NON SPESIFIK IMMUNITY DEFENSE

The human immune system consists of 2 branches: 1) the innate immune

system, which is present at birth and provides non-specific protection against microbes;
and 2) the adaptive immune system, which provides specific protection against
microbes, but must be acquired over time.
The innate and adaptive immune branches can be further broken down into 3 lines of
defense that work together to protect the body against injury and infection.
The first line of defense is non-specific and is part of the innate immune system. The
first line of defense consists of: 1) physical barriers (skin, mucous membranes, cilia);
2) chemical barriers (saliva, sweat,sebum, tears, lysozyme, digestive enzymes,
lactoferrin, urine); and 3) resident bioflora(beneficial microbes living on our skin and in
our bodies that help block infection by disease-causing microbes).
The second line of defense is also part of the non-specific, innate immune system and
includes: 1) non-specific immune cells (eosinophils, basophils, neutrophils,
macrophages); 2) chemical mediators (interleukin-1, interferon, complement); 3) fever;
4) inflammation; and 5)phagocytosis.
The third line of defense (see chapter 15) is part of the adaptive or acquired immune
system. This line of defense provides specific, long-term protection against microbes.
The third line of defense includes: 1) T-cells (helper and cytotoxic); 2) B-cells (memory
and plasma cells); and 3)antibodies.
All blood cells are born or produced in the bone marrow. The 3major types of blood
cells are erythrocytes (red blood cells), thrombocytes (platelets), and leukocytes
(white blood cells). Red blood cells help transport oxygen and nutrients to the cells of
the body. White blood cells (WBCs) defend the body against infection.
The immune system relies upon 2 systems for transport of immune cells and proteins:
1) the circulatory system and 2) the lymphatic system.
Thelymphatic system includes the thymus, spleen, tonsils, lymph nodes and other
lymph tissues found in the gut (GALT), skin (SALT), mucosal membranes (MALT), and
bronchial tubes (BALT). T cells mature in the thymus, the spleen filters out damaged
blood cells and microbes, and thelymph nodes serve as the "headquarters" of the
immune system.
Leukocytes (white blood cells) can be classified as: 1) granulocytes (eosinophils,
neutrophils, basophils and mast cells); or 2) agranulocytes(monocytes, macrophages, T-
lymphocytes, and B-lymphocytes).


Eosinophils are granular, non-specific immune cells that protect against parasitic
infections.
Basophils are granular, non-specific immune cells found in the blood that release
histamine in response to injury, infection and allergens.
Mast cells are granular, non-specific immune cells found in the tissues that release
histamine in response to injury, infection and allergens.
Neutrophils are granular, non-specific immune cells that patrol the borders of the body
and eliminate microbes by phagocytosis (amateur eaters).
Monocytes are agranular, non-specific immune cells that circulate in the blood and
mature into macrophages when they migrate into tissues.
Macrophages are agranular, non-specific immune cells that perform the following
functions: 1) phagocytosis (professional eaters); 2) sound chemical alarm to alert other
immune cells; and 3) present information about the foreign microbes (antigens) to the T
cells, which are the generals of the immune army.
Phagocytosis is a second line of defense process in which foreign materials (microbes)
are engulfed and broken down by neutrophils or macrophages within a digestive
compartment known as the lysosome.
Inflammation is a non-specific response to tissue injury or infection that: 1) walls off
damaged or infected tissue; 2) recruits immune cells to the site of injury or infection;
and 3) clears away microbes or damaged cells so tissue repair can occur.
There are 4 signs of inflammation: 1) rubor; 2) calor; 3) tumor; and 4) dolor.
Fever is an increase in body temperature induced by pyrogens (interleukin-1 and LPS)
and regulated by the hypothalamus, which decreases bacterial cell growth and increases
immune cell activity.
Interferons are anti-viral proteins released by virally-infected cells that help prevent the
spread of infection to neighboring cells by degrading viral RNA and blocking production
of viral proteins.
Complement is a set of immune proteins that aid or "complement" immune function.
Complement proteins C3a and C5a induce inflammation. Complement protein C3b
opsonizes or binds to microbial cells marking them for destruction by phagocytes.
Complement proteins C5-C9 form the membrane attack complex, which forms holes on
the surface of targeted microbes and leads to their lysis.
3 Lines of Immune Defense


The body utilizes 2 types of immunity to defend against microbial
invaders: Innate andAcquired Immunity. Innate immunity is a type of natural, built-in defense
system that provides non-specific protection against pathogens. Innate immunity includes
the 1st line of defense (physical & chemical barriers & resident bioflora) and the 2nd line of
defense (inflammation, fever, phagocytosis and non-specific immune cells). Acquired
immunity is a specific, long-term form of protection that develops over time. Acquired
immunity represents the 3rd line of defense and is mediated by specific immune cells (T cells
and B cells).
Non-Specific (Innate) Immunity
Innate immunity is a natural defense system present at birth that provides non-specific
protection against a wide range of pathogens. Although the innate immune system cannot
specifically recognize or remember individual pathogens, it does NOT require prior exposure to
the pathogen in order to be effective against it. This means it can protect you from microbes
that your body has never encountered before. The innate immune system consists of the 1st
and 2nd lines of defense.








