Christiane Wegner

Inflammation, demyelination, and degeneration — Recent insights from MS pathology

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which responds to anti-inflammatory treatments in the early disease phase. However, the pathogenesis of the progressive disease phase is less well understood, and inflammatory as well as neurodegenerative mechanisms of tissue damage are currently being discussed. This review summarizes current knowledge on the interrelation between inflammation, demyelination, and neurodegeneration derived from the study of human autopsy and biopsy brain tissue and experimental models of MS.

Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis

We investigated the effect of laquinimod on inflammatory demyelination, axonal damage, cytokine profiles and migratory capacities of lymphocytes in C57BL/6 mice with active EAE induced with MOG(35-55) peptide. The mice were treated at disease induction and after disease onset. Spinal cords were assessed histologically. Cytokines and adhesive properties were analyzed in splenocytes. Preventive and therapeutic laquinimod treatment reduced clinical signs, inflammation, and demyelination. VLA-4-mediated adhesiveness and pro-inflammatory cytokines such as IL-17 were down-regulated in treated animals. Within lesions, treated mice showed similar axonal densities, but less acute axonal damage than controls. Laquinimod might thus protect myelin and axons by decreasing pro-inflammatory cytokines and impairing the migratory capacity of lymphocytes.

Cortical pathology in multiple sclerosis.

Purpose of reviewMultiple sclerosis is the most common chronic, disabling central nervous system disease in young adults, characterized by inflammatory demyelinating white matter lesions with glial scar formation and axonal loss. Lately, evidence has accumulated that large areas of grey matter are affected in multiple sclerosis patients. Recent findingsFindings in post-mortem brain tissue support the notion that cortical demyelination is frequent and extensive, especially in patients with chronic multiple sclerosis. Cortical lesions differ from white matter lesions with respect to inflammatory cell infiltration, gliosis, and remyelination. Thus, differences in cortical and white matter lesion pathogenesis have been proposed. Experimental models suggest a decisive role for antimyelin antibodies in cortical demyelination. Topical studies focus on damage to neurons, dendrites, and synapses in cortical multiple sclerosis lesions. Improved imaging techniques for the detection of cortical lesions are currently developed and will provide the basis for future clinicopathological correlative studies. SummaryIn summary, recent years have opened our eyes to the extensive grey matter involvement in multiple sclerosis. Studies on the pathogenesis of cortical demyelination, cortical damage, and repair will elucidate basic principles of multiple sclerosis lesion formation. However, more sensitive imaging tools are required to study the impact of cortical lesions on clinical symptoms, disability, and disease progression.

Favourable response to plasma exchange in tumefactive CNS demyelination with delayed B-cell response.

We report a case of multiple sclerosis-associated fulminant tumefactive demyelinating lesion (TDL) with the special feature of delayed humoral immune response. Plasma exchange (PE) yielded significant benefit in two consecutive steroid-unresponsive relapses, while signs of an intrathecal B-cell response were only present 2 years later at the second relapse. Remission was achieved and sustained thereafter with natalizumab. Our case indicates that PE might be a therapeutic option even when the B-cell response is not fully developed. This delay in the development of a humoral immune response may reflect the step-wise B-cell colonization of the CNS and represent an attractive therapeutic window of opportunity.

Oligodendroglia in cortical multiple sclerosis lesions decrease with disease progression, but regenerate after repeated experimental demyelination

Cerebral cortex shows a high endogenous propensity for remyelination. Yet, widespread subpial cortical demyelination (SCD) is a common feature in progressive multiple sclerosis (MS) and can already be found in early MS. In the present study, we compared oligodendroglial loss in SCD in early and chronic MS. Furthermore, we addressed in an experimental model whether repeated episodes of inflammatory SCD could alter oligodendroglial repopulation and subsequently lead to persistently demyelinated cortical lesions. NogoA+ mature oligodendrocytes and Olig2+ oligodendrocyte precursor cells were examined in SCD in patients with early and chronic MS, normal-appearing MS cortex, and control cortex as well as in the rat model of repeated targeted cortical experimental autoimmune encephalomyelitis (EAE). NogoA+ and Olig2+ cells were significantly reduced in SCD in patients with chronic, but not early MS. Repeated induction of SCD in rats resulted only in a transient loss of NogoA+, but not Olig2+ cells during the demyelination phase. This phase was followed by complete oligodendroglial repopulation and remyelination, even after four episodes of demyelination. Our data indicate efficient oligodendroglial repopulation in subpial cortical lesions in rats after repeated SCD that was similar to early, but not chronic MS cases. Accordingly, four cycles of experimental de- and remyelination were not sufficient to induce sustained remyelination failure as found in chronic cortical MS lesions. This suggests that alternative mechanisms contribute to oligodendrocyte depletion in chronic cortical demyelination in MS.

