The immunopathophysiology of multiple sclerosis

Abstract

This review explores the principle features of the immunopathology of multiple sclerosis (MS), particularly relapsing-remitting MS. It highlights the emerging concepts in the pathogenesis of MS in the context of known features of pathology, including the characterization of cytokine networks promoting inflammatory damage of the central nervous system, B-cell involvement, and inflammatory damage of axons and neurons. This article preferentially focuses on MS rather than animal models of the disease, such as experimental autoimmune encephalomyelitis.

Figure 1

Gross and histologic features of MS plaques. (A) Gross examination of the brain at autopsy of a 79 year old with RR-MS. A dorsal view of the corpus callosum after separation of the cerebral hemispheres reveals a hardened, discolored area within the body of the corpus callosum (arrow). Photo courtesy of Dr. Robert Schmidt. (B) Acute MS plaque stained with Hematoxylin and Eosin revealing hypercellularity due to the perivascular and parenchymal infiltration of leukocytes. (C) Luxol fast blue/periodic acid–Schiff (LFB-PAS) stained section of a plaque margin reveals a blurred but discrete edge (arrows). (D) Inactive plaque demonstrating borders that are distinct and devoid of inflammation (E) CD3 + lymphocytes clustering in a perivascular cuff within an active lesion area (F) Foamy macrophages characterized by fragments of myelin (arrow) engulfed by macrophages are identified using LFB-PAS at a plaque margin. Images in B-F used with permission; (copyright Elsevier, 2010).

Figure 2

Cortical lesions in MS revealed by sections immunohistochemically labeled for MBP. (A) Type 1 cortical lesions encompass both white and gray matter. Solid arrows indicate the cortex (CTX)/white matter (WM) border, while the lesion border is delineated by open arrows. (B) Type 2 lesions are contained entirely within the CTX and do not extend to the subcortical WM (solid arrow) or pial surface. The border of this type 2 lesion is indicated by the open arrows. (C) Type III cortical lesions represent cortical demyelination below the pial surface that often cover several gyri and stop at cortical layers three or four. Open arrows indicate the lesion border. (D) Type 4 lesions (border represented by filled arrow) span the entirety of the CTX without involvement of WM (solid arrow). The arrowhead indicates a small area likely undergoing remyelination. Figure from used with permission (copyright Wolters Kluwer Health, 2003).

Figure 3

Involvement of IL-17 in MS lesions. Immunohistochemical identification of CD3 (left column) and IL-17 (right column) in consecutive sections. Abundant IL- 17 staining (arrowhead) is observed in perivascular cells in both acute (A & B) and chronic active (C &D) lesions. (E & F) Whereas CD3+ cells do not co-localize with IL- 17 staining within the internal region of a chronic lesion, the fibrillary pattern of IL- 17 immuno-reactivity is representative of possible astrocyte production of IL-17. Minimal staining is observed in tissue from an inactive lesion (G & H). Sparse Th17 cells are observed in NAWM in MS or within control tissue (arrow heads, I-L). Scale bar = 30 μm. Reprinted from Am J Pathol 2008, 172: 146-155 with permission from the American Society for Investigative Pathology.

Figure 4

Cellular and molecular factors involved in the immuno-pathogenesis of MS. Rather than representing an all-inclusive summary of the immuno-pathologic features of MS, this diagram highlights recent advances in the understanding of the neural-immune interactions in MS, including factors involved in leukocyte trafficking, axonal injury and antigen presentation. APC = antigen presenting cell; B = B lymphocyte; T = T lymphocyte; Mφ = macrophage, PVMφ = perivascular macrophage; PC = plasma cell; FDC = follicular DC; μglia = microglia; pDC = plasmacytoid DC.