STEP ONE

This is clinically silent and takes place in the subarachnoid space (SAS) and within the cerebral ventricles. Between 10⁵ and 5 × 10⁵ lymphoid cells are present in the noninflamed CSF of humans at any point in time. Eighty percent of these are CD4⁺ T_CM cells in search of their cognate antigen, with lesser representations of CD8⁺ T_CM cells and of CD4⁺ T_E cells, these last probably derived from CD4⁺ T_CM cells that have found their cognate antigen (see later).

Postcapillary venules on the pial surface and within the choroid plexuses express CCL21 and ICAM-1, whereas CD4⁺ T_CM cells express CCR7, the counter­ligand for CCL21, and richly express LFA-1, the counterligand for ICAM-1. CCR7-CCL21 and LFA-1–ICAM-1 interactions permit CD4⁺ T_CM cells to pass from postcapillary venules into the SAS and from choroid plexus venules into the ventricles. CD4⁺ T_CM cells, once in the SAS, move first along the outer surface of meningeal vessels and then along the pial surface, searching for their cognate antigen. Should they encounter their cognate antigen, offered to them in processed form by an APC, a local immune response is initiated. Should surveillance of the SAS prove fruitless, CD4⁺ T_CM cells return to the blood.

In humans, major histocompatibility complex (MHC) class II–expressing DCs with up-regulated co-stimulatory molecule expression are present in the CSF compartment. They are situated on the surface of meningeal microvessels and on pial and ependymal surfaces. Their numbers appear to be enriched in MS. Abundant myelin debris with contained protein antigens, residua of prior MS relapses, follows the established drainage paths of interstitial fluid through the ependyma into the ventricular CSF and via Virchow-Robin spaces into the SAS. Residual myelin particles are extracellular for the better part but are also detected within DCs and macrophages. Myelin debris is not found in controls.

CD4⁺ T_CM cells prepare the terrain for the subsequent entry of T_E cells into the CNS parenchyma and the onset of the clinically evident component of a relapse. Adhesion molecules are not expressed by resting brain parenchymal endothelial cells, nor do meningeal vessels ordinarily express vascular cell adhesion molecule-1 (VCAM-1), the adhesion molecule required for CD4⁺ T_E-cell exit from the blood. CD4⁺ T_CM cells, having made synaptic contact with a DC, may undergo several cycles of division, still within the meninges or the ventricles to generate a small locally restricted CD4⁺ T_E-cell cohort. Some members of this cohort cross the pia or ependyma to enter the subjacent CNS parenchyma. These pioneer CD4⁺ T_E cells secrete interferon-γ (IFN-γ), as does a subpopulation of still SAS-confined CD4⁺ T_CM cells that are perhaps transitioning into T_E cells.

Released IFN-γ diffuses from the pial and ventricular ependymal surfaces and from the immediately subjacent CNS parenchyma for a considerable depth into the CNS parenchyma, oozing preferentially along fiber tracts. In addition, the released IFN-γ activates intraparenchymal microglia as evidenced morphologically by retraction and thickening of their processes. Microglial activation is essential for the subsequent invasion of the CNS parenchyma by T_E cells and by blood monocytes destined to become macrophages. Activated microglia secrete cytokines, and notably tumor necrosis factor-α (TNF-α), which activates nearby parenchymal post­capillary venules. These venules quickly come to resemble the high endothelial venules of LNs and, most important, now begin to express the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and VCAM-1.

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