MELANY C.
CAGABCAB INSTRUCTOR: JAY-EM AJOC
BSN-1
CHAPTER 15:
NONSPECIFIC HOST DEFENSE MECHANISM
The first two lines of defense are nonspecific, in the
sense that they are directed against any foreign
substances that enter our bodies. The third line of
defense, on the other hand, is very specific.
These foreign substances are called antigens because
they stimulate the production of specific antibodies; they
are “antibody-generating” substances. The antibodies
that are produced are very specific, in that they usually
can only recognize and attach to the antigen that
stimulated their production.
NONSPECIFIC HOST DEFENSE MECHANISMS
Nonspecific host defense mechanisms are general and
serve to protect the body against many harmful
substances. One of the nonspecific host defenses is the
innate, or inborn, resistance observed among some
species of animals and some persons who have a
natural resistance to certain diseases. Innate or inherited
characteristics make these people and animals more
resistant to some diseases than to others. The exact
factors that produce this innate resistance are not well
understood, but are probably related to chemical,
physiologic, and temperature differences between the
species as well as the general state of physical and
emotional health of the person and environmental
factors that affect certain races, but not others.
FIRST LINE OF DEFENSE
Skin and Mucous Membranes as Physical Barriers
The intact, unbroken skin that covers our bodies
represents a nonspecific host defense mechanism, in
that it serves as a physical or mechanical barrier to
pathogens. Very few pathogens are able to penetrate
intact skin. Most pathogens can only pass through when
these membranes are cut or scratched. As is true for
skin, even the tiniest of cuts can serve as portals of entry
for pathogens. The sticky mucus that is produced by
goblet cells within the mucous membranes serves to
entrap invaders; thus, it is considered part of the first line
of defense.
Cellular and Chemical Factors
The dryness, acidity, and temperature of the skin inhibit
colonization and growth of pathogens; perspiration
flushes them away. Also, the acidity (pH 5.0) and
temperature (37°C) of the skin inhibit the growth of
pathogens. The oily sebum that is produced by
sebaceous glands in the skin contains fatty acids, which
are toxic to some pathogens. Perspiration serves as a
nonspecific host defense mechanism by flushing
organisms from pores and the surface of the skin.
Perspiration also contains the enzyme, lysozyme, which
degrades peptidoglycan in bacterial cell walls (especially
Gram-positive bacteria). Even the sloughing off of dead
skin.
Sticky mucous serves as a nonspecific host defense
mechanism by trapping pathogens. It also contains toxic
substances, such as lysozyme, lactoferrin, and
lactoperoxidase.cells removes potential pathogens from
As previously mentioned, lysozyme destroys bacterial
cell walls by degrading peptidoglycan. Lactoferrin is a
protein that binds iron, a mineral that is required by all
pathogens. Because they are unable to compete with
lactoferrin for free iron, the pathogens are deprived of
this essential nutrient. Lactoperoxidase is an enzyme
that produces superoxide radicals, highly reactive forms
of oxygen, which are toxic to bacteria. the skin.
The mucociliary covering on epithelial cells in the
respiratory tract move trapped dust and microbes
upward toward the throat, where they are swallowed or
expelled.
Lysozyme and other enzymes that lyse or destroy
bacteria are present in nasal secretions, saliva, and
tears. Even the swallowing of saliva can be thought of as
a nonspecific host defense mechanism, because
thousands of bacteria are removed from the oral cavity
every time we swallow. Humans swallow approximately
1 L of saliva per day.