The first line of defense is non-specific and consists of: 1) physical barriers (skin, mucous
membranes, cilia); 2) chemical barriers (saliva, sweat, sebum, tears, lysozyme, digestive
enzymes, lactoferrin, urine); and 3) resident bioflora (beneficial microbes living on our skin and
in our bodies that help block infection by disease-causing microbes).




1st Line of Defense: Physical Barriers (p. 415-417)
Physical barriers, which include the outer layer of skin (epidermis), cilia, and mucous
membranes, block the entry of pathogens into the body, much like a castle wall blocks or
prevents foreign invaders from entering the castle.
The skin consists of an outer layer called the epidermis, which is composed of multiple layers of
tightly packed skin cells that serve as a physical barrieragainst infection. As new cells are
produced in the layers below, the dead outermost layers of the epidermis are shed. Any
microbes attached to these dead skin layers are shed along with the dead skin cells. The dermis,
which lies just beneath the epidermis, contains collagen fibers that give the skin strength and
flexibility. This layer contains sweat glands that use salty perspiration to flush microbes and
other contaminants out of the pores. Sweat also contains a special enzyme called lysozyme,
that breaks down the bacterial cell wall. In addition to sweat glands, the skin also
has sebaceous glands that coat the skin with sebum, which is an oily substance that contains
fatty acids that lower the pH of the skin surface to inhibit microbial growth.
As the dead outermost layers of the epidermis are shed, any infectious microbes attached to
this layer are also shed from the body. For this reason, you should always wash your sheets,
towels, and other personal clothing items after you have been ill, as the microbes attached to
these dead skin layers can remain infectious!


So, where does all of that dead skin go? Dead skin cells can be found on our sheets, pillows,
clothes, and even in the dust particles that form in our homes. Dead skin cells are broken down
by dust mites, which are microscopic parasites that live on our skin, hair, and eyelashes.
Mucous membranes line the respiratory, urinary, gastrointestinal, and reproductive tracts.
Mucous membranes consist of a single layer of tightly-packedciliated epithelial cells.
Neighboring goblet cells secrete a thick, sticky substance called mucus, which coats the
epithelial cells. Mucus contains lysozyme, which is an enzyme that breaks down the bacterial
cell wall. As bacteria and other debris become trapped in the thick mucus, cilia sweep it up and
out of the respiratory tract, where it is expelled from the body by coughing, sneezing, or
even swallowing!





1st Line of Defense: Chemical Barriers (p. 417)
Chemical barriers (tears, saliva, sweat,sebum, lysozyme, digestive enzymes, lactoferrin, urine)
help break down or destroy microbial invaders. Lysozyme, an enzyme found in tears, sweat,
mucus, saliva and urine, acts by destroying the peptidoglycan cell wall of bacteria. Sweat also
contains salt, which creates a hypertonic environment that can lead to dehydration of microbial
cells. Fatty acids found in sebum contain fatty acids, which give the skin an acidic pH of 5. The
stomach maintains an acidic pH (below 7) and contains digestive enzymes that can break down
microbes that pass through the gastrointestinal (GI) tract. Bile is found in the intestinal tract,
where it contributes to a basic or alkaline pH (above 7) that inhibits growth of some microbes.
Vaginal and prostrate secretions contain lactoferrin, which is an iron-binding protein that
prevents microbes from attaching to and using free iron to enhance their metabolism.

Can you answer the questions below?
























1st Line of Defense: Resident Bioflora (p. 416-417)


Normal bioflora are beneficial microbes living on our skin and in our bodies that help block
infection by disease-causing microbes. Resident bioflora provide non-specific protection to the
host by competing with pathogens for nutrients and blocking attachment to the host, and by
secreting toxins (bacteriocidins) that inhibit or kill microbes. These beneficial microbes also aid
in digestion and absorption of our food. Staphylococcus epidermidis is a normal resident of the
skin and Escherichia coli is a normal resident of the intestinal tract. Current research also shows
that by maintaining a constant level of beneficial bacteria in our body, we keep the second line
of defense active and ready to fight off infection if needed. Frequent or chronic antibiotic use
can destroy many of the beneficial bacteria that live in the GI tract, making us more susceptible
to other types of infection.

