STEP THREE

Perivascular cuff monocytes function as APCs. They capture local antigenic material, process it, and present processed antigen in the context of surface-expressed MHC class II molecules so as to prime abutting CD4⁺ T_E cells for full effector function. In addition, microglial-derived DCs, resident in the juxtavascular CNS parenchyma, extend processes between astrocyte foot processes and through the basement membrane of the glia limitans (see later), express MHC class II alleles, and likewise present antigen to perivascular T_E cells, further priming them in anticipation of their movement into the CNS parenchyma.

STEP FOUR

Plasma proteins leak into the CNS parenchyma at sites of acute MS disease activity. Plasma proteins, including fibrinogen and high-molecular-weight IgM, are carried across endothelial cells by an energy-requiring intra­cytoplasmic vesicular transport mechanism. Gado­linium (GD) is also transported into the CNS paren-chyma in this same fashion, at least in guinea pigs with EAE. Transport is maximal across capillaries rather than across the postcapillary venules that CNS-invading immune system cells traverse. Most gadolinium positive lesions are silent clinically so that transendothelial cell transport of blood elements into the perivascular space need not, even when extensive, engender symptoms of an MS relapse.

STEP FIVE

Perivascular cuff T cells and monocytes must next cross the glia limitans (GL). The GL is composed of astrocytic end-foot processes and a basement mem-brane. It covers the entire surface of the brain and spinal cord, where it faces the SAS. Internally, the GL forms the outer barrier of the extravascular space. The laminins of this outer basement membrane (LAM-1, LAM-2) differ from those of the vascular basement membrane. The GL blocks T-cell transmigration. However, monocytes, co-migrants with T cells into perivascular spaces, secrete the matrix metalloproteinases (MMP)-2 and MMP-9 in response to the VLA-4–VCAM-1 interaction that permitted their diapedesis into a perivascular cuff. These proteases acting together, cleave the dystroglycan that anchors astrocyte end feet to the GL basement membrane so that dystroglycan no longer binds to LAM-1, LAM-2, or to agrin, a laminin stabilizer. As astrocyte foot processes retract, the GL opens. Products released from perivascular cells can now freely percolate into the CNS parenchyma, and T cells and macrophages can migrate into the CNS parenchyma and induce the neurologic deficits that characterize an MS relapse.

Related posts:

Hydrocephalus Memory Circuits Social Anxiety disorder Visual Inputs to the Hypothalamus Brain Death Cerebellovestibular Pathways

Stay updated, free articles. Join our Telegram channel

Join