high endothelial venule
Summary
High endothelial venules (HEVs) are specialized postcapillary venules with plump, cuboidal endothelial cells found in lymph node paracortex, Peyer patches, and tonsils (but NOT spleen). They are the main site where naive and central memory T cells and B cells exit blood and enter secondary lymphoid tissue, via L-selectin (CD62L) binding to HEV ligands (PNAd: GlyCAM-1, CD34) and CCR7/LFA-1 signaling.
Detail
**Structure:** Postcapillary venules lined by tall, cuboidal ("plump") endothelium instead of the flat endothelium seen elsewhere. Located in the paracortex (T-cell zone) of lymph nodes, and in Peyer patches, tonsils, and other mucosa-associated lymphoid tissue. Absent in the spleen, which has no HEVs (lymphocytes enter via the marginal zone/open circulation) and no afferent lymphatics.
**Lymphocyte homing (multistep adhesion cascade):** 1. **Tethering/rolling:** L-selectin (CD62L) on naive/central memory lymphocytes binds sialylated, sulfated carbohydrate ligands on HEVs, collectively called peripheral node addressin (PNAd; includes CD34, GlyCAM-1, MAdCAM-1 in part). In Peyer patches, α4β7 integrin binds MAdCAM-1. 2. **Activation:** Chemokines CCL21 (and CCL19) displayed on HEVs bind CCR7 on lymphocytes, triggering integrin activation. 3. **Firm adhesion:** LFA-1 (integrin) on lymphocytes binds ICAM-1 on HEVs. 4. **Diapedesis/transmigration:** Lymphocytes cross the endothelium (via PECAM-1/CD31 and others) into the node parenchyma. B cells then migrate to follicles (CXCL13/CXCR5), T cells stay in the paracortex.
**Clinical significance/associations:** - Allows continuous lymphocyte recirculation and immune surveillance, so naive cells can meet antigen presented by dendritic cells. - Chronic inflammation can induce HEV-like vessels in non-lymphoid tissue (tertiary lymphoid structures), seen in rheumatoid arthritis, Hashimoto thyroiditis, IBD, and some tumors (associated with better prognosis). - Lymphadenopathy during infection is partly due to increased HEV blood flow and lymphocyte entry, plus lymphocyte trapping (S1P1 downregulation) in the node. - Effector T cells downregulate L-selectin and CCR7, so they preferentially go to inflamed tissue (via selectin ligands such as E-/P-selectin, and integrins) instead of HEVs. - Related to leukocyte adhesion deficiency (LAD): LAD type 1 (CD18/β2 integrin defect) impairs firm adhesion, with delayed umbilical cord separation, neutrophilia, and no pus. LAD type 2 (fucosylation defect, loss of sialyl Lewis X) impairs selectin-mediated rolling. - Drug link: Natalizumab (anti-α4 integrin) and vedolizumab (anti-α4β7) block lymphocyte homing (to CNS or gut respectively). Fingolimod (S1P receptor modulator) traps lymphocytes in lymph nodes. Natalizumab is associated with PML (JC virus). - HIV and other infections often show HEV hyperplasia in reactive lymph nodes (follicular and paracortical hyperplasia).
**High-yield pearl:** HEVs = lymphocyte entry points into lymph nodes from blood; afferent lymphatics carry antigen/APCs into the subcapsular sinus; efferent lymphatics carry lymphocytes out via the medulla.
Sources
- Abbas, Lichtman, Pillai - Cellular and Molecular Immunology
- First Aid for the USMLE Step 1 - Immunology: Lymphoid structures, lymph node anatomy, leukocyte extravasation
- Robbins & Cotran Pathologic Basis of Disease - Diseases of white blood cells, lymph nodes
- Janeway's Immunobiology - Lymphocyte trafficking
- Sketchy/Pathoma - Immunology and hematology lymph node sections
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