Fever & Antimicrobial Substances
higher temperature until the cytokines are
INFLAMMATION- Is a local response of the
body to injury.
FEVER- One of the most important
systemic, or overall, responses.
- An abnormally high body temperature, a
third component of the second line of
defense.
- Is considered a defense against disease.
* The most frequent cause of fever is
infection from bacteria (and their toxins) or
viruses.
Brain’s hypothalamus is sometimes called
the body’s thermostat, and it is normally
set at 37°C (98.6°F).
* It is believed that certain substances
affect the hypothalamus by setting it at a
higher temperature.
* When phagocytes ingest gram-negative
bacteria, the lipopolysaccharides (LPS) of
the cell wall are released.
LIPOPOLYSACCHARIDES (LPS)- Causes the
phagocytes to release the cytokines
interleukin-1 along with TNF-α.
CYTOKINES- Cause the hypothalamus to
release prostaglandins.
PROSTAGLANDINS- Reset the hypothalamic
thermostat at a higher temperature,
thereby causing fever
* The body will continue to maintain the
eliminated.
* The thermostat is then reset to 37°C.
* As the infection subsides, heat-losing
mechanisms such as vasodilation and
sweating go into operation.
CRISIS- This is a phase of the fever that
indicates that body temperature is falling.
INTERLEUKIN-1- Helps step up the
production of T cells.
* High body temperature intensifies the
effect of antiviral interferons and increases
production of transferrins.
TRANSFERRINS- Decrease the iron available
to microbes.
* Also, because the high temperature
speeds up the body’s reactions, it may help
body tissues repair themselves more
quickly.
* The higher temperature may slow the
growth rate of some bacteria.
Complications of fever:
- Tachycardia (rapid heart rate),
- Increased metabolic rate
- Dehydration
- Electrolyte imbalances
- Seizures in young children
- Delirium and coma.
* As a rule, death results if body
temperature rises above 44° to 46°C (112°
to 114°F).
ANTIMICROBIAL SUBSTANCES- produced
by body, a final component of the second
line of defense.
Most important antimicrobial substances:
- Proteins of the complement
system
- Interferons
- Iron-binding proteins
- Antimicrobial peptides
Proteins of the Complement System
COMPLEMENT SYSTEM- consists of over 30
proteins produced by the liver that circulate
in blood serum and within tissues
throughout the body.
- The system is so named because it
“completes,” or enhances, cells of the
immune system in destroying microbes.
- It is not adaptable, never changing over a
person’s lifetime.
- It is considered part of the innate immune
system.
- It can be recruited into action by the
adaptive immune system.
* Proteins of the complement system
destroy microbes by cytolysis, opsonization,
and inflammation and they also prevent
excessive damage to host tissues.
COMPLEMENT PROTEINS- Are inactive until
split into fragments (products), which
activates them.
- Are usually designated by an uppercase
letter C and are numbered C1 through C9,
named for the order in which they were
discovered.
- Act in a cascade, where one reaction
triggers another, which in turn triggers
another.
ACTIVATED FRAGMENTS- carry out the
destructive actions. Complement proteins
- Are indicated by lowercase letters a and b.
* For example, inactive complement protein
C3 is split into activated fragments, C3a and
C3b.
COMPLEMENT ACTIVATION- The cascade
of complement proteins that occurs during
an infection.
Three pathways in which it occurs: (end in
the activation of C3)
1. Classical Pathway- Was the first
discovered.
- It is initiated when antibodies bind to
antigens.
2. Alternative Pathway- Is so named
because it was discovered after the classical
pathway.
- Unlike the classical pathway, it does not
involve antibodies. The alternative pathway
is activated by contact between certain
complement proteins and a pathogen.
3. Lectin Pathway- Is the most recently
discovered mechanism for complement
activation.
- When macrophages ingest bacteria,
viruses, and other foreign matter by
phagocytosis, they release cytokines that
stimulate the liver to produce lectins.
LECTINS- Proteins that bind to
carbohydrates.
MANNOSE-BINDING LECTIN (MBL)- Binds
to the carbohydrate mannose.
- MBL binds to many pathogens because
MBL molecules recognize a distinctive
pattern of carbohydrates that includes
mannose.
MANNOSE- Is found in bacterial cell walls
and on some viruses.
Outcomes of Complement Activation:
1. CYTOLYSIS- Involves the membrane
attack complex (MAC).
MEMBRANE ATTACK COMPLEX (MAC)-
Creates a hole on a pathogen’s cell
membrane and makes transmembrane
channels, allowing for flow of extracellular
fluid into the pathogen.
- Forms the basis for the complement
fixation test used to diagnose some
diseases.
* Plasma membranes of the host cell
contain proteins that protect against lysis
by preventing the MAC proteins from
attaching to their surfaces.
