Lymphocyte Circulation and Adhesion Molecules

• Lymphocytes use two circulatory systems to monitor the body for microbes.
• Recirculation is essential for a rapid and effective immune response.
• Lymphocytes move throughout the body allowing maximal numbers of antigenically committed lymphocytes to encounter antigen.
• Lymphocytes live in the bloodstream for approximately 30 minutes.
• About 45% of all lymphocytes are carried from the blood to the spleen.
• Roughly 42% of lymphocytes enter peripheral lymph nodes, and live there for about 12 hours.
• Approximately 10% of lymphocytes migrate to extra lymphoid tissues, mainly to areas frequently exposed to the external environment.
• Adhesion molecules bind cells and stabilize cell-to-cell interaction.
• Adhesion molecules temporarily connect cells to stabilize interactions, involving APCs with T and B cells.
• Epithelial cells express adhesion molecules to stabilize interaction with lymphocytes before extravasation and cell trafficking.

Adhesion Molecules

• Cadherins bind cells together, maintaining tissue integrity and requiring calcium for adhesion.
• Selectins mediate leukocyte migration to inflammation sites and contain a lectin domain for carbohydrate binding.
• Immunoglobulin (Ig) superfamily adhesion molecules fine-tune leukocyte binding to blood vessel endothelial cells.
• Integrins consist of heterodimeric transmembrane chains with alpha and beta subunits, where the beta two subunit is exclusively on leukocytes.
• Integrin binding triggers changes in intracellular cytoplasmic domains and interaction with other proteins, also sending bidirectional signals across the plasma membrane.
• Selectins on endothelial cells bind to sialyl Lewis carbs on leukocytes
• ICAM-1 and VCAM-1 on endothelial cells bind to integrins on leukocytes, and are members of the Ig superfamily.

Extravasation process

• Initial rolling reduction is mediated by B selectin binding to cytosolated carbohydrate moieties on leukocytes.
• Chemokine IL-8, secreted by the endothelial cells, binds to a protein linked receptor on the neutrophil/leukocyte, causing a conformational change.
• Integrin conformational changes in the host cell facilitate binding to IG superfamily ICAM and IVAM molecules on the endothelium.

Leukocyte Extravasation

• Activated leukocytes migrate from blood vessels via a four-step process called extravasation.
• Endothelium upregulates P and E selectin in response to cytokine stimulus, to bind to and slow down fast-moving leukocytes.
• Selectins bind to sialyl Lewis molecules on leukocytes, causing controlled rolling on the endothelial cell surface.
• Integrins, such as LFA one and Mac one, on leukocytes bind to Ig superfamily molecules on endothelial cells, anchoring the cells.
• Diapedesis occurs as leukocytes migrate through high endothelial venules (HEVs).
• HEVs allow for greater leukocyte adhesion due to their structure.
• Leukocytes migrate to sites of microbial invasion guided by cytokines and chemokines after exiting the blood.

Leukocyte Adhesion Deficiency (LAD)

• LAD results from a dysfunctional adhesion molecule mechanism
• Mutation in a gene encodes molecules mediating interaction between phagocytes and endothelial cells
• LAD Type One is a failure to express CD 18, a subunit of integrin molecules, preventing adhesion.
• LAD Type Two, extremely rare, results from the absence of sialyl Lewis x on leukocytes, affecting rolling.
• In both types, phagocytes get trapped in circulation, unable to reach infected tissue.
• Pathogens spread uncontrollably, causing tissue injury, while tissue debris removal and wound healing are slowed.
• Umbilical cord detachment is delayed in infants with LAD.
• Both LAD types are inherited in an autosomal recessive pattern.
• Symptoms include recurrent bacterial or fungal infections of skin or mucosal membranes without pus or abscess formation.
• Wounds heal slowly, leading to poorly formed, thin scars, and umbilical cord sloughing is delayed.
• Life expectancy is often shortened without treatment.

Adhesion Molecules in Leukocyte Recruitment/Extravasation

• Adhesion molecules facilitate leukocyte migration from the bloodstream to infection/inflammation sites.
• Selectins (E-selectin, P-selectin) on endothelial cells mediate initial weak interactions with leukocytes, causing them to roll along the endothelium.
• Chemokines are signaling proteins that activate leukocytes and guide them to inflammation sites.
• Chemokines bind to leukocyte receptors, triggering intracellular signaling pathways.
• Integrins (LFA-1, VLA-4) on leukocytes undergo conformational changes upon encountering chemokines, allowing firm adhesion to endothelial cells.
• Leukocyte integrins interact with endothelial adhesion molecules like ICAM-1 and VCAM-1 for strong adhesion.
• Leukocytes transmigrate through endothelial cell junctions, facilitated by adhesion molecules interacting with junctional proteins like PECAM-1.

Interleukin-8’s Role in Extravasation

• IL-8 is produced at infection/inflammation sites by cells like macrophages, neutrophils, and endothelial cells.
• It acts as a chemoattractant, binding to CXCR1 and CXCR2 receptors on neutrophils and leukocytes.
• IL-8 binding triggers intracellular signaling, increasing adhesion molecule expression and cell activation.
• IL-8 contributes to the rolling-to-firm adhesion transition of leukocytes on the endothelium.
• Under IL-8 influence, integrins on leukocytes activate and bind to endothelial adhesion molecules like ICAM-1 and VCAM-1.

CD18 Deficiency in Leukocyte Adhesion Deficiency

• Patients deficient in CD18 are susceptible to encapsulated organism infections due to impaired leukocyte function.
• LAD impairs the ability of leukocytes to adhere to the vascular endothelium and migrate to infection/inflammation sites.
• Leukocytes cannot properly adhere to and phagocytose pathogens due to impaired adhesion.
• Encapsulated organisms are not efficiently engulfed and neutralized by leukocytes.

Lymphocytes recirculate through the body via circulatory systems for immune surveillance. Adhesion molecules mediate cell-to-cell interactions, crucial for immune responses. Understanding these processes is key to understanding immunity.