Transcript Nonspecific Defenses of the Host - Cal State LA

Nonspecific Defenses of the
Host
Innate Immunity
Nonspecific defenses of the host
 The ability to ward off disease through our defenses is
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called resistance.
Vulnerability or lack of resistance to disease is called
susceptibility.
Non-specific defenses are also called innate defenses
and they protect us from infections by pathogens in
general.
This type of innate immunity which one is born with is
distinguished from adaptive immunity which protects one
from infection against a specific organism and which
develops after exposure to that specific organism.
Innate versus adaptive immunity
 As will be seen, the innate and adaptive
immune systems do not operate
independently of each other, but are very
inner-connected in their activities.
Innate immunity
 The first line of defense is intact skin and
mucous membranes. Both mechanical and
chemical factors are involved in this first line of
defense:
 Mechanical factors
 Intact skin – consists of the connective tissue the inner
dermis and the outer epidermis which is a continuous sheet
of closely packed epithelial cells. The top layer contains a
waterproofing protein called keratin. This all provides a
formidable physical barrier to the entrance of
microorganisms. When the epithelial surface is broken, a
subcutaneous infection may develop, frequently by Staph.
aureus.
Intact skin
Innate immunity
 Intact mucous membranes – also consists of outer
epithelial and inner connective tissue layers.
 Mucous membranes line the digestive, respiratory,
urinary, and reproductive tracts.
 Goblet cells in the epithelial layers secrete mucous to
prevent the tracts from drying out and the mucous may
act to trap microorganisms that enter.
 Some pathogens (T. pallidum, M. tuberculosis, S.
pneumoniae), however, actually survive in these moist
secretions and, if present in sufficient numbers, are able
to penetrate the membranes.
Innate immunity
 Cilia – the cells of the mucous membranes of the
respiratory tract contain cilia which move
synchronously to propel inhaled dust and
microorganisms that have become trapped in the
mucous, upward toward the throat.
Ciliated mucous membranes
Innate immunity
 The lacrimal apparatus of the eye manufactures
and drains away tears. By its continual washing
action it helps keep microorganisms from settling
on the surface of the eye. If something irritates
the eye, the lacrimal glands will secrete heavily to
wash away the irritating substance.
Lacrimal apparatus
Innate immunity
 In a similar cleansing action, saliva produced by the salivary
glands, washes microorganisms from the teeth and mucous
membranes of the mouth.
 The mucous membranes of the nose has mucous coated hair
that filter inspired air and trap microorganisms, dust and
pollutants.
 The epiglottis, which covers the larynx during swallowing,
helps to prevent microorganisms from entering the lower
respiratory tract.
 The flow of urine through the urethra provides a mechanical
cleansing of the urinary tract.
Innate immunity
 Chemical factors
 Sebum produced by the oil glands of the skin provides a
protective film over the surface of the skin. It contains
unsaturated fatty acids which inhibit the growth of certain
bacteria and fungi and contribute to the low pH of the skin
which is also inhibitory to the growth of microorganisms.
What also contributes to the low pH? What is the relationship
between sebum and the acne that sometimes occurs,
particularly in adolescents?
 Perspiration produced by the sweat glands contributes to the
high salt content of the skin that is osmotically unfavorable
for the growth of many microorganisms.
Innate immunity
 Perspiration, tears, saliva, nasal secretions and tissue fluids
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all contain lysozyme. What is the activity of lysozyme?
Gastric juice produced by the stomach is very acidic and will
destroy most bacteria and bacterial toxins. Food particles,
however, may protect enteric pathogens from the effects of
the acid.
Defensins - are cysteine rich peptides produced by the skin
that have antibacterial activity
Cryptocidins – are antimicrobial peptides produced by the
epithelium of the intestine
The presence of normal flora may protect from colonization
by potentially pathogenic bacteria. How?
Innate immunity
 The second line of defense:
 Phagocytosis – cells in the human body that
counter infection by phagocytosing
microorganisms are called phagocytes and
they are all either types of white blood cells
(WBCs) or derivatives of blood cells.
