The immunopathology of multiple sclerosis: an overview

Abstract

Multiple sclerosis (MS) is traditionally seen as an inflammatory demyelinating disease, characterized by the formation of focal demyelinated plaques in the white matter of the central nervous system. In this review we describe recent evidence that the spectrum of MS pathology is much broader. This includes demyelination in the cortex and deep gray matter nuclei, as well as diffuse injury of the normal-appearing white matter. The mechanisms responsible for the formation of focal lesions in different patients and in different stages of the disease as well as those involved in the induction of diffuse brain damage are complex and heterogeneous. This heterogeneity is reflected by different clinical manifestations of the disease, such as relapsing or progressive MS, and also explains at least in part the relation of MS to other inflammatory demyelinating diseases.

Figure 1

Multiple sclerosis pathology: from focal plaques to diffuse brain damage. A. Acute multiple sclerosis (MS) (Pattern II); multiple perivenous inflammatory demyelinating lesions, which form in some places confluent demyelinated plaques. B. Acute MS (Pattern III); focal large demyelinated plaques (green lesions), the right periventricular lesions shows concentric layering. C,D. Benign MS; inactive demyelinated lesions in the spinal cord (D); very few and tiny lesions in the brain white matter and cortex. E. Relapsing/remitting MS; multiple white matter lesions; most of the lesions are remyelinated shadow plaques; the few demyelinated lesions are active; very few and small lesions in the cerebral cortex. F. Secondary progressive MS; multiple large white matter plaques; most plaques are demyelinated, only few are remyelinated; extensive cortical demyelination and multiple lesions in the deep gray matter. G. Primary progressive MS; multiple small focal white matter lesions, most of them remyelinated; extreme cortical demyelination; in addition there is extensive diffuse injury in the normal‐appearing white matter (see figures I–M). H. Secondary progressive MS, large focal demyelinated white matter lesions are associated with extreme cortical demyelination and diffuse white matter atrophy; several lesions are also present in the deep gray matter. I–M. Same patient as shown in figure G; massive injury of the normal‐appearing white matter, consisting of inflammation (CD8 positive lymphocytes are shown in figure I); massive microglia activation with the formation of microglia nodules (shown by staining for HLA‐D in figure J,K) and expression of inducible nitric oxide synthase (shown in figure L); this inflammatory process is associated with extensive axonal injury (staining for neurofilament in figure M). N–O. Secondary progressive MS with massive inflammation in the meninges, composed of T cells (CD8⁺; figure N) and plasma cells (staining for immunoglobulin; figure O). Green: demyelinated lesions in the white matter; blue: remyelinated lesions in the white matter; red: demyelinated lesions in the cortex; pink: demyelinated lesions in the deep gray matter.