To a certain extent, the following factors protect the
gastrointestinal (GI) tract from bacterial colonization and
are therefore considered to be nonspecific host defense
mechanisms:
• Digestive enzymes • Acidity of the stomach
(approximately pH 1.5)
• Alkalinity of the intestines
Pathogens entering the GI tract are often killed by
digestive enzymes or the acidity or alkalinity of different
anatomical regions.
Peristalsis and urination serve to remove pathogens
from the GI tract and urinary tract, respectively.
Many invading microorganisms are trapped in the sticky,
mucous lining of the digestive tract, where they may be
destroyed by bactericidal enzymes and phagocytes.
Peristalsis and the expulsion of feces serve to remove
bacteria from the intestine. Bacteria make up about 50%
of feces.
The acidity of vaginal fluid usually inhibits colonization of
the vagina by pathogens.
Microbial Antagonism
When indigenous microflora prevent the establishment
of arriving pathogens, it is known as microbial
antagonism.
The inhibitory capability of the indigenous
microflora has been attributed to the following
factors:
• Competition for colonization sites
• Competition for nutrients
• Production of substances that kill other bacteria
A decrease in the number of indigenous microflora at a
particular anatomical site can lead to an overgrowth of
pathogens or opportunistic pathogens present at the
site; this is referred to as a superinfection.
The antibiotics reduce or eliminate certain members of
the indigenous microflora (e.g., the vaginal and
gastrointestinal flora), leading to overgrowth by bacteria
or fungi that are resistant to the antibiotic(s) being
administered. This overgrowth or “population explosion”
of organisms is called a superinfection. A superinfection
of Candida albicans in the vagina may lead to the
condition known as yeast vaginitis. A superinfection of
Clostridium difficile in the colon may lead to C. difficile–
associated diseases known as antibiotic-associated
diarrhea (AAD) and pseudomembranous colitis (PMC).
Colicin and other bacteriocins are proteins produced by
some bacteria to kill other bacteria.
Similar antibacterial substances are produced by some
strains of Pseudomonas and Bacillus species as well as
by certain other bacteria. Bacteriocins have a narrower
range of activity than do antibiotics, but they are more
potent than antibiotics.
SECOND LINE OF DEFENSE
Transferrin, fever, interferons, the complement system,
inflammation, and phagocytosis are all part of the
second line of defense.
A complex sequence of events develops involving
production of fever, production of interferons, activation
of the complement system, inflammation, chemotaxis,
and phagocytosis.
Transferrin
Transferrin, a glycoprotein synthesized in the liver, has
a high affinity for iron. Its normal function is to store and
deliver iron to host cells. Like lactoferrin (mentioned
earlier), transferrin serves as a nonspecific host defense
mechanism by sequestering iron and depriving
pathogens of this essential nutrient.
Transferrin serves as a host defense mechanism by
depriving pathogens of iron
. Fever Normal body temperature fluctuates between
36.2°C and 37.5°C (97.2°F and 99.5°F), with an
average of about 37°C (98.6°F).
A body temperature greater than 37.8°C (100°F) is
generally considered to be a fever. Substances that
stimulate the production of fever are called pyrogens or
pyrogenic substances. Pyrogens may originate either
outside or inside the body. Those from outside the body
include pathogens and various pyrogenic substances
that they produce or release (e.g., endotoxin). Interleukin
1 (IL-1) is an example of a pyrogen that is produced
within the body (i.e., it is an endogenous pyrogen).
Fever augments the host’s defenses in the following
ways:
