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Innate Immune Response - DOC

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									                      Innate Immune Response

                         Kathy Huschle
            Northland Community and Technical College

The Human Body
we are made up of warm, moist, nutrient rich substances, an ideal
environment for the housing of microorganisms
–every drop of water we drink contains 100’s of bacteria
–the air we breath introduces millions of bacteria daily to our lungs
–every time we brush our teeth we drive microorganisms into our
gums
despite this environment our body is relatively sterile (pathogen
free)
in most cases the presence of microorganisms are controlled by our
defense mechanisms
–innate immunity
–adaptive immunity
these 2 systems interact to keep out microorganisms, remove
microorganisms if they get in, and combat them if they remain inside

Immunity
immunity is the ability to ward off diseases through nonspecific and
specific defenses
our bodies normally have 2 defense mechanisms against pathogens
–innate immunity
nonspecific resistance that refers to all body defenses that protect
the body against any kind of pathogen
–adaptive immunity
specific resistance that refers to defenses against specific
microorganisms

Innate Immunity
the protection provided by the innate immune system is one the
human body is born with
initially it was thought to be a very generalized system and was
often referred to as the non-specific immune system
recent research has determined that though the system will attack a
variety of microbial pathogens, the system does rely on recognition of
patterns of invading pathogens
innateimmunity is supplemented by the adaptive immune response
which will be discussed in the next lecture

Innate Defenses Overview
first-line defenses
–physical barriers
–antimicrobial substances
–normal flora
sensor systems
–toll like receptors
–complement
–phagocytes
inflammation
interferons
fever

First Line Defenses: Physical Barriers
skin and mucosa
–body’s first line of defense
–the function of defense is both mechanical and chemical
skin and mucosa
–mechanical function involves physical barriers that block entry or
processes that remove microbes
–chemical function include substances that the body makes that
inhibit microbial growth or destroys microbes

intact skin physically blocks   the entrance of microorganisms
made up of 2 distinct layers
–dermis
thick inner portion made up of tight connective tissue
–epidermis
outer layer of skin made up of many layers of epithelial cells
the top layer of the epidermis contains dead cells embedded in a
protective protein called keratin
–keratin is a water-repelling protein
the presence of dead cells and keratin in the outer layers of our skin
plays a major role in inhibiting any microorganisms from gaining a
foot hold
–microorganisms require water to survive: keratin repels water
–viruses require a living host to invade: dead cells are obviously not
suitable for viral invasion
–the outer layer of cells are periodically shed which helps remove any
microbes that may have found a home on the skin’s surface

