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The underlying principle of the immune system is
to provide protection from potentially harmful invaders in our environment |
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To do this requires the body to distinguish self
from nonself (foreign) |
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Self is good and nonself is usually bad |
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Each day we encounter millions of potential
disease producing bacteria |
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If we didn’t have a means to ward off these
potential invaders, we would become sick or die |
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The main methods we have to defend ourselves
against these invaders are two immune systems |
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Antigen - Any material that generates a specific
immune response |
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Immunogen - Regularly induces an immune response
by itself - a Complete Antigen |
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Foreign to the host (species or individual) |
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High molecular wt. (>10,000) |
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Protein, polysaccharide, lipoprotein,
lipopolysaccharide (Gm – cell wall) |
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Must be biodegradable |
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Have multiple antigen determinants |
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Antigen determinants - also called epitopes |
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An antigen determinant contains about 6-8
amino acid molecules or monosaccharide units |
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Has a characteristic 3 dimensional shape |
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An antigen may have many antigenic determinants
and a structure like a flagellum may have hundreds of antigenic
determinants |
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Each antigen determinant (epitope) elicits a
specific immune response |
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Hapten - does not induce an immune
response by itself |
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- Must complex with a body protein
(albumin) |
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Hapten ~ ’half an antigen’ |
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Penicillin G (2-5% of population allergic) |
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Local anesthetics (procain type) |
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Sedatives (i.e. Barbiturates) |
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Acrylic polymers |
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Atropine |
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Sulfonamides |
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Poison Ivy |
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Aspirin |
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2 Types - both protect body from infection |
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Early studies |
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Some immune reactions could be transferred by
blood serum (humor) |
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Others could only be transferred by living blood
cells |
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This was the discovery of the 2 immune systems |
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Antibody-Mediated (Humoral) Immune Response |
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Main protection vs. bacterial infections and
viral reinfections |
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Cell-Mediated Immune Response |
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Main protection vs. primary infections with
fungi and viruses |
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Question: If AIDS primarily affects the
cell-mediated immune system, what kind of infections would you expect to
find |
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Answer: Viral and Fungal - Kaposi’s Sarcoma, Candida
infections, Pneumocystis pneumoniae pneumonia |
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These two systems are not independent |
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Foreign material is dealt with by one or both
systems |
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Phagocytic cells also act as general scavengers |
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They eat foreign material and process it for use
by the immune systems |
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The immune systems reside mainly in the blood
and lymphatic systems throughout the body |
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Early studies done in chickens showed that a
special organ, the Bursa of Fabricius was necessary for antibodies to be
produced in chickens |
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Mammals don’t have a Bursa of Fabricius |
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In mammals the Fetal Liver and the Bone Marrow
are the organs involved in antibody formation |
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It was also found that the Thymus was involved
in cell-mediated immunity |
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Based on their origins, the specific cells
involved in the formation of the two systems are called |
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“T” cells (from thymus) and |
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“B” cells (from bursa) |
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T cells evolve into lymphocytes responsible for
cellular immunity |
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B cells evolve into plasma cells responsible for
antibody formation |
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The two systems interact |
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T cells can be distinguished based on function
and on whether they have surface proteins of type CD4 or CD8 |
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CD4 - T helper cells - produce chemicals called cytokines
- stimulate B cells to proliferate and differentiate into
antibody-producing plasma cells |
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T helper cells are required for both the humoral
and cellular immune systems to function |
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CD8 - T-killer cells - kill cells infected with
viruses and cancer cells which continually occur as a result of random
mutation |
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CD8 - T-suppressor cells - suppress the
activation of TH and TK cells |
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T cells don’t produce antibodies but they react
specifically with other cells |
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Each T cell is unique and is able to recognize
only one very specific antigen |
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T cell receptors are similar to antibodies |
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The T cell receptor only recognizes an antigen
if the same antigen is bound to a certain type of protein at the surface of
an antigen presenting cell (usually a macrophage but it can also be a
dendritic cell, a form of leukocyte found in lymphoid tissue) |
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This protein is called the major
histocompatibility complex (MHC) protein |
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An antigen gets to this position by being
partially degraded inside the macrophage and then carried to the surface
and bound to an MHC protein |
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When a cell is infected by a virus, new viruses
are synthesized within the cell and appear in the ER |
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In contrast, bacteria are normally engulfed by
phagocytes and end up in the phagosome |
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There are 2 classes of MHCs: MHC class I and MHC
class II |
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MHC class I molecules - transport antigens from
the endoplasmic reticulum to the cell surface |
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MHC class II molecules - transport bacterially
derived antigens from endosomal compartments, including phagosomes, to the
cell surface |
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As a result |
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The MHC class I CD8 cells control viral
pathogens and |
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The MHC class II CD4 cells control bacterial
pathogens |
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The macrophages phagocytize the foreign material |
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They assist the T cells in recognizing foreign
antigens by processing the foreign antigens to an immunogenic form, which
is recognized by and activates helper T cells |
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All phagocytes engulf foreign particles,
including bacteria, forming a phagosome (a sac) around them |
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The phagosome fuses with lysosomes forming a phagolysosome |
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The lysosomes contain acid hydrolases, lysozyme,
neutral proteases, myeloperoxidase, lactoferrin, and phospholipase A |
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The macrophages can also kill the bacterial
cells via the release of superoxide (O2–) and
hydrogen peroxide (H2O2). |
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Lymphokines (cytokines) |
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When a T-cell meets a foreign antigen it
enlarges, divides, and some of the daughter cells release large molecules
called lymphokines that help to eliminate the foreign material |
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MIF - Migration Inhibition Factor |
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Inhibits the migration of macrophages from the
area so that they can phagocytize the foreign antigen |
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LTF - Lymphocyte Transformation
Factor |
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Transforms non-sensitized
T-lymphocytes to a sensitized state |
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MAF - Macrophage Activating Factor |
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Increases the metabolic activity of macrophages
so that they can more readily kill phagocytized cells |
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CF - Chemotactic Factor |
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Nonspecifically attracts mononuclear cells to
the area |
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LT - Lymphotoxin |
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Nonspecifically destroys body tissue cells in
the localized area in which the cellular immune reaction is taking place |
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This may be involved in killing cancer cells |
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TNF - Tumor Necrosis Factor |
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Kills tumor cells, also inhibits parasites and
viruses |
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OAF - Osteoclast Activating Factor |
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Activates Osteoclasts |
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Osteoclast - cell that “eats” bone |
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Osteoblast - cell that “makes” bone |
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T-cells produce Lymphokines when activated |
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B-cells produce Antibodies when activated &
also produce Lymphokines |
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Many lymphokines (cytokines) have been renamed
as “interleukins” because they are messengers between leukocytes |
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Additional interleukins have been discovered and
named IL-1, IL-2 etc. |
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See table in handout |
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Antibody - a special group of soluble
glycoproteins produced in response to foreign antigens |
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Antibodies are immunoglobulins - a type of
glycoprotein produced by plasma cells |
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Plasma cells come from B-cells when
antigenically stimulated |
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Plasma cells synthesize and secrete between
1,000 and 10,000 identical antibody molecules per second until they die (usually a few days after reaching
maturity) |
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B-cells can also be activated nonspecifically by
substances called mitogens |
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Bacterial mitogens appear to reside in the cell
wall |
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When blood is spun in a centrifuge, the red and
white blood cells fall to the bottom leaving behind a straw-colored liquid
called “serum” |
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The antibodies are located in the serum |
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The basic unit of an antibody molecule is a Y
shaped molecule |
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By chemically breaking apart the molecule at the
disulfide bonds |
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Breaking all the bonds results in 4 pieces,
usually called chains |
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Centrifugation of the pieces separates the longer, heavier chains, |
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If we
break the heavy chains above the disulfide bonds we create two fragments |
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These are called the |
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Fab fragment |
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The Fab fragment is the antibody reactive part
of the molecule |
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The actual part of the antibody molecule
involved in antigen-antibody reactions is the end of the Fab fragment |
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Monomer, 70-80% of total globulins, fixes C' |
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The second antibody synthesized |
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Crosses the placenta |
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Pentamer, 5-10% of total globulins, fixes C’ |
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The first antibody synthesized |
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Doesn’t cross the placenta |