• By stimulating white blood cells (leukocytes) to deploy
and destroy invaders
• By reducing available free plasma iron, which limits the
growth of pathogens that require iron for replication and
synthesis of toxins
• By inducing the production of IL-1, which causes the
proliferation, maturation, and activation of lymphocytes
in the immunologic response
A fever can slow down the rate of growth of certain
pathogens and can even kill some especially fastidious
ones.
The following scenario illustrates one way in which
fever develops during an infectious disease:
1. A patient has septicemia caused by Gram-
negative bacteria (referred to as Gram-negative
sepsis).
2. The bacteria release endotoxin into the
patient’s bloodstream. (Endotoxin is part of the
cell wall structure of Gram-negative bacteria; it is
the lipid component of lipopolysaccharide.)
3. Phagocytes ingest (phagocytize) the
endotoxin.
4. The ingested endotoxin stimulates the
phagocytes to produce IL-1, an endogenous
pyrogen. IL-1 is produced primarily by
macrophages.
5. IL-1 stimulates the hypothalamus (a part of
the brain referred to as the body’s thermostat) to
produce prostaglandins.
6. Once metabolized, the prostaglandins cause
the hypothalamic thermostat to be set at a
higher level.
7. The increased thermostatic reading sends out
signals to the nerves surrounding peripheral
blood vessels. This causes the vessels to
contract, thus conserving heat.
8. The increased body heat, resulting from
vasoconstriction, continues until the temperature
of the blood supplying the hypothalamus
matches the elevated thermostat reading.
Interferons
Interferons are small, antiviral proteins produced by
virusinfected cells. They are called interferons because
they “interfere” with viral replication. The three known
types of interferon, referred to as alpha (), beta (), and
gamma () interferons, are induced by different stimuli,
including viruses, tumors, bacteria, and other foreign
cells. The different types of interferons are produced by
different type of cells. -Interferon is produced by B
lymphocytes (B cells), monocytes, and macrophages; -
interferon, by fibroblasts and other virus-infected cells;
and -interferon, by activated T lymphocytes (T cells) and
natural killer cells (NK cells).
Interferons are small, antiviral proteins produced by
virus-infected cells. They interfere with viral replication.
The interferons produced by a virus-infected cell are
unable to save that cell from destruction, but once they
are released from that cell, they attach to the
membranes of surrounding cells and prevent viral
replication from occurring in those cells.
Interferons are not virusspecific, meaning that they are
effective against a variety of viruses, not just the
particular type of virus that stimulated their production.
Interferons are species-specific, however, meaning that
they are effective only in the species of animal that
produced them.
Interferons are not virus-specific, but they are host-
specific.
The Complement System Complement is not a single
entity, but rather a group of approximately 30 different
proteins (including nine proteins designated as C1
through C9) that are found in normal blood plasma.
These proteins make up what is called “the complement
system”—so named because it is complementary to the
action of the immune system.
The proteins of the complement system (collectively
referred to as complement components) interact with
each other in a stepwise manner, known as the
complement cascade—a nonspecific host defense
mechanism that assists in the destruction of many
different pathogens.
The major consequences of complement activation
are listed here:
• Initiation and amplification of inflammation
• Attraction of phagocytes to sites where they are
needed (chemotaxis; to be discussed later)