 Blood= plasma + the formed elements:
 RBCs are called erythrocytes
 Platlets are called thrombocytes
 WBCs are called leukocytes
Innate immunity
 During a bacterial infection, there is often an
increase in the number of leukocytes and this is
called a leukocytosis.
 Some diseases cause a decrease in leukocytes and
this is called leukopenia.
 The source of the increase or decrease of of
leukocytes can be determined by performing a
differential count. The percentage of each type of
WBC is determined by counting 100 WBCs. The
normal values are:
Formed elements of the blood
Innate immunity
 Note that the WBCs are divided into two basic
types, granulocytes, which contain granules and
agranulocytes which lack granules, both of which
may be phagocytic:
Innate immunity
 What are the basic functions of the various WBCs?
 PMNs are highly phagocytic and can leave the blood to enter
infected tissues to destroy foreign substances
 Basophils release histamine and heparin in the inflammatory
response and in hypersensitivity reactions
 Eosinophils are somewhat phagocytic. They ingest antigenantibody complexes and are increased during parasitic
infections and hypersensitivity reactions.
 Lymphocytes are found mainly in lymphoid tissue, but some are
in circulating blood. They are important in antibody production
and in modulating the immune response.
 Monocytes are poorly phagocytic until stimulated by infection.
Then they move into the tissues and differentiate into
macrophages which are highly phagocytic.
Innate immunity
 During an infection both PMNs and monocytes, which
become macrophages, migrate to the infected area.
Neutrophils are the first cell type to arrive at the infected site
and are the predominant cell found during the initial stage of
the infection. In the latter stages of the infection monocytes
will predominate (more on this later).
 Phagocytosis occurs in two stages:
 Adherence – this refers to the attachment of the phagocytic cell with
the surface of the invading microorganism via a receptor on the
phagocytic cell that recognizes structures that are characteristic of
microbial pathogens and are not present on mammalian cells
(pathogen associated molecular patterns or PAMPs). The receptors are
called pattern recognition receptors.
PAMPs
Innate immunity
 The pattern recognition receptors are also called toll-like
receptors because they resemble, both in structure and
function, receptors, called toll receptors, that were originally
identified in the innate immune response of Drosophila.
 Binding of a PAMP to a toll-like receptor triggers a signaling
cascade in which a transcription factor is translocated into the
nucleus leading to the expression of genes involved in the
innate response.
 When this occurs it is said that the phagocytic cell has been
activated.
 LPS is an example of a PAMP which binds to a toll-like receptor
to trigger a subsequent signal transduction pathway that leads
to expression of genes involved in the innate response.
TLRs and signal transduction
pathways
LPS activation of innate immunity
Innate immunity
 The process of adherence is facilitated by chemotaxis which is
the attraction of phagocytes to the microorganisms via
chemical factors (cytokines) released by certain WBCs,
damaged tissues, microbial products or peptides derived from
the complement cascade (more on this later).
 Adherence of encapsulated microorganisms is difficult and may
occur by two mechanisms:
 Non-immune or surface phagocytosis – the phagocyte
traps the microorganism against a rough surface which the
microorganism cannot slide away from.
 Opsonization – the microorganism is first coated by an
opsonin which can be either an antibody or a component
of the complement cascade. Phagocytic cells may contain
receptors for these opsonins which serve to act as a bridge
to promote the attachment of the microorganism to the
phagocyte.
Opsonization
Innate immunity
 Ingestion is the second stage of phagocytosis and it follows
adherence and activation of the phagocytic cell.
 The microorganism is engulfed by pseudopods.
 Once the microorganism is surrounded, the phagocytic
membrane will fold inward enclosing the microorganism in a
sac called a phagosome or phagocytic vacuole.
 The phagosome will pinch off and enter the cytoplasm where it
will fuse with a lysosome.
