The immune system relies on a complex network of specialized components to protect the body from threats. Among these are high endothelial venules, or HEVs, which are specialized blood vessels that serve a fundamental role in immune surveillance. These unique vessels act as precise gateways, orchestrating the movement of immune cells throughout the body. Their importance in maintaining health and responding to disease is well-recognized.
Unique Anatomy and Primary Locations
High endothelial venules distinguish themselves from other blood vessels through their unique cellular structure. Unlike typical flattened endothelial cells that line most vessels, HEVs are characterized by plump, cuboidal endothelial cells. These “high” endothelial cells give the venules their name and reflect an intense biosynthetic activity not observed in other flat endothelial cells.
The specialized surface of these cuboidal cells is covered with various receptors and adhesion molecules. One such molecule is peripheral node addressin (PNAd), which specifically binds to L-selectin on lymphocytes. These specialized ligands and receptors enable HEVs to support high levels of lymphocyte extravasation.
HEVs are consistently found in secondary lymphoid organs, which are key sites for immune responses. These locations include lymph nodes, tonsils and adenoids in the pharynx, and Peyer’s patches in the small intestine. While HEVs are present in most secondary lymphoid organs, they are notably absent from the spleen.
Orchestrating Immune Cell Movement
The primary function of HEVs is to facilitate the entry of lymphocytes from the bloodstream into lymphoid tissues, a process known as lymphocyte extravasation. This multi-step process allows immune cells to continuously circulate and survey the body for foreign invaders and abnormal cells.
The extravasation process begins with initial tethering and rolling of lymphocytes along the HEV wall. This weak attachment is mediated by L-selectin molecules on the lymphocyte surface binding to PNAd on the HEV endothelium. This rolling mechanism allows the lymphocytes to “scan” the endothelial surface for further signals.
Following rolling, chemokines presented on the HEV surface activate the rolling lymphocytes. This activation triggers a change in integrin molecules on the lymphocyte surface, leading to firm adhesion of the lymphocytes to adhesion molecules on the HEV wall.
After firm adhesion, lymphocytes undergo diapedesis, which is their passage through the HEV wall into the lymphoid tissue. This transmigration can occur through or between endothelial cells. Once inside the lymphoid tissue, these lymphocytes can interact with antigen-presenting cells to initiate immune responses.
HEVs in Health and Disease
Beyond their normal role in immune surveillance, HEVs have broader implications in various health and disease states. During chronic inflammation, infection, or cancer, HEV-like structures, often referred to as tertiary lymphoid structures (TLSs), can form in non-lymphoid tissues. These structures resemble secondary lymphoid organs and can contribute to the amplification and maintenance of chronic inflammation.
Dysregulation of HEV function can contribute to the development and progression of autoimmune conditions. For example, in diseases like rheumatoid arthritis and inflammatory bowel diseases, HEV-like vessels are induced in affected tissues. This abnormal presence of HEVs can lead to increased infiltration of immune cells into these tissues, contributing to the pathological inflammation characteristic of these disorders.
In the context of cancer, tumor-associated HEVs (TA-HEVs) are frequently observed in solid tumors. The presence of these TA-HEVs has been correlated with reduced tumor size and improved patient outcomes in some cancers, suggesting they play a role in anti-tumor immunity. TA-HEVs are believed to promote anti-tumor immunity by recruiting naive lymphocytes into the tumor, allowing for the local generation of cancer-destroying lymphocytes.