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Has 5 "J" (Joining) pieces at the
center of a cluster |
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Antibody to blood group antigens |
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Antibody to endotoxin (lipopolysaccharide) |
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In Periodontal Disease IgA and IgG are found
in the crevicular fluid but not IgM |
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It is theorized that the IgM is absent
because it is reacting with the endotoxin |
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Monomer, Dimer, Trimer, 10-15% of total
globulins, doesn't fix complement |
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The third antibody synthesized |
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Has a "J" piece holding the monomers |
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Dimer |
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Contains a J piece |
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Contains a Secretory Component (SC) |
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It protects the molecule from proteases in the
fluids |
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It is produced by the epithelial cells of the
salivary gland |
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Found in secretions: saliva, milk, tears,
colostrum, urine, and fluids of the mucous membranes of the nose, bronchial
mucosa, and the GI tract |
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The most prominent immunoglobulin in the saliva
(normally 4 mg/100 ml of saliva) |
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Monomer, <1%, anti-insulin, anti-nuclear antibodies |
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Monomer, <0.01%, doesn’t fix complement |
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Involved in anaphylaxis, asthma, hay fever |
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Synthesized in the respiratory or GI tract (food
allergies) and circulates & attaches to Mast Cells and Basophils |
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If two or more IgEs on the Mast Cells are
bridged, then the cell releases the intracellular granules containing a
variety of enzymes |
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These enzymes include |
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Histamine - causes contraction of smooth muscles
and increases capillary permeability |
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SRS - slow reacting substance-causes slow
contraction of smooth muscles |
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It is composed of 4 substances called
“leukotrienes” which are related chemically to prostaglandins and
thromboxanes |
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Heparin - inhibits blood clotting |
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Bradykinin - a slow reacting substance-causes
slow contraction of smooth muscles |
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Serotonin - causes smooth muscle contraction and
vasodilation |
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Active immunity - due to an individual’s immune
system learning new antigens, and acquiring the ability to make B- and
T-cells specific for that antigen (makes antibodies) |
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May be naturally acquired if the exposure to the
antigen happens naturally |
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May be artificially acquired if the exposure is
through vaccination |
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Active immunity lasts for a long time, sometimes
for life |
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Passive immunity is due to acquiring preformed
antibodies from another individual (no antibody formation) |
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Example: an unimmunized person gets a tetanus
shot after stepping on a rusty nail |
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The shot consists of antibodies to the tetanus
toxin made in the body of some animal (e.g. horse) |
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It provides immediate protection, but will not
last |
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Passive immunity typically is lost after 6
months |
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Newborn children do not yet have active immunity |
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For the first 6 months, they don’t get many
diseases because they are protected by the mother’s antibodies which are
passed to the newborn’s blood system before birth |
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After 6 months, the infant must rely on its
immune system to “learn” and acquire immunity to a series of diseases |
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Passive immunity |
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May be naturally acquired if it occurs via
placental transfer |
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May be artificially acquired if the exposure
occurs by transferring antibodies from humans or animals that are already
immune to the disease (Tetanus) |
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When the body first experiences an antigen,
there is elicited the Primary Immune Response, which requires about 1 week
after exposure before Ab levels in the blood rise |
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IgM appears first, followed by IgG |
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The Secondary Immune Response occurs when the
body next experiences the antigen |
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This activates the memory cells |
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This antibody response is detectable within a
day |
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It yields much higher Ab levels, and a higher
IgG response |
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When one gets a booster shot, this is to foster
the secondary immune response |
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Precipitation.
If the antigen is soluble (e.g. a
protein) it can combine with antibody (also soluble) |
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If the Ag and Ab are present in roughly similar
amounts, it will form a visible precipitate; otherwise with either Ab
excess or Ag excess, there is no precipitate |
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Agglutination.
If the Ag is particulate (e.g. on surface of cell), Ab will bind to
sites |
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If enough Ab is present, it will cause
agglutination (clumping) of cells carrying Ag |
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This is the basis for the standard ABO blood
typing reaction |
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Neutralization.
If Ag has some toxic properties (e.g., a toxin molecule, a virion), being bound tightly to the Ab
will neutralize the Ag and keep it from binding to its normal receptors |
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Note: Binding of Ab to Ag does not by itself
destroy the Ag |
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Ab acts like a “flag” to alert the body |
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Other systems are responsible for the actual
destruction of Ag |
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Titer.