 The digestive enzymes present in the lysosome may kill the
bacteria.
 It should be noted that not all bacteria are killed by lososomal
enzymes.
Phagocytosis and intracellular
destruction
Mechanism of phagocytosis
Innate immunity
 In addition to killing bacteria via the digestive enzymes present
in lysosomes, phagocytic cells have two other mechanisms by
which they might kill bacteria (both intra and extracellular):
 Present in the plasma membrane of the phaocytic cell and
in the membrane of the phagosome is a phagocytic
oxidase enzyme that is activated to produce reactive
oxygen intermediates (ROIs) such as the superoxide
radical which may be toxic to bacteria. The process by
which ROIs are produced is called the respiratory or
oxidative burst.
 There is also a nitric oxidase synthase that may be
activated to produce nitric oxide (NO) which can interact
with the ROIs to generate a highly toxic peroxynitrite
radical.
Microbicidal mechanisms of phagocytes
Phagocytosis
Innate immunity
 In addition to killing phagocytosed microbes, activated
macrophages serve many other functions in defense
against infections including leukocyte recruitment and
tissue remodeling.
 Many of these functions are mediated by cytokines.
Cytokines are chemicals produced by in innate
immunity, mainly by PMNs, macrophages and NK
cells (discussed later).
 Endothelial cells and epithelial cells may also produce
cytokines.
 Cytokines serve to communicate information among
inflammatory cells and between inflammatory cells
and responsive tissue cells.
More second line defense…
 Inflammation – damage to the bodies’ tissues will
trigger an inflammatory response. The four
fundamental symptoms of inflammation are redness,
pain, heat, and swelling. There is also sometimes loss
of function. Inflammation has the following three
functions:
 To destroy the injurious agent, if possible, and to remove it
and its by-products from the body.
 If destruction is not possible, to wall off the injurious agent
and its by-products.
 To repair or replace damaged tissue.
More second line defense
 Inflammation occurs in three stages:
 Damage to the tissues causes a release of histamine, kinins,
and prostoglandins. The release of these substancees causes
vasodilation and increased permeability of the blood vessels.
 Vasodilation (increase in the diameter of blood vessels) in the
area of injury causes an increase in blood flow to the injured
area. This causes redness and heat.
 Increased vascular permeability permits defensive substances
normally present in the blood to enter the injured area
resulting in edema and swelling. Pain from the pressure of
swelling as well as from nerve damage and irritation by toxins
will occur.
More second line defense
 Clotting elements are also delivered to the injured area. The
clots that form prevent the spreading of the microorganisms
and result in a localized collection and pus in a cavity formed
by the breakdown of body tissues (an abscess forms).
 Phagocytic migration occurs. Within one hour phagocytes
appear on the scene.
 As the blood flow decreases, the phagocytic cells begin to stick
to the lining of the blood vessels (margination), and then the
cells squeeze through the walls of the vessels to move to the
damaged area (diapodesis).
 PMN’s arrive first and are attracted to the area by chemotactic
factors.
 Leokocytosis promoting factor released from inflamed tissues
causes the production and release of additional PMNs from the
bone marrow.
More second line defense
 As the inflammatory response continues monocytes enter
the inflamed area and differentiate into macrophages
which are much larger than and several times more
phagocytic than the PMNs.
 After PMNs and macrophages engulf large numbers of
microorganisms and tissue, they, themselves, die. A
collection of dead cells and various tissue fluids is called
pus. Pus formation will continue until the infection
subsides.
 Repair is the last stage of the inflammatory
process. This is the process by which tissues
replace dead or damaged cells.
Inflammation
Inflammation
More second line defense
 Fever – fever is a systemic response to
infection.
 Body temperature is controlled by the
hypothalamus.
 Certain antigens such as the LPS can cause the
phagocytic cells to release leukocyte pyrogen (IL1) that causes the hypothalamus to release
prostoglandins that reset the hypothalmic
thermostat at a higher temperature.
