Once the mesaxon spirals on itself, the 12to 14-nm gaps disappear and the membranes form the compact myelin sheath. Compaction of the sheath corresponds with the expression of transmembrane myelin-specifc proteins such as protein 0 (P0), a peripheral myelin protein of 22 kilodaltons (PMP22),and myelin basic protein (MBP). The inner (cytoplasmic) leaflets of the plasma membrane come close together as a result of the positively charged cytoplasmic domains of P0 and MBP. With the TEM, these closely aligned inner leaflets are electron opaque, appearing as the major dense lines in the TEM image of myelin (Fig. 12.10d). The concentric dense lamellae alternate with the slightly less dense intraperiod lines that are formed by closely apposed, but not fused, outer (extracellular) membrane leaflets. The narrow 2.5-nm gap corresponds to the remaining extracellular space containing the extracellular domains of P0 protein (Fig. 12.10d). P0 is a 30-kilodalton cell adhesion molecule expressed within the mesoaxial plasma membrane during myelination. This transmembrane glycoprotein mediates strong adhesions between the two opposite membrane layers and represents a key structural component of peripheral nerve myelin. Structural and genetic studies indicate that mutations in human genes encoding P0 produce unstable myelin and may contribute to the development of demyelinating diseases (see Folder 12.2).
In general, demyelinating diseases are characterized by preferential damage to the myelin sheath. Clinical symp-toms of these diseases are related to decreased or lost ability to transmit electrical impulses along nerve fibers. Several immune-mediated diseases affect the myelin sheath. Guillain-Barré syndrome, known also as acute in-fammatory demyelinating polyradiculoneuropathy, is one of the most common life-threatening diseases of the PNS. Microscopic examination of nerve fibers obtained from patients affected by this disease shows a large accu-mulation of lymphocytes, macrophages, and plasma cells around nerve fibers within nerve fascicles. Large segments of the myelin sheath are damaged, leaving the axons ex-posed to the extracellular matrix. These findings are consis-tent with a T cell–mediated immune response directed against myelin, which causes its destruction and slows or blocks nerve conduction. Patients exhibit symptoms of as-cending muscle paralysis, loss of muscle coordination, and loss of cutaneous sensation. Multiple sclerosis (MS) is a disease that attacks myelin in the CNS. MS is also characterized by preferential damage to myelin, which becomes detached from the axon and is eventually destroyed. In addition, destruction of oligodendroglia, which are responsible for the synthesis and maintenance of myelin, occurs. The myelin basic protein appears to be the major autoimmune target in this disease. Chemical changes in the lipid and protein con-stituents of myelin produce irregular, multiple plaques throughout the white matter of the brain. Symptoms of MS depend on the area in the CNS in which myelin is dam-aged. MS is usually characterized by distinct episodes of neurologic deficits such as unilateral vision impairment, loss of cutaneous sensation, lack of muscle coordination and movement, and loss of bladder and bowel control. Treatment of both diseases is related to diminishing the causative immune response by immunomodulatory therapy with interferon as well as by administrating adrenal steroids. For more severe, progressive forms, immunosup-pressive drugs may be used.
 FOLDER 12.2 Clinical Correlation: Demyelinating Diseases
The thickness of the myelin sheath at myelination is determined by axon diameter and not by the Schwann cell.