• Activation of leukocytes

• Lysis of bacteria and other foreign cells

• Increased phagocytosis by phagocytic cells

(opsonization.

Opsonization is a process by which phagocytosis is

facilitated by the deposition of opsonins, such as
antibodies or certain complement fragments, onto the
surface of particles or cells. In some cases, phagocytes
are unable to ingest certain particles or cells (e.g.,
encapsulated bacteria) until opsonization occurs. One of
the products formed during the complement cascade,
called C3b, is an opsonin. It is deposited on the surface
of microorganisms. Neutrophils and macrophages
possess surface molecules (receptors) that can
recognize and bind to C3b.
Opsonization is a process by which phagocytosis is
facilitated by the deposition of opsonins (e.g., antibodies
or certain complement fragments) onto the surface of
particles or cells.
There are a variety of hereditary complement
deficiencies that interfere with activities of the
complement system. Some of these inherited
deficiencies are associated with defects in activation of
the classical pathway.b A deficiency of C3 leads to a
defect in activation of both the classical and alternative
pathways. Defects of properdin factors impair activation
of the alternative pathway. Any of these defects leads to
increased susceptibility to pyogenic (pusproducing)
staphylococcal and streptococcal infections.
Acute-Phase Proteins
Plasma levels of molecules collectively referred to as
acutephase proteins increase rapidly in response to
infection, inflammation, and tissue injury. They serve as
host defense mechanisms by enhancing resistance to
infection and promoting the repair of damaged tissue.
Acute-phase proteins include C-reactive protein (which
is used as a laboratory marker for, or indication of,
inflammation), serum amyloid A protein, protease
inhibitors, and coagulation proteins.
Cytokines
Cytokines are chemical mediators that are released from
many different types of cells in the human body. They
enable cells to communicate with each other.
Inflammation
The body normally responds to any local injury, irritation,
microbial invasion, or bacterial toxin by a complex series
of events collectively referred to as inflammation or the
inflammatory response.
During the inflammatory process, many nonspecific host
defense mechanisms come into play. These interrelated
physiologic reactions result in the four cardinal (main)
signs and symptoms of inflammation: redness, heat,
swelling (edema), and pain.c There is often pus
formation, and occasionally a loss of function of the
damaged area (e.g., an inflamed elbow might prevent
bending of the arm).
The accumulation of fluid, cells, and cellular debris at the
inflammation site is referred to as an inflammatory
exudate. If the exudate is thick and greenish yellow,
containing many live and dead leukocytes, it is known as
a purulent exudate or pus.
When pyogenic microbes (pus-producing microbes),
such as staphylococci and streptococci, are present,
additional pus is produced as a result of the killing effect
of bacterial toxins on phagocytes and tissue cells.
Although most pus is greenish yellow, the exudate is
often bluish green in infections caused by
Pseudomonas aeruginosa. This is caused by the
bluish green pigment (called pyocyanin) produced by
this organism.
The primary functions of the lymphatic system include
draining and circulating intercellular fluids from tissues,
transporting digested fats from the digestive system to
the blood, removing foreign matter and microbes from
the lymph, and producing antibodies and other factors to
aid in the destruction and detoxification of any invading
microbes.
Phagocytosis
The three major categories of leukocytes found in blood
are monocytes, lymphocytes, and granulocytes.
Phagocytic white blood cells are called phagocytes, and
theprocess by which phagocytes surround and engulf
(ingest) foreign material is called phagocytosis. The two
most important groups of phagocytes in the human body
are macrophages and neutrophils; they are sometimes
called “professional phagocytes,” because phagocytosis
is their major function.d Macrophages serve as a
“cleanup crew” to rid the body of unwanted and often
harmful substances, such as dead cells, unused cellular
secretions, debris, and microorganisms.
The two most important groups of phagocytes in the
human body— sometimes referred to as “professional
phagocytes”—are macrophages and neutrophils
Granulocytes are named for the prominent cytoplasmic
granules that they possess. Phagocytic granulocytes
include neutrophils and eosinophils. Neutrophils (also
known as polymorphonuclear cells, polys, and PMNs)
are much more efficient at phagocytosis than
eosinophils. An abnormally high number of eosinophils
in the peripheral

A complex series of physiologic events occurs

immediately after the initial damage to the tissue.

Vasodilation—an increase in the diameter of capillaries

—leads to redness, heat, and edema.
 cytoplasm of the phagocyte, the object is contained
within a membrane-bound vesicle called a phagosome.

During ingestion, the particle becomes surrounded by a

membrane. The membrane-bound vesicle is called a
phagosome

Digestion

The phagosome next fuses with a nearby lysosome to

form a digestive vacuole (phagolysosome), within which
killing and digestion occur.

The fusion of a lysosome and a phagosome results in a

phagolysosome, within which the ingested particle is
digested.

Macrophages develop from a type of leukocyte called

monocytes during the inflammatory response to
infections. Those that leave the bloodstream and migrate
to infected areas are called wandering macrophages.
Fixed macrophages (also known as histocytes or
histiocytes) remain within tissues and organs and serve
to trap foreign debris. Macrophages are extremely
efficient phagocytes. They are found in tissues of the
reticuloendothelial system (RES).

Wandering macrophages leave the bloodstream and

migrate to sites of infection and other areas where they
are needed. Fixed macrophages remain within tissues
and organs.

Chemotaxis

Phagocytosis begins when phagocytes move to the site

where they are needed.

The directed migration of phagocytes is called

chemotaxis. It is caused by chemicals referred to as
chemotactic agents.