First-Line Defenses: Mucous Membranes
mucous membranes line the internal spaces of organs and tubes
that open to the outside, and also line the body cavities
mucous membranes inhibit the entrance of microorganisms, but
offer less protection than intact skin
mucous, the sticky fluid found in mucous membranes, functions to
keep the membranes moist
–this moist environment enhances the presence of some
microorganisms
these microorganisms, if present in a large enough number, are
often capable of penetrating the membrane
–but on the other hand, the bathing of mucous membranes by
mucosa can in some cases wash the microorganisms from the
surfaces
in the digestive tract, many microorganisms are directed towards
elimination by a process called peristalsis
–peristalsis is the rhythmic contraction of the intestinal tract that
moves food through the system
–this process also enhances the removal of microorganisms
cilia line the respiratory tract
–with a constant beating upward by the cilia, microorganisms are
propelled away from the lungs to the throat where they are either
swallowed or coughed away
more penetrable than skin
dry conditions thin mucous layer making them even more
penetrable
–this explains why we are more vulnerable to colds and respiratory
infections during dryer winters
cells of the mucous membranes are alive
–high concentrations of viruses and pathogens can overwhelm them
mechanical methods of microbial removal from mucous membranes
–respiratory: coughing, sneezing, gagging
–gastrointestinal: peristalsis, vomiting, defecation
–genitourinary: urination
First Line Defenses: Antimicrobial
many of the body fluids found in or on the skin or mucous
membranes are antimicrobial
–they can effectively limit ability of invading organisms to infect by
inhibiting growth: bacteriostatic
killing: bactericidal
–examples include
sweat
lysozyme
acids
lactoferrin
sweat has a high salt content
–as it evaporates on our skin, it leaves behind a residue that is high in
salt
–a salty environment on the skin is not conducive to growth for most
microorganisms
lysozyme
–an enzyme that is found in tears, saliva, sweat, and mucus
–lysozyme degrades peptidoglycan which is found in bacterial cell
walls
particularly effective against Gram – cells
–the degradation of the cell wall causes the organism to die from
osmotic shock: it no longer has the rigid protection of the cell wall
acids
–generally microorganisms require a neutral environment
–the presence of acid kills or prevents the growth of most
microorganisms
vaginal tract has a pH of 4.4 - 4.6
digestive tract has a pH of 1-2
the presence of normal “friendly” microorganisms on the skin break
down the sebum found in the skin
–the break down of sebum releases fatty acids which make the skin
more acidic, inhibiting the growth of invading microorganisms
blood and body fluids also contain antimicrobial chemicals
–iron-binding proteins
transferrin
–found in blood and tissue fluids
lactoferrin
–found in saliva, mild and mucus
transferrin and lactoferrin
–inhibit bacterial growth by reducing the amount of available iron
bind the available iron so the pathogens can’t
–the probability of contracting a STD during menstruation is increased
due to increased amount of blood in the vaginal tract: more iron
available for the invading microorganism

First Line Defenses: Fluid Flow
the cleansing action of fluids also assists in the removal of
microorganisms from mucous membranes
–saliva
dilutes the number of microorganisms and washes them from the
surface of the teeth and the mucous membranes of the mouth
–urinary tract
the cleansing of the urethra by the flow of urine prevents
colonization of microorganisms
–eye
production of tears by the lacrimal apparatus continually washes
over the eyes
this continuous washing of the eyes with tears prevents
microorganisms from settling on the surface of the eye

First Line Defenses: Microbial Barriers
on a cellular basis, our body is made up of 90% microbial cells and
only 10% “human”
–most of the bacterial cells found in our body are associated with the
gastrointestinal tract
–S. aureus is prevalent on skin
–Lactobacilli are prevalent in the vaginal tract
this large number of microbial cells are indigenous (naturally
occurring) and are referred to as normal microbita or normal flora
microbial barriers play a key role in our immune system by
inhabiting specific body surfaces
normal flora are nonpathogenic
–colonize body tissues thus preempting other microorganisms from
colonizing
–they are capable of producing antimicrobial substances that interfere
with the growth of other microorganisms
–they reduce the availability of oxygen
–they compete for nutrients
the normal flora found in our body are a balanced complex
–but an imbalance can lead to disease
nonpathogenic normal flora are opportunistic and will take
advantage of any opportunity to invade which can lead to disease
opportunities that can lead to an imbalance can be injury or a
depressed or non-functioning immune system
the process of acquisition of our normal flora begins during birth
–the human fetus is sterile and through a successional process
occurring in stages, acquires the microbiota necessary for survival
–the first step of acquiring the normal flora for some newborns is the
transfer of microorganisms from mother’s milk

Cells of the Immune System
cells are capable of moving around the body through the circulatory
system
cells of the immune system are found in normal blood
–develop in the bone marrow
–increase in amounts during infection
–leukocytes: white blood cells
granulocytes
mononuclear phagocytes
lymphocytes
stem cell is the common ancestor to all blood cells: red, white, and
platelets

Granulocytes
presence of large granules in their cytoplasm filled with biologically
active chemicals critical to their function
granulocytes differentiate into three types of cells
–neutrophils
–basophils
–eosinophils

Neutrophils
neutrophils
–professional phagocytes – 50% of the leukocytes found in the body
are neutrophils
these numbers increase during the presence of a bacterial infection
–chemical found in their granules assists in the degradation of
engulfed material
–often referred to as polymorphonuclear neutrophilic leukocyte or
poymorphs (PMN)
–have the ability to leave the blood, enter an infected tissue and
destroy microbes and foreign particles
–always present for protection and surveillance

