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General structures of the four families of cell-adhesion molecules * Glycosylated proteins * Heterodimeric proteins * Expressed by leukocytes * Facilitate adherence (LAD disease) * Contain Ig/mucin-like domains * Expressed on endothelial cells * Bind to integrin/selectin molecules * Interact with sialylated carbohydrate moieties of mucin-like molecules. * Responsible for the initial stickiness of leukocytes to vascular endothelium.
Steps in neutrophil extravasation Inflammatory response ↓ cytokines, inflammatory mediators Vascular endothelium activated Increased expression of CAMs Receptor activation- induced conforma-tional change in the integrin molecules → increased affinity & adhesion Neutrophil activation by chemoattractant stimulus: chemokines, PAF, C5a, C3a, C5b67, bacterial peptides The neutrophil tumbles end-over-end along the endothelium. The neutrophil migrates through the vessel wall into the tissues.
Schematic cross-sectional diagram of a lymph node postcapillary venule with high endothelium (HEV) As many as 1.4 x 104 lymphocytes extravasate every second through HEVs into a single lymph node. Each of the secondary lymphoid organs, with the exception of the spleen, contains HEVs.
Steps in extravasation of a naïve T cell through a high endothelial venule into a lymph node • Activation of • integrin molecules (a homing receptor) • G-protein-coupled • receptors • Lymphocyte-specific • chemoattractants
Mediators of inflammation • Chemokines and other mediators released by tissue • mast cells, blood platelets, leukocytes and lymphocytes. • Mediator-producing systems in plasma: • - the kinin system • - the clotting system • - the fibrinolytic system • - the complement system • Some lipids act as inflammatory mediators • Some cytokines are important inflammatory mediators
Chemokines • A superfamily of small polypeptides (90-130 aa residues) • Major regulators of leukocyte traffic • (adhesion, chemotaxis, activation) • Involved in inflammation, homeostatic/developmental • processes, angiogenesis, wound healing • Induced in response to infection • → Assembly of leukocytes at sites of infection • > 50 chemokines, possess 4 conserved cysteine residues • (C-C subgroup, C-X-C subgroup) • > 15 chemokine receptors (CC receptors, CXC receptors) • The interaction between chemokines and their receptors • is of high affinity (Ka > 109) and high specificity.
Chemokines signal through receptors coupled with heterotrimeric large G proteins • Changes in shape of leukocytes • Activation of integrins • Generation of oxygen radicals • Release of granular contents and proteases
The complement system • anaphylatoxins (C3a, C4a, C5a) • → mast cell degranulation & mediators (histamine…) release • → increase vascular permeability • induce smooth-muscle contraction • C3a, C5a and C5b67 • → adhesion, extravasation and migration • of monocytes and neutrophils • Influxes of fluid that carry antibody and • phagocytic cells to the site of antigen entry.
A localized acute inflammatory response • redness & heat • vasodilation - an increase in vascular diameter • an increase in the volume of blood in the area • & a reduction in the flow of blood • swelling • an increase in vascular permeability • leakage of fluid from the blood vessels • an accumulation of fluid in the tissue (edema) • extravasation of leukocytes • activation of the kinin, clotting, fibrinolytic • and complement (C53a, C4a, C5a) systems
Macrophages: • arrive about 5-6 hours after an inflammatory response begins • exhibit increased phagocytosis • exhibit increased release of mediators, cytokines and • lytic enzymes that contribute to the inflammatory response • (IL-1, IL-6, TNF-a)
The acute-phase response produces molecules that bind pathogens but not host cells. On vertebrate cells, these mannose residues are covered by other sugar groups, especially by sialic acid while avoiding complement activation on host cell surfaces.
Comparison of the structure and function of C/EBP and NF-IL6 *Both transcription factors are dimeric proteins containing a leucine-zipper domain and a basic DNA-binding domain. *Both proteins bind to the same nucleotide sequence in the promoter or enhancer of the genes encoding various liver proteins.
