MS Relapses: Consequences

STEP EIGHT

The Ending of the Relapse. MS relapses have a finite duration. They are curtailed by a classic feedback loop in which the end product eliminates the originator. Most CNS-invading Th1 and Th17 T_E cells apoptose in situ. Apoptosis is facilitated by a cytokine-mediated induction of the macrophage/microglial enzyme indoleamine-2,3-dioxygenase (IDO). IFN-γ released by invading Th1 cells activates IDO, with synergistic support provided by macrophage-secreted TNF-α. IDO shunts tryptophan, an amino acid essential for cell growth and functioning, along a pathway that leads to kynurenine. IDO-mediated tryptophan starvation compromises immune cell function and initiates stress-induced apoptosis, chiefly of Th1 effector cells. In addition, catabolites derived from the kynurenine metabolic pathway are directly cytotoxic to Th1 effector cells.

Th17 effector cells are relatively insensitive to tryptophan starvation and kynurenine toxicity. However, CD4⁺ regulatory T cells, now evident in the inflammatory infiltrates, further activate IDO-mediated production of kynurenine via a CTLA-4- CD80/86 interaction. Kynurenine then back-signals to these same regulatory T cells instructing them to send a pro-apoptotic message to Th17 effector cells. In addition, regulatory T cells up-regulate protective cytokines, including interleukin-10 (IL-10). All three mechanisms contribute to the ending of a relapse.

As a relapse is ending, some of the amplified activated microglia are culled by apoptosis, whereas others revert to their earlier ramified state. Astrocytes become gliotic, whereas lipid-laden macrophages make their way to the perivascular space and are thought to slowly exit the CNS.

STEP NINE

Repair. Demyelinated segments may be remyelinated by preoligodendrocytes that enter demyelinated plaques from surrounding areas. Remyelinated segments are readily recognized because internodal distances are shorter, and the myelin sheaths are thinner than their predecessors. Areas of remyelination are known as shadow plaques. Remyelination is spotty at best and becomes minimal as disease evolves. Remyelinated areas are seldom protected from demyelination in subsequent relapses. There is interest currently in neurotrophins as vectors for repair of tissue damage in MS (see later).

EVOLUTION OF THE MS PLAQUE

Pathologists have classified MS plaques in numerous ways. Perhaps the simplest has been to judge them as acute, chronic active, or chronic silent. Acute plaques are likely to be responsible for a new exacerbation. They manifest as regions of active demyelination with illdefined boundaries, extensive inflammatory cell infiltrates throughout, perivascular cuffs, macrophages engaged in myelin stripping and removal, plus diffuse MHC class II–positive macrophages/microglia that release IL-1β, TNF-α, lymphotoxin (LT) and other cytokines, nitric oxide and other free radicals, proteolytic enzymes such as MMPs, and express surfacebound co-stimulatory molecules.

The chronic active plaque shows recent disease at its periphery, or parts of it, but chronic changes in its center. Ongoing demyelination is restricted to the plaque edge extending into the adjacent parenchyma in a centrifugal fashion, and there is a border of MHC class II positivity.⁶¹ The chronic silent plaque has a marked down-regulation of MHC class II reactivity throughout, an absence of further demyelinating activity, and a sharp border. Astrocytes now take on a fibrillary morphology and express the sinuous processes of chronic gliosis. There may be clusters of demyelinated axons in a chronic silent plaque, but also clearly evident is axonal loss that is maximal centrally. OGCs are absent.

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