Differential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis

Cortical demyelination is a widely recognized hallmark of multiple sclerosis (MS) and correlate of disease progression and cognitive decline. The pathomechanisms initiating and driving gray matter damage are only incompletely understood. Here, we determined the infiltrating leukocyte subpopulations in 26 cortical demyelinated lesions of biopsied MS patients and assessed their contribution to cortical lesion formation in a newly developed mouse model. We find that conformation-specific anti-myelin antibodies contribute to cortical demyelination even in the absence of the classical complement pathway. T cells and natural killer cells are relevant for intracortical type 2 but dispensable for subpial type 3 lesions, whereas CCR2+ monocytes are required for both. Depleting CCR2+ monocytes in marmoset monkeys with experimental autoimmune encephalomyelitis using a novel humanized CCR2 targeting antibody translates into significantly less cortical demyelination and disease severity. We conclude that biologics depleting CCR2+ monocytes might be attractive candidates for preventing cortical lesion formation and ameliorating disease progression in MS.

Brain iron accumulation in Wilson disease: a post mortem 7 Tesla MRI - histopathological study.

In Wilson disease (WD), T2/T2*‐weighted (T2*w) MRI frequently shows hypointensity in the basal ganglia that is suggestive of paramagnetic deposits. It is currently unknown whether this hypointensity is related to copper or iron deposition. We examined the neuropathological correlates of this MRI pattern, particularly in relation to iron and copper concentrations.

Increased Meningeal T and Plasma Cell Infiltration is Associated with Early Subpial Cortical Demyelination in Common Marmosets with Experimental Autoimmune Encephalomyelitis

Subpial cortical demyelination (SCD) accounts for the greatest proportion of demyelinated cortex in multiple sclerosis (MS). SCD is already found in biopsy cases with early MS and in marmosets with experimental autoimmune encephalomyelitis (EAE), but the pathogenesis of SCD is not well understood. The objective of this study was to investigate whether and, if so, which meningeal inflammatory cells were associated with early SCD in marmosets with EAE. Immunohistochemistry was performed to analyze brain samples from eight control animals and eight marmosets immunized with myelin oligodendrocyte glycoprotein. Meningeal T, B and plasma cells were quantified adjacent to SCD, normal‐appearing EAE cortex (NAC) and control marmoset cortex. SCD areas appeared mostly hypocellular with low‐grade microglial activation. In marmosets with EAE, meninges adjacent to SCD showed significantly increased T cells paralleled by elevated plasma cells, but unaltered B cell numbers compared with NAC. The elevation of meningeal T and plasma cells was a specific finding topographically associated with SCD, as the meninges overlying NAC displayed similarly low T, B and plasma cell numbers as control cortex. These findings suggest that local meningeal T and plasma cell infiltration contributes to the pathogenesis of SCD in marmosets with EAE.

Recent insights into the pathology of multiple sclerosis and neuromyelitis optica

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system. Traditionally, demyelinating lesions in the white matter have been regarded as the most important pathological feature in MS, but recent pathological and imaging studies confirmed substantial changes in grey matter and normal-appearing white matter. MS lesions are characterized by inflammation, demyelination, axonal damage and astrogliosis. During early MS lesion formation acute axonal injury is extensive and correlates with inflammation. In addition to focal lesions, diffuse wide-spread changes including neuroaxonal degeneration and compartmentalized inflammation are likely to contribute to increasing disability in progressive MS. Neuromyelitis optica (NMO) is classically characterized by severe transverse myelitis and optic neuritis, but brain lesions are also present in the majority of NMO patients. The discovery of the NMO-specific antibody demonstrated that NMO is a disease entity distinct from MS. This antibody binds to aquaporin-4 expressed in astrocytes and ependymal cells. NMO lesions are characterized by inflammation, demyelination, axonal damage and a marked loss of aquaporin-4. Early NMO lesions demonstrate a pronounced humoral inflammatory response and astrocytic cell death with loss of aquaporin-4, followed by inflammatory demyelination and axonal damage. These recent findings contribute to a better understanding of different mechanisms leading to inflammatory demyelination.

A New Targeted Model of Experimental Autoimmune Encephalomyelitis in the Common Marmoset.

Multiple sclerosis (MS) is the most common cause for sustained disability in young adults, yet treatment options remain very limited. Although numerous therapeutic approaches have been effective in rodent models of experimental autoimmune encephalomyelitis (EAE), only few proved to be beneficial in patients with MS. Hence, there is a strong need for more predictive animal models. Within the past decade, EAE in the common marmoset evolved as a potent, alternative model for MS, with immunological and pathological features resembling more closely the human disease. However, an often very rapid and severe disease course hampers its implementation for systematic testing of new treatment strategies. We here developed a new focal model of EAE in the common marmoset, induced by myelin oligodendrocyte glycoprotein (MOG) immunization and stereotactic injections of proinflammatory cytokines. At the injection site of cytokines, confluent inflammatory demyelinating lesions developed that strongly resembled human MS lesions. In a proof‐of‐principle treatment study with the immunomodulatory compound laquinimod, we demonstrate that targeted EAE in marmosets provides a promising and valid tool for preclinical experimental treatment trials in MS research.