* Gram-negative bacteria are more
susceptible to cytolysis because they have
only one or very few layers of peptidoglycan
to protect the plasma membrane from the
effects of complement.
* Gram-positive bacteria have many layers
of peptidoglycan, which limit complement’s
access to the plasma membrane and thus
interfere with cytolysis.
MAC RESISTANT- Bacteria that are not
killed by the MAC.
2. OPSONIZATION/ IMMUNE ADHERENCE-
Promotes attachment of a phagocyte to a
microbe.
- This enhances phagocytosis.
3. INFLAMMATION- It is the damage to the
body’s tissues which triggers a local
defensive response.
- A host response to tissue damage
characterized by redness, pain, heat, and
swelling; and sometimes loss of function.
Regulation of Complement
* Once complement is activated, its
destructive capabilities usually cease very
quickly to minimize the destruction of host
cells.
REGULATORY PROTEINS- Are present at
higher concentrations than the complement
proteins.
- These proteins bring about the breakdown
or inhibition of activated complement.
Example: Regulatory protein CD59 prevents
the assembly of C9 molecules to form the
MAC.
Complement and Disease
* Complement System assumes a role in
causing disease as a result of inherited
deficiencies.
Evading the Complement System
* Some bacteria evade the complement
system by means of their capsules, which
prevent complement activation.
* With respect to viruses, some viruses,
such as the Epstein Barr virus, attach to
complement receptors on body cells to
initiate their life cycle.
Interferons
INTERFERONS (IFNs)- family of cytokines,
with this, there is a one way an infected
host cell counters viral infection.
- Are a class of proteins produced by certain
animal cells, such as lymphocytes and
macrophages.
- IFNs produced by people protect human
cells, but they produce little antiviral activity
for cells of other species, such as mice or
chickens.
- Would seem to be ideal antiviral
substances, but certain problems do exist.
- Have no effect on viral multiplication in
cells already infected, and some viruses
(such as adenoviruses) have resistance
mechanisms that inhibit antiviral proteins.
* High concentrations of interferons are
toxic to the heart, liver, kidneys, and red
bone marrow.
Three main types of human interferons:
1. Alpha Interferon (IFN-α) &
2. Beta Interferon (IFN-β):
- Both are produced by virus-infected host
cells only in very small quantities that
diffuse to uninfected neighboring cells.
ANTIVIRAL PROTEINS (AVPs)- Proteins are
enzymes that disrupt various stages of viral
multiplication.
3. Gamma Interferon (IFN-γ)- Is produced
by lymphocytes and induces neutrophils
and macrophages to kill bacteria.
* The importance of interferons in
protecting the body against viruses, as well
as their potential as anticancer agents, has
made their production in large quantities a
top health priority.
RECOMBINANT INTERFERONS (rIFNs)- The
interferons produced with recombinant
DNA techniques.
Important for two reasons:
1. they are pure, and
2. they are plentiful.
Iron-binding Proteins
* Most pathogenic bacteria require iron for
their vegetative growth and reproduction.
* Many pathogens also require iron to
survive.
* The concentration of free iron in the
human body is low because most of it is
bound to iron-binding proteins.
TRANSFERRIN- Is found in blood and tissue
fluids.
LACTOFERRIN- Is found in milk, saliva, and
mucus.
FERRITIN- Is located in the liver, spleen, and
red bone marrow.
HEMOGLOBIN- Is located within red blood
cells.
* To survive in the human body, many
pathogenic bacteria obtain iron by secreting
proteins called SIDEROPHORES.
* Once the iron–siderophore complex is
formed, it is taken up by siderophore
receptors on the bacterial surface and
brought into the bacterium.
* A few pathogens do not use the
siderophore mechanism to obtain iron.
Antimicrobial Peptides
ANTIMICROBIAL PEPTIDES (AMPs)- These
are one of the most important components
of innate immunity.
- They were first discovered in the skin of
frogs, the lymph of insects, and human
neutrophils.
- They have a broad spectrum of
antimicrobial activities, including activity
against bacteria, viruses, fungi, and
eukaryotic parasites.
- They have shown synergy (working
together) with other antimicrobial agents.
- Are also very stable over a wide range of
pH.
- Also participate in a number of other
immune functions.
AMPs produced by humans:
DERMCIDIN- Produced by sweat glands.
DEFENSINS and CATHELICIDINS- Produced
by neutrophils, macrophages, and
epithelium
THROMBOCIDIN- Produced by platelets.
Other Factors
1. GENETIC RESISTANCE- Is an inherited
trait in a person’s genome that provides
resistance to a disease.
Example: the relationship between sickle
cell trait and Plasmodium falciparum;
individuals who have sickle cell trait are
relatively protected against P. falciparum
malaria.
2. AGE
3. OBSERVING HEALTHY PROTOCOLS
---- & lastly maganda ung gumawa.