Basophils
the role of basophils is not particularly well understood
–they are involved in allergic reactions and inflammation

Eosinophils
important defense against parasites
–capable of leaving the blood and infiltrating tissue
–major function is to produce toxic proteins against parasites
physically too small to ingest parasites, eosinophils are able to
attach to the outer surface of a parasite and discharge a toxin that
destroys them

Mononuclear Phagocytes
2 types of phagocytic cells arise from monocytes
monocytes circulate in the blood after leaving the bone marrow
monocytes migrate to tissue and form:
–macrophages
also considered to be professional phagocytes
abundant in spleen, liver, lymph nodes, lungs, peritoneal cavity
–dendritic cells
scout phagocytes; highly mobile cells
more involved with adaptive immune system which will be discussed
later

Lymphocytes
cells that are players in the adaptive immune system
–these cells are not phagocytes
–occur in the lymphoid tissue of the lymphatic system; tonsils, spleen,
red bone barrow, lymph nodes
B cells
–produce antibodies
T cells
–destroy infected/abnormal cells and coordinate the immune
response
Natural Killer cells (NK)
–kill cells
–are capable of recognizing a target and then destroying that cell
Cell Communication
the function of the immunes system relies on cooperation between
many factors
–this cooperation relies on a method of communication between the
players
receive signals from environment
send messages
direct contact
surface receptors
–proteins that bind signal molecules or specific chemical messengers
–connect outside of the cell to the inside
eyes and ears of the cell
–allows cell to respond to what’s happening outside it’s cell wall
–the response that is made is called chemotaxis
movement made in response to a chemical
cytokines
–proteins that bind to certain surface receptors
–chemical messengers of the immune system
–there are numerous types of cytokines that have various affects on
the behavior of cells
–please view the table 15-3 on page 380 in your textbook for
examples of the many kinds of cytokines
adhesion molecules
–“grab” other cells as they pass such as phagocytic cells
–allow cells to make direct contact enabling delivery of cytokines to a
cell

Sensor Systems
responsible for detecting signs of tissue damage or microbial
invasion within the blood or tissue
recognize and respond to patterns associated with “danger”
–toll-like receptors
–complement system

Toll-Like Receptors
a very recent discovery in the microbial world
                                                     so far, each
10 different toll-like receptors have been discovered
recognizing a specific or group of specific compounds associated with
“danger” for the cell

Complement
glycoproteins found in blood that are responsible for
–removal of invading pathogens
–preventing and limiting bacterial infections
–assisting in other defenses that protect
complement system destroys microbes by cytolysis, inflammation or
phagocytosis
complement proteins act in a cascade; one reaction triggers
another, triggers another, etc
–this amplifies the effect as the reaction continues
complement is activated by
–classical pathway: antibody/antigen complex
–alternative pathway
–lectin pathway
classical pathway
–is initiated by an antigen-antibody reaction
–this complex activates complement which ultimately initiates
cytolysis, inflammation or opsonization
alternative pathway
–complement is activated by the contact between specific
complement proteins and a pathogen
–can be stopped by regulatory proteins which are found in host cells
but are not associated with microbial surfaces
lectin pathway
–requires mannan-binding lectins (MBL)
mannan is a substance that is found on microbial cells and not
mammalian cells
as a result of binding, the MBL acts as an opsonin (serum protein)
to enhance phagocytosis
activation of complement generally leads to
–inflammation: contributes to vascular permeability
–lysis of foreign cells
assembles a membrane attack complex (MAC)
–creates pores in the cell, disrupting cell integrity
–most effective against Gram – cells because of the outer membrane
of the Grams – cell
–opsonizaion: the coating of microorganisms with serum particles to
make them more susceptible to phagocytosis

