(Transcribed from Dr. Laville’s lecture started 18 Feb 2000 by Brian Buschman)
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Cell-mediated immunity defends against intracellular pathogens and has three major components:
1) Lymphocytes
2) Phagocytes
3) Cytokines
T-lymphocytes
1) T-helper cells which assist in the binding of an antigen to the antibodies on the plasma membrane of B-cells. AIDS is a disease that kills the T-helper cells so that humeral (B-cell) responses cannot be activated.
2) T-cytotoxic cells act to kill foreign and virally infected cells by:
a) Producing perforins that create channels in the plasma membrane of the cells to cause osmolysis. (Osmolysis is where the holes produced in the plasma membrane allow the free flow of water but not of proteins. There is as excess water diffusing into the cell, because of the hypertonic environment, until the point where the plasma membrane bursts.)
b) Activation of genes for apoptosis.
3) Memory T-cells have antibodies (Ab) on their surface made to fight previous antigens (Ag). When the same Ag infects the body again the memory T-cells launch a rapid response to the infection.
4) Suppressor cells regulate cellular and humeral immunity by inactivating immune cells and limiting response.
NK Cells (Natural killer cells) attack virus infected cells without previous stimulation.
Dendritic cells present antigens to T-cells.
Granulocytes (like eosinophils, basophils and neutrophils) release substances to assist in the response.
Mast cells release effecter molecules like histamine and seretonin to increase vascular permeability.
Macrophages are involved in phyaocytosis, antigen presentation to T-lymphocytes and removal of damaged tissue.
The complement system is a method for activating the immune response. It has two important pathways by which it can follow.
Classical Pathway – This pathway is activated by the Ag-Ab complexes involving IgG and IgM. It is made up of components labeled by a C and a number (C1-C9). The part that is exclusively classical pathway only involves activation of C1-C3.
Alternative Pathway – This pathway is activated by the Ag-Ab complexes involving IgA and IgE. Its components are called factors and identified by a letter (Factor B).
Complement components are readily available in the blood stream and when activated proceed through a cascade in a similar manner as that of clotting. The set of factors also includes a number of regulatory factors that prevent the unnecessary activation of the pathways such as C1 INH and factor H.
Both the classical and alternative pathway can cleave C3 into C3a and C3b. The larger C3b binds to the target cell and induces the continuation of the classical pathway as opsonization of the target cell. The classical pathway continues the later components are called membrane attach complexes because they lead to the insertion of C9 into the cell membrane. This produces a channel that causes osmolysis. The smaller fragment C3a leads to chemotaxis of leukocytes and release of proteins to cause vasodilatation.
The effects of the complement system are:
1) Vasodilatation
2) Cellular production of inflammatory mediators.
3) Cytolysis
4) Opsonization
Activation of the compliment system past the point of C3 leads to hypersensitivity reaction and the production of anaphylatoxins.
Opsonization is the process of altering a bacterial plasma membrane to make it more readily taken up by phagocytes. The fastest acting opsonin is the C3b-Ab complex.
Cytokines are a group of various mediators of immune response. They are small proteins that act in either an autocrine or paracrine method to induce steps in the immune response. There are many types of cytokines, which include:
1) Interferons (INF) are produced early in viral infections. INFa and INFb are produced by virally infected cells to act in an autocrine manner while INFg is released by activated t-cells.
2) Interluekins (IL), IL-1 to IL-17, are produced by t-cells and act on a limited group of cells that express the correct receptor. They are used by one immune cell to cause another immune cell to do it’s job.
3) Colony Stimulating Factors (CSF) direct the division of stem cells to produce blood leukocytes.
4) Tumor Necrosis Factor (TNF) and Transforming Growth Factor (TGF). Include TNFa, TNFb and TGFb. Both function in mediation of the inflammatory response.
IL-6 acts to induce:
1) Megakaryocytes to make platelets.
2) Regulate bone turnover.
3) Hepatocytes to make C-reactive protein.
IL-2 Receptor
The IL-2 receptors have three subunits. The a and b subunits bind the cytokine while the g signals for the desired process to take place in the cell.
The IL-4 receptor only had the a chain for binding but still has the g chain for signaling.
In a cytokine, receptor the cytokine binds and induces polymerization of the receptor polypeptides that act to produce products or otherwise induce the cells activation. That is the receptors will recognize the presence of the cytokine intercellularly and will induce the production of intracellular signals.
There are five
events of the immune response:
1) Recognition of the specific antigen.
2) Recruitment of inflammatory cells.
3) Removal of antigen.
4) Rebuilding of the immune response.
5) Repair the tissue damaged by the immune response.
Antigen presenting cells (APC) will bring the antigen fragment to the helper (CD-4) T-cell. The helper T-cell will recognize the APC and antigen because the APC presents the antigenic fragments while they are complexed with MHC II (major histocompatibility complex II). As previously discussed the helper T-cell will assist in the binding of an antigen to the B-lymphocyte or assist in the activation of the cytotoxic (CD-8) T-cells. APCs can automatically activate cytotoxic T-cells by showing them a piece of an antigen mixed with MHC I.
APCs can release IL-1 and INF that will activate:
1) Endothelial cells to make intercellular adhesion molecules (ICAM).
2) Liver to make acute phase proteins.
3) Hypothalamus to raise the body’s temperature.
APCs also release IL-8 to cause chemotaxis of leukocytes.
Antigen presenting cells release TNFa and IL-12 to cause leukocyte recruitment, leukocyte recruitment, and to activate tissue phagocytotic cells to begin response while T-cells response is building.
Macrophages secrete TNF and IL-1 which endothelial bound proteins to loosely bind leukocytes to the endothelial cell layer to make them bind and slowly roll along this layer. It also leads to binding of factors that cause the leukocytes to stop rolling and bind to endothelial cells when they reach the site of infection.
Macrophages are activated in multiple steps involving carious cytokines and mediators. One example is of a macrophage that is stimulated by INFg and then by TNFa which them produces NO (nitrous oxide) that helps kill bacteria.
The first step in the immune response is the recognition and binding of new antigens to phagocytotic cells. This is done by the APC recognizing the antigen because of common components that only exist on antigens. It will then take a chunk off the antigen by phagocytosis, complex it with either MCH I or II and present it to either the CD-8 (cytotoxic) T-cells or CD-4 (helper) T-cells respectively.
Summary of the Immune Response
We have three pathways discussed to attack antigens:
1) Antibodies are secreted by B-cells and plasma cells. They activate the complement system that causes chemotaxis of leukocytes, agranulation of granulocytes, opsonization of antigenic cell and anaphylaxis.
2) Cell-mediated cytotoxicity – CD-8 (cytotoxic) T-cells have antigen specific cell lysis abilities (because they produce perforins and induce apoptosis).
3) Delayed-type hypersensitivity involves the production of MHC II to activate CD-4 (helper) T-cells to cause cell accumulation, antigen isolation and cell activation.
Inflammation occurs in response to tissue damage when infection enters the body. The pathway includes:
1) Increase in blood supply because of vasoconstriction of other blood vessels in the body.
2) Endothelial cells retract which increases the cell’s vasopermeability.
3) C3a is released from the compliment pathway and causes degranulation (histamine and seretonin) which lead to further vasopermeability.
4) Phagocytes exit from the capillaries and move towards the site of the infection.
5) Phagocytes engulf and destroy the bacteria.
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