Pharmacology Ii - 2/12/10

Front 1

Most immune reactions begin with innate immunity. Name 3 characteristics of innate immunity.

Back 1

Histamine release
Phagocytosis
Antigen Presentation

Front 2

Name 2 characteristics of adaptive immunity.

Back 2

Antibodies
Cytotoxic T Cells

Front 3

In the treatment of inappropriate and eventually chronic inflammation, there are two strategies. To treat the underlying cause with anti-infective agents and to prevent immune system response. This lecture deals with the modification of signaling mediators in inflammation.

Back 3

The pharmacology of Eicosanoid, Histamine and Bradykinin

Front 4

Name the 3 main functions of innate immunity.

Back 4

(1) Defense against pathogens (phagocytosis/cytotoxic proteins)
(2) Antigen Processing
(3) Cytokine secretion

Front 5

Describe the cells of innate immunity.

Back 5

Granulocytes = Neutrophils, Basophils, Eosinophils, Mast cells

Antigen Presenting Cells - Macrophages and Monocytes, Dendritic cells

Front 6

Neutrophils are the most abundant cell type. What do they defend against?
What is their method of action?

Back 6

Bacteria (phagocytosis + myeloperoxidase)

Front 7

What do Eosinophils defend against? What is their method of action?

Back 7

Parasites (Attach to parasite and secrete cytotoxic substances)

Front 8

What do Basophils and Mast cells defend against?
What is their method of action?

Back 8

Allergic reactions
They bind IgE antibody and display it on their surface. IgE cross-linking then releases histamine from granules.

Front 9

What are the 5 main functions of antigen presenting cells?

Back 9

They initiate the immune response
They display antigen on their surface
They process macromolecules of invading agents
They display non-self antigens to T-cells
They provide co-stimulatory signals necessary for T-cell activation

Front 10

Monocytes are circulating, where as macrophages are tissue resident. How do these cells carry out their actions against invaders?

Back 10

They engulf invaders as well as release cytokines to kill bacteria. This is their innate capacity.
They also act as antigen presenting cells and therefore have a role in adaptive immunity.

Front 11

What two things enhance macrophage/monocyte killing ability?

Back 11

Antibodies and cytokines

Front 12

Dendritic cells are the most important antigen presenting cell. Where does their immature form reside? Their mature form?

Back 12

Non-lymphoid tissue
Lymphoid tissue

Front 13

What is a TLR?

Back 13

Toll Like Receptor - Carries out the pattern recognition function of innate immunity. This allows them to phagocytose a class of infectious agents. They are transmembrane proteins that bind to common microbial components such as LPS. Binding of a infectious ligand to the TLR activates an intracellular signaling cascade. This function lacks a memory.

Front 14

What does this cascade ultimately result in?

What is the TLR receptor agonist?

Back 14

The immune inflammatory response via proinflammatory cytokine expression

Imiquimod

Front 15

MHC class I molecules are located on all nucleated cells and work through the CD8 co-receptor on T-cells. What type of particles are presented via MHC class I vs class II?

Back 15

Class I displays cytosolic protein fragments
Class II displays protein fragments that are endocytosed. Recognized by CD4 T-cells. Located on antigen presenting cells.

Front 16

Describe the difference between Humoral and Cellular immunity.

Back 16

Humoral - Antibody production for a specific antigen. Most effective against extracellular infective agents like bacteria

Cellular - Activation and clonal expansion of T-cells for a specific antigen.

Front 17

How do dendritic cells express a virus?

Back 17

If dendritic cells are infected by virus, it is displayed via MHC I, not II

Front 18

During cellular immune response, T-cells are expanded and secrete these cytotoxic proteins to kill infected cells.

Back 18

Perforins
Granzymes

Front 19

Each T-cell evolves so that it is activated by only one specific MHC:antigen-specific T-cell receptor.
T-cells are divided into cytotoxic and helper based on the type of co-receptor expressed.

Back 19

Cytotoxic T-cells express the CD8 co-receptor which recognizes MHC I proteins. If the antigen complex is specific for that T-cell, it binds with enough affinity to activate that T-cell. The T-cell then secretes perforins and granzymes that kill the infected cell.

Front 20

Helper T-cells express the CD4 co-receptor. This reacts in a similar fashion but with MHC II proteins. If the antigen presented is specific for that helper T-cell, the T-cell is activated.

Back 20

Helper T-cells are split into 2 subtypes. The first subtype, when activated produces IFN-gamma and IL-2, which influence the development of both cytotoxic and helper T-cells. The second subtype produces IL's 4,5 and 10. These cytokines enhance antibody production by B-cells.

Front 21

Describe the co-stimulation associated with T-helper cells.

Back 21

CD-28 of T-helper cells interacts with B-7 of the antigen presenting cell.
This is needed for T-helper cell activation in addition to T-cell-MHC and CD-4 interactions.

Front 22

What is the process known as tolerance?

Back 22

Cells of the immune system undergo a series of steps during development to ensure that mature immune cells do not recognize native proteins.

Front 23

Describe the role of co-stimulation in the activation of T-cells.

Back 23

If there is co-stimulation, the T-cell becomes activated. If there is no co-stimulation via CD-28 - B-7, then the T-cell is not activated and may become anergic.

Front 24

What is signal 1? What does it provide?

Back 24

MHC - TCR
Specificity

Front 25

What is signal 2? What does it provide?

Back 25

CD28 - B-7
Signal 2 is permissive, ensuring that an inflammatory response is appropriate.