Phagocytosis
phagocytes are cells that engulf and digest
they are capable of pattern recognition which is critical in the
determination between self and non-self cells
there are six general steps in the process of phagocytosis which
include
–chemotaxis
–recognition and attachment
–engulfment
–fusion of phagosome
–destruction and digestion
–exocytosis
chemotaxis
–presence of a chemical stimuli from microorganisms, damaged
mammalian tissue and complement
–chemical stimuli recruits phagocytes to the site
recognition and attachment
–direct binding occurs with surface receptors
–indirect binding occurs when a particle has been opsonized
engulfment
–engulfment of the particle forms a membrane-bound vacuole called
a phagosome
–this does not destroy the microorganism
fusion with lysosome
–within the phagocyte the phagosome fuses with a lysosome, which
is vesicle filled with digestive enzymes
–this fusion results in the formation of a phagolysosome
destruction and digestion
–within the phagolysosome the microorganism is broken down with
the aid of enzymes
–this process generally takes 10-30 minutes to kill most types of
bacteria
exocytosis
–the vesicle containing the digested material joins with the plasma
membrane
–the vesicle is then expelled to the external environment
types  of phagocytes
–macrophages
scavengers and sentries of the system
long lived: weeks to months
are able to maintain their killing power by regenerating their
lysosomes

Phagocytosis-neutrophils
rapid response team: quickly move to an area when needed
extremely effective in the early stages of infection
short life span:1-2 days
have more killing power than the larger macrophages but do not last
as long
both are replaceable

Inflammatory Response
generalized, coordinated response to
–localize invading microorganisms (penetration of skin)
–production of toxic compounds
the inflammatory responses role is to
–arrest the spread of infection
–localize the response
–restore tissue function
initiation of inflammatory response
–microbial products such as LPS , flagella, bacterial DNA trigger
–microbial surfaces can trigger the complement cascade which can
trigger the inflammatory response
–tissue damage can trigger
symptoms of inflammation includes
–swelling
– pain
–reddening
–elevated temp
all of the above symptoms of inflammation are a result of the
process of inflammation, which begins with
–the dilation of blood vessels at the site of damage
–leakage of fluid from those vessels allowing for the migration of
leukocytes to the site
redness is due to capillary dilation
elevated   temp is due to capillary dilation which brings heat to the
site
swelling is due to increased capillary permeability
pain is due to lysis of the blood cells
dilation of blood vessels
–increases circulation
–increase phagocytes
increased blood flow
–brings more phagocytic cells to the site
–area of inflammation is walled off due to fibrin which is more
prevalent due to vasodilatation
–the blood clots formed around the area prevent the microbe and/or
its toxin from spreading
as a result, there may be a localized collection of inflammatory
exudate or pus
–dead microorganisms
–dead phagocytic cells
–debris
–body fluids
final stage of inflammation is repair of affected tissue
Following infection or injury, mast cells release vasodilators that
increase capillary permeability allowing plasma and leukocytes to
leave the bloodstream and enter the tissue.

Steps of Phagocytosis in the Inflammatory Response
Interferons
a class of antiviral proteins produced by certain animal cells after
viral stimulation
principal function of interferons is to block replication of viral genetic
material
–blocks translation of viral mRNA
–interferons do not block entry

Interferons
non-specific protection against viral infection
–response of interferons to one virus offers protection against other
viruses
–it only works with limited quantities: neighboring cells are protected,
but not cells throughout the body
interferons  play a major role in the short-term acute infections such
as the common cold and influenza
the commercial production of interferons is being explored
–not only for their antiviral properties but also as potential anticancer
agents

Fever
homoeothermic animals maintain a constant body temperature
fever is a:
–systemic response
–abnormal increase in temp
–strong indication of infectious disease, particularly those of bacterial
origin
fever
–enhances natural defenses
stimulates phagocytosis
increases rate of enzyme reactions which enhances
–degradation of microorganism
–tissue repair
–intensifies the action of interferons
–reduces the blood iron concentration
up to a certain point, fever is considered a defense against disease
–for this reason, one should consult a physician before taking drugs
to reduce a fever

								
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