Early cellular events in multiple sclerosis

Abstract

In a previous immunohistological study of tissues from unusually early cases of MS cluster analysis revealed a progression of demyelination through five distinct stages [Gay F, Drye T, Dick G, et al. The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain 1997;120:1461-83]. Tissues from six of the earliest cases in this series contained regions of normal appearing white and grey matter in which well developed inflammatory events, concentrated in perivascular spaces, were found to extend locally into the perivascular parenchyma to envelop ostensibly intact myelin sheaths. The beginnings of myelin sheath lysis and phagocytosis were subsequently detected within these lesions and similar foci were found in subpial and in subependymal tissues. They were characterised by a spreading HLA Class II antigen expression on microglia, and by the presence of co-locating C3 complement-IgG complexes on capillary basement membranes, on microglial cell membranes and within the cytoplasm of large bodied activated astrocytes. Parenchymal lesions contained significantly few CD4+ T cells and showed no evidence of capillary leakage of plasma proteins. Despite the presence of complexed immunoglobulin and complement, opsonization of the myelin sheath could not be demonstrated. These observations point to the presence in early MS of a diffusing, complement-fixing, myelinolytic antigen, processed mainly within the Virchow-Robin spaces and distributed in the cerebrospinal and extracellular fluid compartments of the central nervous system.

Fibrinogen Signal Transduction as a Mediator and Therapeutic Target in Inflammation:Lessons from Multiple Sclerosis

“…Results of these studies find fibrinogen deposition to be one of earliest events associated with lesion formation. The presence of fibrinogen has been documented extensively in lesions from postmortem MS patients primarily as a marker for blood brain barrier disruption [139][140][141][142] (Table 2). Extravascular fibrinogen deposition was observed in early, pre-active MS lesions and became more extensive in active demyelinating MS lesions to chronic inactive lesions preceding histopathological symptoms of MS.…”

Apoptosis of Oligodendrocytes and Post-Translational Modifications of Myelin Basic Protein in Multiple Sclerosis: Possible Role for the Early Stages of Multiple Sclerosis

“…Direct evidence is supported by only one study so far [6]. Indirect evidence comes from microglia activation and complement deposits, suggesting the activation of apoptotic clearance mechanisms [6,14]. Actually, microglia activation consists of an independent marker of biological stress [56].…”

“…Early changes in NAWM in MS seem to precipitate late autoimmune reactions [4,5,6,14]. Some type of biological stress, such as infections, minerals, etc., should affect CNS parenchyma, causing early pathological phenomena.…”

“…An autopsy study of 6 cases with recent onset MS has interesting findings [14]. The predemyelinating plaques, isolated from NAWM, appear to be well-developed inflammation processes limited to Virchow-Robin spaces (perivascular cuffs) and around arterioles in the subependymal and subpial white matter, while there is no evidence of blood-brain barrier leakage.…”

Postulated Role of Vasoactive Neuropeptide‐Related Immunopathology of the Blood Brain Barrier and Virchow‐Robin Spaces in the Aetiology of Neurological‐Related Conditions

“…Complement-fixing myelinolytic antigens have been identified in the VRS in early MS [27], indicating the possible involvement of VRS in immune activity.…”