Cell adhesion molecules / endothelial leukocyte adhesion molecules involved in inflammatory response md pathology exam question Robbins based answer use answer
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Robbins pathology leukocyte adhesion molecules selectins integrins ICAM VCAM inflammatory response
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Cell adhesion molecules in leukocyte recruitment during inflammation
Leukocyte emigration from blood into tissues occurs mainly in postcapillary venules. It is a coordinated multistep process involving endothelial and leukocyte adhesion molecules.
Sequence of leukocyte recruitment
-
Margination
- Vasodilatation and loss of plasma cause stasis.
- Leukocytes move from the central axial blood column toward the endothelial surface.
-
Rolling
- Mediated by selectins.
- Selectin interactions are weak, transient, and repeatedly break and reform, producing rolling.
-
Leukocyte activation
- Endothelial-bound chemokines activate rolling leukocytes.
- This produces conformational change and clustering of leukocyte integrins, converting them to a high-affinity state.
-
Firm adhesion
- Mediated by high-affinity integrins on leukocytes binding to immunoglobulin-superfamily adhesion molecules on activated endothelium.
-
Transmigration / diapedesis
- Mainly at inter-endothelial junctions.
- Mediated primarily by PECAM-1 (CD31) on both leukocytes and endothelial cells.
- Leukocytes then cross the basement membrane using collagenases and migrate toward chemotactic stimuli.
Major adhesion molecules
| Family | Molecule | Principal site | Ligand / counter-receptor | Main role |
|---|---|---|---|---|
| Selectins | L-selectin (CD62L) | Leukocytes | Sialyl-Lewis X-containing glycoproteins on endothelium | Rolling |
| E-selectin (CD62E) | Activated endothelium | Sialyl-Lewis X on neutrophils, monocytes, T cells | Rolling | |
| P-selectin (CD62P) | Activated endothelium and platelets | Sialyl-Lewis X on leukocytes | Rolling | |
| Integrins | LFA-1 (CD11a/CD18) | T cells and other leukocytes | ICAM-1 (CD54) on activated endothelium | Firm adhesion |
| Mac-1 (CD11b/CD18) | Neutrophils, monocytes and other leukocytes | ICAM-1 | Firm adhesion | |
| VLA-4 (α4β1) | Lymphocytes, monocytes and other leukocytes | VCAM-1 (CD106) | Firm adhesion | |
| α4β7 integrin | Lymphocytes and monocytes | MAdCAM-1 on gut endothelium | Gut homing | |
| Ig superfamily CAMs | ICAM-1 | Activated endothelium | LFA-1, Mac-1 | Firm adhesion |
| VCAM-1 | Activated endothelium | VLA-4 | Firm adhesion | |
| MAdCAM-1 | Gut-associated endothelial cells | α4β7 integrin | Mucosal lymphocyte trafficking | |
| PECAM family | PECAM-1 / CD31 | Leukocytes and endothelial junctions | Homotypic PECAM-1 interaction | Transmigration |
Regulation of endothelial adhesion molecules
P-selectin
- Stored preformed in endothelial Weibel-Palade bodies.
- Also present in platelet alpha granules.
- Rapidly translocated to the endothelial surface within minutes after stimulation by:
- Histamine
- Thrombin
E-selectin and ligands for L-selectin
- Not significantly expressed on resting endothelium.
- Induced by inflammatory cytokines, especially:
- TNF
- IL-1
ICAM-1 and VCAM-1
- Upregulated on endothelial cells by:
- TNF
- IL-1
- Permit firm leukocyte attachment through leukocyte integrins.
Chemokines
- Produced at inflammatory sites and displayed on endothelial proteoglycans.
- Activate leukocyte integrins, allowing strong binding to ICAM-1 and VCAM-1.
Important concepts
- Selectins = rolling
- Integrins = firm adhesion
- PECAM-1/CD31 = transmigration
- TNF and IL-1 activate endothelium and increase adhesion molecule expression.
- Adhesion molecule expression localizes leukocyte recruitment to the site of infection or tissue injury.
Clinical correlation: Leukocyte adhesion deficiency
Defects in leukocyte adhesion molecules cause impaired neutrophil recruitment and recurrent bacterial infections.
Leukocyte adhesion deficiency type I
- Defect of β2 integrins (CD18).
- Impaired LFA-1 and Mac-1 function.
- Features:
- Recurrent bacterial infections
- Delayed separation of umbilical cord
- Impaired wound healing
- Minimal pus formation
- Persistent neutrophilia in blood
Leukocyte adhesion deficiency type II
- Defective synthesis of sialyl-Lewis X, the ligand needed for selectin-mediated rolling.
- Causes defective leukocyte rolling and recruitment.
Exam summary: In acute inflammation, E-, P-, and L-selectins mediate weak leukocyte-endothelial interactions and rolling. Chemokines activate leukocyte integrins. LFA-1 and Mac-1 bind ICAM-1, while VLA-4 binds VCAM-1, producing firm adhesion. PECAM-1 mediates leukocyte diapedesis across endothelial junctions.
Source: Robbins & Kumar Basic Pathology, “Leukocyte Recruitment to Sites of Inflammation,” pp. 45-46.
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