Macrophages and Autoantibodies in Demyelinating Diseases

Abstract

Myelin phagocytosis by macrophages has been an essential feature of demyelinating diseases in the central and peripheral nervous systems, including Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multiple sclerosis (MS). The discovery of autoantibodies, including anti-ganglioside GM1 antibodies in the axonal form of GBS, anti-neurofascin 155 and anti-contactin 1 antibodies in typical and distal forms of CIDP, and anti-aquaporin 4 antibodies in neuromyelitis optica, contributed to the understanding of the disease process in a subpopulation of patients conventionally diagnosed with demyelinating diseases. However, patients with these antibodies are now considered to have independent disease entities, including acute motor axonal neuropathy, nodopathy or paranodopathy, and neuromyelitis optica spectrum disorder, because primary lesions in these diseases are distinct from those in conventional demyelinating diseases. Therefore, the mechanisms underlying demyelination caused by macrophages remain unclear. Electron microscopy studies revealed that macrophages destroy myelin as if they are the principal players in the demyelination process. Recent studies suggest that macrophages seem to select specific sites of myelinated fibers, including the nodes of Ranvier, paranodes, and internodes, for the initiation of demyelination in individual cases, indicating that specific components localized to these sites play an important role in the behavior of macrophages that initiate myelin phagocytosis. Along with the search for autoantibodies, the ultrastructural characterization of myelin phagocytosis by macrophages is a crucial step in understanding the pathophysiology of demyelinating diseases and for the future development of targeted therapies.

Keywords: Schwann cell; demyelination; electron microscopy; macrophage; paranode; pathogenesis; pathology; the node of Ranvier; treatment.

Figure 1

Representative electron microscopy photograph of demyelination caused by myelin phagocytosis by macrophages. A cross section of a sural nerve biopsy specimen obtained from a patient with AIDP. Various stages of demyelination are observed. The arrow indicates a myelinated fiber surrounded by the cytoplasm of macrophage containing myelin debris. Bold black circles indicated by white asterisks are myelin. The arrowhead indicates a macrophage that completed demyelination. Demyelinated axons are indicated by black asterisks. Uranyl acetate and lead citrate staining. Scale bar = 2 μm.

Figure 2

A macrophage invading the basement membrane tube surrounding the myelinated fiber. A cross section of a sural nerve biopsy specimen obtained from a patient with AIDP. A macrophage whose nucleus is indicated by a black asterisk is invading the basement membrane tube that normally surrounds myelinated fibers. Along with the invasion into the basement membrane tube, the cytoplasm of macrophages apposed to myelin initiates degradation of myelin (white asterisks). Note that the cytoplasm of this macrophage located outside the basement membrane tube does not contain myelin debris. A high-powered view of the region in the box in (A) is shown in (B). Basement membranes surrounding myelinated fibers are indicated by arrowheads. Uranyl acetate and lead citrate staining. Scale bars = 2 μm (A) and 0.5 μm (B).

Figure 3

Stripping of the myelin lamellae by a cytoplasmic process of the macrophage. A cross section of a sural nerve biopsy specimen obtained from a patient with AIDP. Cytoplasmic processes of the macrophage indicated by arrows peel off the myelin layers. A basement membrane surrounding the myelinated fibers is indicated by arrowheads. Uranyl acetate and lead citrate staining. Scale bar = 0.5 μm.

Figure 4

Vesicular dissolution of myelin. A cross section of a sural nerve biopsy specimen obtained from a patient with AIDP. Vesicular dissolution of the myelin is seen in a space between the myelin lamellae indicated by asterisks. Vesicles seem to be formed by the separation of the major dense lines (arrowheads). A process of macrophage indicated by an arrow seems to be invading a gap created by the dissolution of myelin lamellae. Uranyl acetate and lead citrate staining. Scale bar = 0.2 μm.

Figure 5

A demyelinated axon. A cross section of a sural nerve biopsy specimen obtained from a patient with AIDP. A demyelinated axon indicated by an asterisk is surrounded by a space filled with vesicular dissolution of the myelin. The cytoplasm of a macrophage indicated by an arrow is also within the basement membrane tube. Uranyl acetate and lead citrate staining. Scale bar = 1 μm.

Figure 6

A macrophage escaping from the basement membrane tube surrounding the myelinated fiber. A cross section of a sural nerve biopsy specimen obtained from a patient with AIDP. The sites at which the basement membrane was disrupted are indicated by arrowheads. The nucleus of this macrophage is located outside of the basement membrane tube. Note that an axon located within the basement membrane tube is completely demyelinated. A demyelinated axon and a macrophage nucleus are indicated by a black asterisk and a white asterisk, respectively. Uranyl acetate and lead citrate staining. Scale bar = 2 μm.