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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?

Vascular endothelium

What is the process by which circulating leukocytes enter inflamed tissue or peripheral lymphoid organs by adhering to and passing through endothelial lining?

Extravasation

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?

Sialyl-Lewisx

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?

Extravasation

List the four steps of extravasation of white blood cells.

Rolling
Activation by chemoattractants
Arrest and adhesion
Transendothelial migration

Describe rolling.

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?

Neutrophils

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?

ICAM-1
VCAM-1

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?

L-selectin

Compare lymphocyte rolling to neutrophil rolling?

Less pronounced

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?

Homing receptors

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

What is the effect of bradykinin?

Increases vascular permeability
Causes vasodilation
Induces pain
Triggers contraction of smooth muscle

What activates the clotting system?

Injury to a blood vessel
Initiation of an inflammatory response
Interaction between P-selectin and PSGL-1

How do fibrinopeptides produced by the clotting system act as inflammatory mediators?

Increases vascular permeability
Neutrophil chemotaxis

What part in the inflammatory response do platelets play?

Activated platelets release CD40L which leads to:
Increased production of IL-6 and IL-8
Increased expression of adhesion molecules

What is the effect of plasmin in inflammation?

Plasmin breaks down fibrin clots into degradation products that re chemotactic for neutrophils
Activates the classical complement pathway

What are the anaphylatoxins and what do they do?

C3a and C5a that bind to receptors on the membrane of tissue mast cells
Induces degranulation with release of histamine and other pharmacologically active mediators

What is the effect of anaphylatoxins?

Induces smooth muscle contraction
Increase vascular permeability

What is the combined effect of C3a, C5a, and C5b67 on monocytes and neutrophils?

Adhere to vascular endothelium
Extravasate through the capillary
Migrate to the site of complement

What are the effects of platelet-activating factor (PAF) regarding inflammation?

Activates platelets
Has inflammatory effects
Eosinophil chemotaxis
Activation of neutrophils and eosinophils

What is the effect of prostaglandins with regards to inflammation?

Increases vascular permeability
Increases vascular dilation
Induces neutrophil chemotaxis

What is the effect of thromboxanes?

Platelet aggregation
Constriction of blood vessels

Which cells produce leukotrienes?

Monocytes
Macrophages
Mast cells

What are the functions of the leukotrienes?

Chemoattractant of neutrophils
Induce smooth muscle contraction

What is the dominant leukocyte infiltrating the tissue in the early phases of inflammatory response?

Neutrophils

How long does it take for the inflammatory response to peak

6 hours

What increases the expression of E- and P-selectin on vascular endothelial cells?

Thrombin and histamine induce P-selectin
IL-1 and TNF increase E-selectin

What are the mucins expressed by circulating neutrophils

PSGL-1 or sialyl Lewisa and sialyl Lewisx

What are the chemotactic agents for neutrophils?

Chemokines
Complement split products
Fibrinopeptides
Prostaglandins
Leukotrienes
Microorganism products

What is the relationship between Fc receptors and activated neutrophils?

Activated neutrophils express increased levels of Fc receptors

What are the constituents of purulent exudates (pus)?

Dead neutrophils
Microorganisms
Accumulated fluid
Various proteins

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