Front 26

CD 28 is present on resting T-cell.
B-7, however is not present on resting APC cells. Why is this?

Back 26

B-7 not being present on limits inappropriate adaptive immune response.

Front 27

During the immune response, both signals are present, IL-2 is made, T-cells are activated and clonal expansion occurs. Cytokines are also secreted by the APC that further activate T-cells. What happens as the immune response ends?

Back 27

T-cells down regulate CD-28 and up regulate CTLA-4 which binds with greater affinity to B-7 and inhibits T-cell proliferation limiting the immune response.

Front 28

Describe the CD40 - CD40 L interaction

Back 28

CD 40 L is expressed by T-cells
CD 40 is expressed by APCs such at B-cells and Macrophages. Their interaction stimulates B-cells isotype switching and affinity maturation. It also stimulates macrophage expression of B-7 needed for co-stimulation

Front 29

CD 40 L is expressed in activated T-cells only! CD 40 is expressed in resting APC's however.

Back 29

Once the T-cell is activated, the CD 40 - CD 40 L interaction can take place, which increases B-7 expression in APC's, which is crucial for co-stimulation and activation of T-cells. It is an (+) feedback mechansim.

Front 30

What is the pharmacologic significance of CD 40 and CD40 L?

Back 30

The blockade of this interaction with anti-CD40 L antibody can produce tolerance and long-term graft survival in organ transplantation.

Front 31

What is the significance of regulatory T-cells?

Back 31

They maintain peripheral tolerance by secreting inhibitory cytokines. They limit the immune response to self-antigens and may have applications in transplantation.

Front 32

Where is Histamine stored?
Where does it stimulate dilation?
Where does it stimulate constriction?
When is Histamine release stimulated?

Back 32

Granules of Mast cells and Basophils
Arterioles and Post-capillary venules
Veins
Various injury from trauma to microbial invasion

Front 33

What are Eicosanoids?
How are they released?

Back 33

Metabolites of Arachidonic acid
Inflammatory mediators such as cytokines and complement are able to stimulate the release of arachidonic acid from the plasma membrane, and via enzymatic reactions eicosanoids are created.

Front 34

What are cytokines?
What two main examples of cytokines?

Back 34

Proteins that act in a paracrine manner to regulate leukocyte activity.
Interleukins - secreted by hematopoietic cells
Chemokines - Promote immune cell trafficking and localization to sites of inflammation.
Other notable cytokines include hematopoietic growth factors such at GM-CSF and G-CSF

Front 35

Describe the three complement activation pathways.

Back 35

Classical - Antigen Antibody
Alternative - Direct contact with a foreign surface
Lectin - Interaction with certain complex carbohydrates

In each case, a series of proteolytic reactions converts a complement precursor into an active form.

Front 36

What is the function of activated complement?

Back 36

It triggers further inflammatory responses by two mechanisms.
(1) The cleavage products of the proteolytic cascade are potent stimulators of inflammation
(2) The final step in the cascade is the assembly of the membrane attack complex, which creates large pores in the membrane of Gram (-) bacteria and causing lysis.

Front 37

Which type of mediator plays a role in raising temperature?

Back 37

Interleukins

Front 38

Describe the general 4 steps of the Inflammatory Response.

Back 38

(1) The vasculature reacts to recruit cells of the immune system
(2) These cells migrate into the tissue to carry out both innate and adaptive immunity
(3) Repair and tissue healing occurs and the acute inflammatory process is terminated.
(4) If the events are not halted, chronic inflammation ensues.

Front 39

What causes the blood vessels dilate in the recruitment of immune system cells? What 3 changes occur?

Back 39

Dilation of blood vessels due to histamine release.
Arterioles and post capillary venules are dilated, permeability increases, vascular endothelial cells contract

Front 40

The recruitment of cells across the endothelium into the site of infection is not random. Describe how this process is regulated to only allow immune system cells in?

Back 40

At the onset of the inflammatory response, the endothelial cells are the site of injury are activated to express ICAMs (intracellular adhesion molecules) that bind integrins on leukocytes. These leukocytes then undergo Transmigration or diapedesis as they travel from the vasculature into the interstitium.

Front 41

When are Neutrophils predominant vs Monocytes in terms of the inflammatory response?

Back 41

Neutrophils predominate the early inflammatory response, about 24 hrs in. After 24 hrs, Monocytes predominate.

Front 42

Describe the chemotaxic process that occurs.

Back 42

Inflammatory mediators released at the site of injury such at C3a and Leukotriene B4 create a chemical gradient to which leukocytes respond.

Front 43

Once macrophages, neutrophils and other immune system cells get to the site of injury, they are not yet fully ready to carry out their function. What must happen for phagocytosis to occur?

Back 43

The foreign agent must be opsonized by either complement, immunoglobulins or collectins.
These cells then present the foreign invader to T and B cells.

Front 44

What occurs during Resolution?

Back 44

Growth Factors are released such as EGF, PDGF, bFGF-2, TGF-1, and cytokines IL-1 and TNF-alpha

Front 45

Chronic Inflammation is a pathologic state characterized by continued and inappropriate inflammation. Describe how this occurs.

Back 45

Macrophages predominate and secrete inflammatory mediators such as proteases, eicosanoids, collagenases and growth factors that initiate and maintain a cycle of tissue injury and repair. Tissue is remodeled and over time, destroyed.

Front 46

What 3 main things can be attributed to chronic inflammation?

Back 46

Autoimmune diseases
Organ transplant rejection
Asthma