-inflammatory mechanisms driven by oligodendrocytes may protect the CNS environment and thus limit lesion formation, whereas the activation of pro-inflammatory mechanisms in microglia may favour disease progression. Altogether, our data suggests an endogenous inflammatory reaction throughout the whole white matter of multiple sclerosis brain, in which oligodendrocytes actively participate. This reaction might further influence and to some extent facilitate lesion formation.

Activated leukocyte cell adhesion molecule (ALCAM) has been proposed to mediate leukocyte migration across the blood-brain barrier (BBB) in multiple sclerosis or experimental autoimmune encephalomyelitis (EAE). Here, we confirmed vascular ALCAM expression in human brain tissue samples in situ and on two different human in vitro BBB models. Antibody-mediated inhibition of ALCAM reduced diapedesis of human CD4 Th1 but not of Th17 cells across the human BBB in vitro. In accordance to human Th1 cells, mouse Th1 cells showed reduced diapedesis across an ALCAM in vitro BBB model under static but no longer under flow conditions. In contrast to the limited role of ALCAM in T cell extravasation across the BBB, we found a contribution of ALCAM to rolling, adhesion, and diapedesis of human CD14 monocytes across the human BBB under flow and static conditions. Taken together, our study highlights the potential differences in the CNS expression of ALCAM in mouse and human and supports a prominent role for ALCAM in the multi-step extravasation of monocytes across the BBB.

Oligodendrocytes, the myelinating glial cells of the central nervous system (CNS), are due to their high specialization and metabolic needs highly vulnerable to various insults. This led to a general view that oligodendrocytes are defenseless victims during brain damage such as occurs in acute and chronic CNS inflammation. However, this view is challenged by increasing evidence that oligodendrocytes are capable of expressing a wide range of immunomodulatory molecules. They express various cytokines and chemokines (e.g. Il-1β, Il17A, CCL2, CXCL10), antigen presenting molecules (MHC class I and II) and co-stimulatory molecules (e.g. CD9, CD81), complement and complement receptor molecules (e.g. C1s, C2 and C3, C1R), complement regulatory molecules (e.g. CD46, CD55, CD59), tetraspanins (e.g. TSPAN2), neuroimmune regulatory proteins (e.g. CD200, CD47) as well as extracellular matrix proteins (e.g. VCAN) and many others. Their potential immunomodulatory properties can, at specific times and locations, influence ongoing immune processes as shown by numerous publications. Therefore, oligodendrocytes are well capable of immunomodulation, especially during the initiation or resolution of immune processes in which subtle signaling might tip the scale. A better understanding of the immunomodulatory oligodendrocyte can help to invent new, innovative therapeutic interventions in various diseases such as Multiple Sclerosis. This article is part of a Special Issue entitled SI: Myelin Evolution.