What holds tissue together and are used by leukocytes to interact with tissue cells?
Cell adhesion molecules (CAMs)
What is the gatekeeper regulating the movement of blood-borne molecules and leukocytes into the tissue?
What is the process by which circulating leukocytes enter inflamed tissue or peripheral lymphoid organs by adhering to and passing through endothelial lining?
How is diapedesis regulated by allowing predominantly one type of white blood cell to be released?
Endothelial cells express leukocyte specific CAMs
In addition to leukocyte to vascular endothelium binding, what else do CAMs do?
Interactions between leukocytes and other cells involved in the immune response TH cells and APCs TH and B cells CTLs and target cells
Most CAMs belong to what four families of protein?
Selectin family Mucin-like family Integrin family The immunoglobulin superfamily
Name the 3 main selectins and where they are found.
L-selectin Most circulating leukocytes E-selectin Vascular endothelium during an inflammatory response P-selectin Vascular endothelium during an inflammatory response
In the overall scheme of the inflammatory response, what is the role of the selectins?
Responsible for the initial stickiness of leukocytes to vascular endothelium
What do the mucins present as binding sites to selectins?
Describe what integrins do.
Most bind extracellular matrix molecules and provide cell matrix interactions Some subfamilies bind cell surface adhesion molecules and are involved in cell-cell interactions
What is the significance of clustering of integrins on the cell surface?
Increases the likelihood of effective binding Plays a role in leukocyte migration
Describe Ig superfamilies.
Adhesion molecules that contain a variable number of immunoglobulin-like domains
Name three categories of Ig-superfamily adhesion molecules.
ICAM VCAM PECAM
What are the various functions of chemokines?
Control adhesion, chemotaxis, and activation of leukocytes Regulate leukocyte traffic Involved in the inflammatory process Play a role in homeostatic or developmental roles
List the different changes a leukocyte can undergo if influenced by chemokines.
Cell changes shape Greater adhesiveness to endothelial walls Generate microbial radicals Release proteases of neutrophils and macrophages Basophils release histamine Release cytotoxic proteins from eosinophils
What is the only way a cell can respond to chemokine?
The cell must posses a receptor for that particular chemokine
What happens to endothelial cells in response to inflammatory chemokines?
Increase number of CAMs
What is the process by which leukocytes leave the blood stream and travel to tissue in the periphery?
List the four steps of extravasation of white blood cells.
Rolling Activation by chemoattractants Arrest and adhesion Transendothelial migration
The leukocyte is briefly tethered to a selectin molecules is released and tethered again by a selectin molecule on another endothelial cell
What is the relationship between rolling and activation by chemoattractants?
Rolling slows the leukocytes long enough to allow interactions between chemokines
What allows for specificity of the line of leukocytes that undergo extravasation?
Different chemokines and receptors on the leukocytes and endothelial cells allow for specificity
What is the significance of signal transduction caused by chemokines?
Causes conformational changes on the leukocytes Less likely to be swept away in the blood Can squeeze between two neighboring endothelial cells
What is the first type of leukocyte to extravasate into tissue?
What prevents the binding of neutrophils to non-inflamed endothelium?
Lack of E- and P-selectin
Where do the chemokines come from that attract neutrophils?
Permanently found on endothelial cells Secreted locally by cells involved in the inflammatory response
What are the two chemokines involved in neutrophil extravasation?
IL-8 Macrophage inflammatory protein Iβ
How do the signals from the chemoattractant cytokines affect neutrophils?
Induces conformational changes in the integrin molecules on the neutrophil membrane
What causes the neutrophil to migrate to a specific area once it has successfully left the blood stream?
Gradients of chemoattractants
How does monocyte extravasation differ from neutrophil extravasation, time wise?
Monocytes go to the site much later than neutrophils
What is the relationship between monocytes and uninflammed tissue?
A subpopulation of monocytes migrates at low levels into uninflammed tissues to replenish macrophages and dendritic cells
What two surface markers causes peripheral blood monocytes to adhere more effectively and migrate into the inflamed tissue?
What lures monocytes to areas of infection?
Bacterial peptide fragments Complement fragments
What is the circulation pattern of lymphocytes?
Recirculate continuously through the blood or lymph Spend 30 minutes in the bloodstream 45% are carried to the spleen 42% enter lymph nodes 10% migrate to tertiary extralymphoid tissue
What is the significance of lymphocyte recirculation?
Allows the maximum number of antigenically committed lymphocytes to encounter antigen Insure appropriate populations of B and T cells to be recruited into different tissue
What are plump cuboidal shaped cells found in post capillary venules of lymphoid organs known as?
High-endothelial venules (HEV) found in each secondary lymphoid organs
What influences the development and maintenance of HEVs in lymphoid organs?
Cytokines in response to antigen capture
What adhesion molecules are expressed by HEVs?
CAMs selectin family Mucin-like family Immunoglobulin superfamily ICAM-1, 2, and 3 VCAM-1 MAdCAM-1
What directs the extravasation of different populations of lymphocytes?
Vascular addressins (VAs)
What do naïve lymphocytes bind to on HEVs?
Compare lymphocyte rolling to neutrophil rolling?
What mediates integrin-activating stimulus?
Cytokines either secreted locally or localized on the endothelial surface Thick glycocalyx retains the soluble chemoattractants
What are the junctional adhesion molecules involved in transendothelial migration of leukocytes?
PECAM-1 (ICAM-1) JAM-1 (CD321)
The differential migration of different subsets of lymphocytes traveling to different tissue is know as?
Trafficking or homing
What are receptors that direct lymphocytes during extravasation?
What is necessary for naïve lymphocytes to mount an immune response?
Activated in the specialized microenvironment in secondary lymphoid tissue
What happens in the necessary microenvironment to activate lymphocytes?
Dendritic cells capture antigen and present it to the naïve lymphocytes
What type of secondary lymphoid tissue do naïve lymphocytes prefer?
Have no preference Indiscriminately to secondary lymphoid tissue throughout the body
What happens when naïve lymphocytes encounter an antigen in secondary lymphoid tissue?
Become activated and enlarge into lymphoblasts
During activation, where does the lymphoblast go to in a lymph node?
Remains in the paracortical region
When the naïve lymphocyte is activated, ultimately what is produced?
Effector and memory cells
What is the difference between the trafficking patterns of memory cells and effector cells?
Effector cells go the site of infection Memory cells go to the type of tissue that was infected
Discuss the cell markers found in inflammation on memory cells, effector cells, and endothelial cells?
Effector and memory cells increase levels of certain cell adhesion molecules that interact with ligands Endothelial tissue express number of adhesion molecules that bind to receptors on memory and effector cells E- and P-selectins Ig-superfamily ICAM-1 and VCAM-1
What do tissues do to select subsets of effector lymphocytes?
Display unique sets of adhesion molecules
Where do mediators of inflammation come from?
Cells of the innate and acquired immune system Mast cells Platelets Leukocytes Neutrophils Monocytes-macrophages Eosinophil Basophil Lymphocytes
What are the four interconnected mediator-producing systems?
Kinin system Clotting system Fibrinolytic system Complement system
What activates the four interconnected mediator-producing systems?
When tissue is damaged
Describe the kinin cascade.
Hageman factor is released from injured tissue Hageman factor activates prekallikrein to form kallikrein Kallikrein cleaves kininogen to produce bradykinin