Enigma of Progressive MS

Careful examination of normal-appearing white matter in progressive MS reveals elongated paranodes with a disrupted profile, axonal swellings, and amyloid precursor protein accumulations. These correlate with the density of ramified activated (inducible nitric oxide synthase–positive) microglia but not with the limited presence of perivascular T-cell infiltrates or the limited number of CNS parenchyma-infiltrating T cells, most of which are now CD8⁺ and of uncertain function. Gray matter lesions that contain few T cells become increasingly prominent with accompanying damage to cortical axons, to dendrites, and to neuronal cell bodies. Gray matter lesions in SPMS, as with axonal dysfunction in white matter, are strongly associated with activated microglia.

Of interest, activated T cells are still to be found in the meninges. Meningeal inflammation can be extensive and it has been suggested that it may somehow contribute to subpial cortical demyelinated plaques and an accelerated clinical course. Since T cells and macrophages are rare in cortical demyelinated regions and activated microglia are abundant, a microglia-activating signal delivered from a distance has been proposed. What prevents activated CD4⁺ T cells from entering the CNS gray matter and white matter parenchyma in SPMS is not understood. One possibility is the release of human leukocyte antigen-G (HLA-G) by activated microglia in SPMS. HLA-G is a nonclassic HLA class I antigen first detected at the extravillous cytotrophoblastic fetomaternal interface where it provokes immune tolerance and potently protects the fetus from destruction by maternal T cells. HLA-G has subsequently been found at several immunologically privileged sites including the CNS. In RRMS, HLA-G levels in CSF are far lower when MRI scans are GD-positive, an indicator of T-cell activation within the CNS, than when MRI scans are GD-negative and disease is quiescent. Microglia in tissue sections from autopsied individuals with SPMS show markedly up-regulated expression of HLA-G.

It seems likely that products released from microglia, including nitric oxide and other free radicals; glutamate, known to be toxic in excess; and cytokines, including tumor necrosis factor-α (TNF-α) and lymphotoxin (LT) that are also toxic in excess, have a major role in the diffuse axonopathy and neuronal destruction of progressive MS. Loss of the trophic support to axons normally provided by oligodendrocytes may also contribute. Some MS patients with late-stage disease show meningeal plasma cell-containing lymph follicle-like structures chiefly deep in sulci and superimposed on extensive meningeal T cell and macrophage infiltrates. Paradoxically, TNF-α and LT, released in excess in progressive MS, may actually promote the development of these lymphoid follicle-like meningeal structures because TNF-α and LT are essential for development of LN follicles.

Presumably, in progressive MS microglia no longer receive those signals from neurons and astrocytes that, in homeostasis, hold them in quiescence. Among such signals are norepinephrine, acetylcholine, and dopamine. These neurotransmitters counteract activating signals provided by glutamate and by ATP, which attracts microglia to sites of damage, and adenosine, which holds them there. How to change this for the better remains a challenge.

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