Extravasation: Leukocyte Trafficking

• Immune cells secrete chemical signals at the site of microbial invasion
• This recruits other cells to facilitate inflammation

Extravasation

• Phagocytic cells are recruited from the blood to sites of inflammation
• Extravasation is a tightly regulated four-step process
• This leukocyte recruitment is critical for inflammation and resolving infections
• Extravasation involves recognizing inflammatory markers, adhering to the endothelium, and migrating through tissue

Four Steps of Extravasation:

• Rolling
• Activation by chemoattractants
• Arrest and Adhesion
• Transendothelial Migration (Diapedesis)

Associated Molecules:

• IOA induces a conformational change in integrin molecules
• This increases affinity for adhesion
• Integrin and IG-CAM interactions mediate arrest and adhesion
• Once in tissues, phagocytic cells increase receptors for chemoattractants
• They then exhibit chemotaxis, migrating to infected areas
• Cells use chemical signals (cytokines and chemokines) to migrate to infection sites

Chemotaxis

• After diapedesis, leukocytes migrate towards inflammation/infection sites along a chemical gradient
• Cytokine IL-8 (from monocytes/macrophages) can be a chemoattractant
• Complement C5a (from classical or alternative pathways) also acts as a chemoattractant
• Leukotriene B4 (from membrane phospholipids) can be a chemoattractant
• Formyl peptides released from microorganisms act as chemoattractants
• Chemokine receptor activation occurs on the surface of migrating phagocytes
• CXCR1, CXCR2, and CXCR4 are chemokine receptors expressed on neutrophils

Phagocytic Cell Recruitment

• Blood flow slows, pushing leukocytes to the periphery in process called margination
• Pro-inflammatory cytokines (Interleukin-1 & TNF-alpha) released by macrophages and mast cells
• Endothelial cells and leukocytes then express adhesion molecules
• Selectins on the endothelium bind to Sialyl Lewis proteins on leukocytes, causing rolling
• Integrins on leukocytes bind to VCAMs (vascular cell adhesion molecules) on the endothelium, resulting in firm adhesion
• Pro-inflammatory cytokines induce VCAM expression
• Chemokines induce diapedesis, or leukocyte migration through endothelial cells

Mnemonic Devices

• For neutrophil migration: Sialyl Lewis Selects, Integrates & Peeks on thru
  • Sialyl Lewis on neutrophil binds to selectin (rolling)
  • Integrin binds to ICAM (adhesion)
  • Peeks thru (PECAM; diapedesis)
• Neutrophil chemotaxis: Bacteria party (bacteria products)!! Come at 5AM (C5a), bring 4-liter bottles (Leukotriene B4; LTB4), & don’t be late (Interleukin 8; IL8)

Leukocyte Adhesion Deficiency (LAD)

• There are 3 subtypes of Leukocyte Adhesion Deficiency, each associated with a specific genetic mutation

LAD Type I (LAD-I)

• Underlying cause: mutations in the ITGB2 gene, which encodes the beta-2 integrin subunit CD18.
• Function impairment: CD18 is an essential component of integrins, which are cell surface receptors involved in the adhesion and migration of white blood cells.
• Absence or dysfunction of CD18 impairs leukocyte adhesion and migration

LAD Type II (LAD-II)

• Underlying cause: mutations in the SLC35C1 gene, leading to a deficiency in fucose transporter 1 (FUT1).
• Function impairment: FUT1 is essential for the synthesis of selectin ligands, which are molecules that facilitate the initial interaction between white blood cells and the blood vessel walls.
• Absence of functional FUT1 impairs the ability of white blood cells to roll and adhere to the vessel walls.

LAD Type III (LAD-III)

• Underlying cause: mutations in the KINDLIN3 gene.
• Function impairment: KINDLIN3 is involved in the activation of integrins, promoting their binding to other molecules.
• Dysfunctional KINDLIN3 results in impaired integrin activation, affecting leukocyte adhesion and migration.

LAD Clinical Features:

• Individuals are prone to recurrent and severe bacterial and fungal infections, often starting in infancy.
• Infections can affect the skin, mouth, respiratory tract, and other mucous membranes.
• Delayed wound healing and impaired formation of pus are common features.
• Abscesses and chronic periodontitis may occur.
• Affected individuals may exhibit poor wound healing, delayed separation of the umbilical cord, and impaired inflammatory responses.

Signs and Symptoms of LAD

• Children with LAD are highly susceptible to bacterial and fungal infections
• Infections can affect the skin, respiratory tract, oral cavity, and other mucous membranes
• Common infections include skin abscesses, respiratory infections, and severe periodontitis
• Wounds, cuts, or injuries may take longer than usual to heal
• Infants with LAD may exhibit delayed separation of the umbilical cord
• Pus, which is typically formed as a response to infection, may be absent or impaired
• Chronic infections and the associated inflammatory response may lead to poor growth and development
• In some cases, gastrointestinal symptoms such as diarrhea may occur
• Children with LAD are at an increased risk of developing sepsis
• The inflammatory response to infections may be atypical, with a lack of the usual signs such as redness, warmth, and swelling