In measuring the amount of an antibody that is present in serum, the
serum is usually diluted in half, and that dilution is diluted in half, and
then that dilution is diluted in half, etc. |
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This may continue until the original serum is
very dilute |
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This diluting of the serum is referred to as titrating
the serum |
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These dilutions are then tested for antibody
activity |
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A given antibody matches an antigen much as a
key matches a lock |
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Sometimes the fit is precise, sometimes it is
little better than a skeleton key |
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To some degree, however, the antibody interlocks
with the antigen and thereby marks it for destruction |
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Normally serum contains a mixture of antibodies
to many antigens |
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When the antibody producing cells are grown in
vitro (outside the body), one can isolate single cells that produce only
one kind of antibody |
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When these cells are cultured so that many of
them grow, they continually produce antibodies to a specific antigen |
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Because these antibodies come from a single
clone of cells, they are referred to as monoclonal antibodies |
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Complement is a group of sequentially acting
serum proteins which, when activated, mediate a number of biological
reactions important to host defense against bacteria, viruses, and other
injurious stimuli |
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Activation can be triggered by antigen-antibody
complexes |
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The main triggers are bacterial and plant
polysaccharides, and microbial and tissue enzymes |
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Biological activities mediated by the activated
complement proteins or by their fragments include increased capillary
permeability, chemotaxis of leukocytes at the site of tissue injury, and
cytolysis |
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The classic complement pathway comprises 9
components designated numerically from 1 to 9, the number being preceded by
the capital letter C’ |
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The order of reaction in immune hemolysis is
C’1, C’4, C’2, C’3, C’5, C’6, C’7, C’8, C’9 |
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The first component, C’1 is a complex of 3
protein subcomponents C’1q, C’1r, and C’1s, held together by calcium ions |
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Activation proceeds in a cascade-like fashion:
i.e.; each component is activated by the preceding one and, in turn, leads
to the activation of the next component in the sequence |
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The end point of the reaction sequence of
complement components with a sensitized erythrocyte or bacterial cell is
cell lysis |
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This is usually accomplished by creating a hole
in the cell membrane |
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Many biologically active products are also
generated in the process |
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The sequence of the Complement Cascade and the
resulting actions of the components is as follows: |
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C’1, C’4, C’2 attaches |
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Kinin activity (pain, blood vessel dilation) |
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It may also be responsible for virus
neutralization |
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C’3(cleaves) |
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Yielding 2 parts |
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cell bound part |
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responsible for immune adherence (RBCs attach to
other foreign material coated with complement components) |
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responsible for immune phagocytosis |
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released part |
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anaphylotoxin activity-contracts ilium, causes
histamine release, and causes smooth muscle contraction |
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it is chemotactic for neutrophils and other PMNs |
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causes vascular permeability |
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C’5, C’6, C’7-exist as a complex in serum |
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responsible for PMN chemotaxis |
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responsible for macrophage’s chemotaxis |
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The C’5 or activated C’5 is released as an
anaphylotoxin |
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Inactivates the bacterial lipopolysaccharides
from endotoxin |
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causes lysosomal enzyme release from leukocytes |
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C’6 part |
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enhances blood clotting |
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kinin activity |
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C’9 |
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puts the hole in the cell membrane (RBC or
Gram-negative bacterium) - 9-19 nm in diameter |
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May either act directly or may activate a
cellular enzyme such as a lipase that attacks the cell membrane-we don’t
know which |
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A single molecule of activated C’ generates
thousands of molecules of the later components and the final response is,
thus, greatly amplified |
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There is also an Alternate Complement Pathway-also
called the Properdin System |
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Properdin involves 5 serum proteins called B, D,
H, I, and P that interact to activate C’3 |
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No antigen - antibody reaction is needed |
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There are also other molecules that can directly
activate Complement |
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At C’3 -Lipopolysaccharides (endotoxin) |
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- Zymosan - a carbohydrate from yeast cells |
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- a factor from cobra venom |
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At C’5 -lysosomal enzymes |
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-trypsin |
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Of primary importance here is that you don’t
need an antibody reaction to start the C’ - cascade |
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When complement is present during an
antigen-antibody reaction, it inserts itself between the antigen and the
antibody |
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This is referred to as fixing complement or complement
fixation |
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Complement fixation tests are used to determine
whether a specific antigen or antibody is present |
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A muramidase that can hydrolyze bacterial cell
wall peptidoglycan |
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Lyses Gram-positive bacteria |
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Found in saliva |
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Found in macrophages, and neutrophils |
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These cells are in the gingival sulcus and
are thus protective there |
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Mucin coats bacteria |
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Lysozyme is strongly associated with the sialic
acid portion of mucin and therefore can act on bacteria entrapped by the
mucin |