This directed migration is called chemotaxis and is the

result of chemical attractants referred to as chemotactic
agents (also called chemotactic factors, chemotactic
substances, and chemoattractants). Chemotactic agents
that are produced by various cells of the human body
are called chemokines.e Chemotactic agents are
produced during the complement cascade and
inflammation.
Attachment
The next step in phagocytosis is attachment of the
phagocyte to the object (e.g., a yeast or bacterial cell) to
be ingested. Phagocytes can only ingest objects to
which they can attach.
In opsonization, a particle becomes coated with
opsonins—either complement fragments or antibodies.
Ingestion
Phagocytosis is one type of endocytosis, the process of
ingesting material from outside a cell. Within the
Mechanisms by which Pathogens Escape
Destruction by Phagocytes
Some bacteria and protozoa are able to survive within
phagocytes.
During the initial phases of infection, capsules serve an
antiphagocytic function, protecting encapsulated bacteria
from being phagocytized. Some bacteria produce an
exoenzyme (referred to as a toxin by some scientists)
called leukocidin, which kills phagocytes. For example,
waxes in the cell wall of Mycobacterium tuberculosis
protect the organism from digestion. The bacteria are
even able to multiply within the phagocytes and are
transported within them to other parts of the body. Other
pathogens that are able to survive within phagocytes
include bacteria such as Rickettsia rickettsii, Legionella
pneumophila, Brucella abortus, Coxiella burnetii, Listeria
monocytogenes, and Salmonella spp., as well as
protozoan parasites such as Toxoplasma gondii,
Trypanosoma cruzi, and Leishmania spp.

Ehrlichia and Anaplasma spp., closely related to

rickettsias, are obligate, intracellular, Gram-negative
bacteria that live within leukocytes (i.e., they are
intraleukocytic pathogens).

Ehrlichia and Anaplasma spp. are intraleukocytic

bacteria, able to live and multiply within leukocytes.

FIGURE 15-7.

The ingestion phase of phagocytosis.

(A) A phagocyte has attached to a bacterial cell. (B)

Pseudopodia extend around the bacterial cell. (C) The
pseudopodia meet and fuse together. (D) The bacterial
cell, surrounded by a membrane, is now inside the
phagocyte. The membrane-bound structure, containing
the ingested bacterial cell, is called a phagosome. N,
nucleus.

Disorders and Conditions that Adversely Affect

Phagocytic and Inflammatory Processes

Leukopenia Some patients have an abnormally low

number of circulating leukocytes—a condition known as
leukopenia

Leukopenia—an abnormally low number of circulating

leukocytes. Neutropenia —an abnormally low number of
circulating neutrophils.

Technically, neutropenia is an abnormally low number

of circulating neutrophils; neutropenia neutrophilic
leukopenia.) Leukopenia may result from bone marrow
injury as a result of ionizing radiation or drugs, nutritional
deficiencies, or congenital stem cell defects.

Disorders and Conditions Affecting Leukocyte

Motility and Chemotaxis

The inability of leukocytes to migrate in response to

chemotactic agents may be related to a defect in the
production of actin, a structural protein associated with
motility.

Decreased neutrophil chemotaxis also occurs in the

inherited childhood disease known as Chediak-Higashi
syndrome (CHS). In addition, the PMNs of individuals
with CHS contain abnormal lysosomes that do not
readily fuse with phagosomes, resulting in decreased
bactericidal activity.

Disorders and Conditions Affecting Intracellular

Killing by Phagocytes

This is usually the result of deficiencies in

myeloperoxidase or an inability to generate superoxide
anion, hydrogen peroxide, or hypochlorite. Chronic
granulomatous disease (CGD) is an often fatal genetic
disorder that is characterized by repeated bacterial
infections. The PMNs of individuals with CGD can ingest
bacteria but cannot kill certain species. In one form of
CGD, the person’s PMNs are unable to produce
hydrogen peroxide. In another hereditary disorder, the
individual’s PMNs completely lack myeloperoxidase.
Their PMNs do possess other microbicidal mechanisms,
however, so these individuals usually do not experience
recurrent infections.