More second line defense
 Blood vessel constriction, increased rate of metabolism and
shivering will all help to increase the temperature of the
body. Thus shivering is a definite sign that body temperature
is rising.
 As the infection subsides, heat losing mechanisms such as
vasodilation and sweating will occur.
 Up to a certain point, a fever is beneficial because it inhibits
bacterial growth, intensifies the effects of interferon
(discussed later), and may help the body tissues to repair
themselves more quickly. However, if body temperature gets
too high (>450 C) this may be lethal.
More second line defense
 Antimicrobial substances
 Interferon (IFN) – interferons are substances produced and
released from virally infected cells. Interferons bind to
receptors on neighboring cells and, though a signal
transduction pathway, induce them to produce anti-viral
substances that interfere with viral multiplication and thus
protect the cell from viral infection.
 IFN is host specific, but not viral specific, i.e., interferon in
humans will not work in dogs (why?), and when made, IFN is
made to protect the neighboring cells from viral infections in
general. It doesn’t protect only against a specific virus.
IFN production and activity
More second line defense
 Complement and properdin – complement and
properdin are a group of proteins found in normal
blood serum.
 They are important in both non-specific and specific antigen-
antibody defenses against microbial infection.
 They function to attack and destroy invading microorganisms
and to help stimulate the inflammatory response.
 The proteins act in an ordered sequence or cascade of
reactions. In an ordered sequence of steps, the proteins
activate one another usually by cleaving the next protein in
the series.
 The fragments of the cleaved proteins have new enzymatic
or physiological functions.
More second line defense
 There are three different, interconnected pathways of
complement activation:
 The classical pathway is activated via an antigen-antibody
complex which activates the complement components C1 to
an activated C1 complex which then activates C4, and C2 to
form another activated complex. This complex next activates
C3 which is cleaved into C3a and C3b
 The lectin pathway is initiated by the binding of a serum
protein, mannose-binding lectin (MBL) that is produced
during inflammation. MBL binds to mannose residues on
glycoproteins or carbohydrates that are on the surface of
microorganisms. It functions like an activated C1-like
complex.
More second line defense
 The alternate or properdin pathway is activated by
cell wall polysaccharides that interact with
properdin factors B, D, and P as well as circulating
C3b to create a complex that also activates C3 by
cleavage into C3a and C3b.
 C3b produced by all three pathways involves components
C5 through C9 in a membrane attack complex that
punches a hole in an invading microorganism leading to
its cytolysis (a process called complement fixation)
 C3b, when bound to the surface of a microorganism, can
interact with receptors on the surface of phagocytes to
promate phagocytosis (opsonization)
More second line defense
 C3a and cleavage products from C5, C6, and C7
can contribute to the development of an acute
inflammatory response via their activity on mast
cells, platlets and basophils (leads to increased
permeability of blood vessels) and their ability to
act as chemotactic factors for phagocytic cells.
 Once activated the destructive capabilities of
the complement system are quickly
inactivated.
Complement activation
Lectin pathway
Complement fixation
Results of complement fixation
Complement stimulation of inflammation
More second line defense
 Natural killer (NK) cells – NK cells are large, granular
lymphocytes that are activated by three types of
targets:
 Antibody coated cells
 Cells infected by viruses and some intracellular bacteria
 Cells lacking class I MHC molecules (more on this later). NK
cells express inhibitory receptors that recognize class I MHC
molecules, and therefore NK cells are inhibited by class I
expressing cells and activated by target cells lacking class I
molecules. Some viruses are known to down regulate
expression of class I molecules.
 Activated NK cells lyse the target cells by releasing granules
that contain perforin that creates pores in the target cells
and granzymes that enter the target cells through the pores
and induce apoptosis of the target cell.
NK activity
NK activity with normal cell
NK activity with cell lacking MHC
class I molecules
Summary of components of innate immunity –
note how inner-connected these components are
Innate stimulation of adaptive immunity
 Innate defenses play a major role in
stimulating adaptive defenses: