MS Pathophysiology

Immature DCs in the CNS subarachnoid space ingest myelin elements; after that, they may mature in situ. Mature DCs express the cell surface molecule C-C chemokine receptor 7 (CCR7), whereas endothelial cells in afferent lymphatic channels express chemokine ligand 21 (CCL21) counterligand. Ligation of CCR7 permits mature self-antigen–bearing DCs to migrate via afferent lymphatics to deep cervical LNs. Mature DCs are short lived and have lost their capacity to sample newly presented viral or other antigenic material, whereas long-lived immature DCs or macrophages can do so.

Extracellular debris, including myelin and its peptides, flows from a damaged CNS to deep cervical LNs where subcapsular macrophages and immature DCs capture it. Unlike controls, deep cervical LNs of MS patients with inactive disease contain numerous immature DCs and macrophages with ingested myelin and myelin proteins that can, under appropriate circumstances, be presented to T cells. Immature DCs and macrophages retain the capacity to respond to subsequently encountered viral antigens.

Naïve CD4⁺ T cells (T_N) move swiftly through LNs, making serial brief contacts with antigen-loaded DCs draped atop the fibroblastic reticular cells (FRC) that enwrap the collagen fiber structural backbone of the LN. Lymph is transferred from the subcapsular sinus to the medulla via the collagen-containing channels of the conduit network. DCs insert processes into the conduit channels to capture peptide elements contained therein, which they can then process and present to T cells. T_N cells seek that rare DC expressing the cognate antigen they are programmed to recognize. When a CD4⁺ T_N cell fails in its quest, as usually occurs, it migrates to the LN medulla and exits via efferent lymph. Exit requires expression of the sphingosine-1- phosphate receptor-1 (S1P-1) by migrating CD4⁺ T_N cells. This requirement has been exploited in MS therapy. CD4⁺ T_N cells pass from the efferent lymph into the circulation and move on via the blood to sample another LN. They do not enter the tissues.