Circulation and extravasation

By Levi Clancy for Student Reader on
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Circulating white blood cells are stimulated to cross out of blood circulation (extravasation) by sets of adhesion molecules present on both white blood cells and the vascular endothelium of post-capilarry venules (or PCVs, located downstream of every blood capillary).

Extravasation only occurs when adhesion molecules are expressed in both white blood cells and the vascular endothelium. Adhesion molecules on white blood cells are selectins, while adhesion molecules on PCVs are addressins. The table below describes the steps of extravasation to the site of an infection.

Cell TypeLocation (health)Location (infection)

Granulocyte

Circulating in blood.

Extravasate from blood to infected tissue.

Lymphocyte

Entire body.

Infected tissue.

EventDescription

Infection

When an infection occurs, various molecules are released including: antigens secreted by foreign microbes; tumor necrosis factor (TNF), released by macrophages; byproducts of host cell damage, such as histamines or platelet activating factor (PAF).

Addressins

The molecules released by the infection induce nearby post-capillary venules to begin expressing addressins. ELAM-1 is one of the first addressins to get expressed, and it is capable of binding most white blood cells in a low-affinity but good-enough manner.

Adhesion

These early-infection addressins weakly bind white blood cells to the PCV wall (vascular endothelium), an event called adhesion. The clustering of white blood cells at PCVs prior to extravasation is marginalization.

Selectins

Upon adhesion, white blood cells increase expression of the three high-affinity selectins LFA-1, MAC-1 and p150/95. These three selectins are β-integrins, and all share the same β chain but are distinguished by their unique α chains. LFA-1 is found primarily on T cells, and secondarily on granulocytes, monocytes and macrophages. MAC-1 is found primarily on macrophages, and secondarily on granulocytes and lymphocytes (T cells, B cells and dendritic cells).

ICAMs

The three β-integrins described above bind to intercellular adhesion molecules (ICAMs); once the endothelial cells begin expressing ICAMs, white blood cells bind very tightly and begin to squeeze between the endothelial cells through to the tissue on the other side. Simultaneously, the white blood cells begin expressing the receptor for C5a (C5aR). C5a is a byproduct of complement, and chemotactically helps guide the white blood cells to the infection site.

Similarly, virgin lymphocytes must extravasate to specific organs to complete their maturation. These lymphocytes express selectin-like molecules specific for addressins presented on PVCs adjacent to the target tissue. For example, virgin T cells migrating from the bone marrow express selectin-like molecules which bind specifically to addressins expressed only at the thymus (but not at lymph nodes or in the bone marrow). Similarly, virgin B cells migrating from the bone marrow express selectin-like molecules specific for addressins only at lymph nodes and the spleen.

AddressinExpressedOverview

ELAM-1

Early

Expressed transiently, ELAM-1 binds white blood cell cell-surface carbohydrates.

VCAM-1

Midway

VCAM-1 binds with medium to high affinity to VLA-4 (aka α4β1) and LPAM-1 (aka α4β7).

ICAM-1
ICAM-2

Late

ICAM-1 & -2 bind with high affinity to LFA-1(aka α1β2), MAC-1 (aka αmβ2) and p150/95 (aka α2β2).

The table above lists some addressins, when during an infection they are expressed and their affinity for the selectins they bind.