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The lactoperoxidase of saliva, in the presence
of hydrogen peroxide produced by many bacteria, oxidizes thiocyanate ions
to intermediate toxic products such as hypothiocyanate |
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Both Gram-positive and Gram-negative bacteria
are inhibited in their growth but Gram-negative bacteria are more
susceptible |
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If catalase producing bacteria (the same ones
that produced the H2O2 or others) are present in the
area, they break down the H2O2 and prevent the
production of the toxic hypothiocyanate |
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Salivary lactoperoxidase + thiocyanate +
Bacterial H2O2 è Toxic hypothiocyanate |
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Bacterial catalase breaks down the H2O2
and so the above reaction doesn’t take place. |
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Iron is needed by all bacteria and they must
compete with the animal's iron binding proteins which are mainly: |
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transferrin, an iron binding glycoprotein found
in serum, and |
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lactoferrin, transferrin produced by white blood
cells and found in mucosal secretions |
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Bacteria may produce siderophores which are
chemicals released extracellularly that bind iron compounds and convert
them into substrates the bacteria can use |
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The skin provides a simple physical barrier to
many microorganisms |
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Unless an organism can cause a skin infection,
little harm will occur if it gets on the skin |
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The skin is also normally slightly acidic from
the fatty acids normally there |
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This is inhibitory to many bacteria |
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The stomach is highly acidic and kills virtually
all bacteria that aren’t encased in food |
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Saliva and tears provide a continual flushing
action |
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Both fluids also contain lysozyme and SIgA |
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The normal flora fills an ecological niche and
prevents other bacteria and yeasts from growing in that niche |
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Inflammation is a nonspecific reaction to tissue
damage |
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It is stimulated by a complex series of steps
initiated by cell damage |
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The effects of inflammation include: |
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vasodilation (the opening of junctions between
capillary cells, allowing fluid and WBCs to leave the blood and enter the
surrounding tissues). This causes
swelling of afflicted tissues |
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redness (from heightened blood flow) |
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pain (from prostaglandins released by tissues
binding to nerve receptors) |
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heat (produced by pyrogens liberated at site of
inflammation); may inhibit microbial growth |
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a variety of altered functions at the site of
inflammation: |
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fibrin clotting |
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platelet aggregation |
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chemotactic signaling to attract WBCs |
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activation of complement factor C’3 |
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Allergies and hypersensitivities are very common |
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Basically they can be seen as overreactions to
foreign antigens by a hyperactive or misdirected immune system |
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These conditions include allergic rhinitis (hay
fever) and asthma |
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The antigens that trigger allergy attacks are
called allergens |
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IgE is the antibody that is responsible for
allergic reactions |
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The stages of an allergic reaction are: |
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1. The initial exposure of the immune system to
an allergen |
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At this time there are no symptoms as the immune
system must synthesize the IgE |
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2. On subsequent exposures to the allergen, it
binds to IgE molecules that are located on the surface of mast cells |
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3. This induces a cascade of events that cause
the mast cells to release chemicals present in granules in the mast cells |
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These chemicals include histamines, leukotrienes
and prostaglandins, which in turn induce the various symptoms typical of an
allergic response |
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This entire process can take just seconds |
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This explains the suddenness with which allergic
and hypersensitive reactions can occur |
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One of the more dangerous allergic reactions is anaphylaxis |
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This response to an allergen can kill an
individual in a few minutes |
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Typically, it occurs following an insect sting
or the ingestion of a tiny bit of food |
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In dentistry we see it with penicillin allergies |
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It is characterized by the allergen inducing an
explosive release of chemicals from the mast cells |
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The rush of these chemicals can induce shock
which quickly leads to death |
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In some cases rapid swelling can close off the
trachea causing the victim to suffocate |
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A newer allergen in the dental office that can
cause anaphylaxis is latex allergy |
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A significant immunological reaction that you
should know is the Arthus Reaction |
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Some people believe similar events take place in
Periodontal Disease |
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It occurs as a transient, swollen, edematous,
local reaction following repeated subcutaneous injections of an antigen,
earlier injections having had no local effect |
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Further injections result in local necrosis |
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The response site is not confined to the site of
earlier injections |
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It follows the union within the tissues of an
antibody and its specific antigen which forms a soluble complex that fixes
complement and attaches to an endothelial surface - the blood vessel wall |
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This attracts neutrophils which liberate enzymes
which digest the vessel wall |
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Platelets adhere and the total result is
obstruction of the vessel and hemorrhage |
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Delayed hypersensitivity doesn’t involve
antibodies but is a cell mediated hypersensitivity |
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The delay involved is usually one of days |
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Rejection of skin grafts and contact dermatitis
are examples of delayed hypersensitivity |
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The disease, tuberculosis, involves delayed
hypersensitivity |
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Notes