2nd Line of Defense (p.418, 426-438)
If pathogens do gain entry into the body, the body's 2nd line of defense comes into play.
The second line of defense is also part of the non-specific, innate immune system and
includes: 1) non-specific immune cells (eosinophils, basophils, neutrophils, macrophages);
2) antimicrobial chemicals (interleukin-1, interferon, complement); 3) fever; 4) inflammation;
and 5) phagocytosis.


Role of Blood & Lymph in Immune Defense (p. 421-424)
Blood consists of cells and plasma, which is a fluid that contains ions, dissolved gases, nutrients,
and proteins involved in inflammation (complement proteins) and blood clotting. There are 3
major types of blood cells: 1) erythrocytes (red blood cells); 2) thrombocytes (platelets); and
3) leukocytes (white blood cells). Erythrocytes transport oxygen and carbon dioxide gases
between the cells and the lungs. The average adult male has 4-6 million red blood cells per
microliter of blood, whereas the average female has 4-5 million red blood cells per
microliter of blood. Leukocytes (white blood cells) defend the body against infection and injury.
The average person has between 4500-11,000 per microliter of blood.
All blood cells originate in the bone marrow, within the hollow cavities of the large bones. In a
process calledhematopoiesis, stem cells are used to produce each of the 3 major types of
blood cells: 1) erythrocytes (red blood cells), which arise from erythroid stem cells;
2) thrombocytes (platelets), which arise from myeloid stem cells; and 3) leukocytes (white
blood cells), which arise from both myeloid and lymphoid stem cells.



White blood cells have specialized receptors on their surface that enable them to determine
what is "self" and belongs in the body and what is "non-self"and does not belong. When "non-
self" proteins are encountered, an immune response is mounted to destroy the foreign (non-
self) substance.












Immune Transport: The Circulatory & Lymphatic Systems (p. 424-426)
Immune cells move throughout the body via the circulatory system (with vessels that run in
opposite directions, like an interstate) and the lymphatic system(with vessels that run in only
one direction, like a one-way street). Blood and immune cells are transported quickly through
the circulatory system via a pump (heart), while lymph is moved slowly back toward the heart
through the contraction of skeletal muscles. This dependence on muscle movement explains
why bed- or wheel-chair ridden patients tend to have swelling or edema of the hands and feet.
Lymphoid organs include the thymus (site of T-lymphocyte maturation), the spleen (filters out
damaged red blood cells and pathogens from the blood),lymph nodes (immune system
headquarters where white blood cells attack foreign invaders),tonsils, gut-associated lymphoid
tissue (GALT) which includes the appendix and intestinal Peyer's patch, mucosal-associated
lymphoid tissue (MALT), skin-associated lymphoid tissue (SALT) and broncial-associated
lymphoid tissue (BALT).





One of the functions of the lymphatic system is the reabsorption of extracellular body fluids,
which are returned to the heart via the lymph vessels. Lymphatic fluid is filtered in the lymph
nodes (immune system headquarters), allowing immune cells within the nodes to see and
respond to foreign cells or antigens. Disruption of the lymphatic system by parasites, such as
the filarial worm (shown below), can interfere with the reabsorption of extracellular body fluids
and lead to edema or swelling.
Leukocytes: Warriors of the Immune System
Leukocytes (white blood cells) are microscopic immune warriors that protect us from injury and
infection caused by invading microbes and disease-causing pathogens. Produced in the bone
marrow, leukocytes (white blood cells) include basophils, eosinophils, mast cells, neutrophils,
monocytes, macrophages and lymphocytes.
T-lymphocytes leave the bone marrow and mature in the thymus. There are several types of T-
lymphocytes produced in the body-- cytotoxic, helper, memory and suppressor T-cells. B-
lymphocytes are born and mature in the bone marrow. After activation, B-lymphocytes can
become plasma cells that secrete antibodies or memory cells. Some cells within the lymphatic
system become antigen-presenting cells (APCs). Macrophages are one type of APC that eat
microbial invaders and then display foreign antigens to the generals of the immune arrmy, the
CD4+ T helper cells.




Non-Specific Immune Cells (p. 422-424)
Leukocytes (white blood cells) can be divided into 2 groups based upon their appearance under
the microscope: 1) granulocytes; or 2) agranulocytes. Granulocytes contain large granules or
compartments that store pre-formed chemicals such as histamine, leukotrienes and
prostaglandins. Granulocytesinclude: eosinophils, neutrophils, basophils and mast cells. In
contrast, agranulocytes do not appear to have granules when viewed under a light
microscope.Agranulocytes include:monocytes, macrophages, T-lymphocytes, and B-
lymphocytes.



Granulocytes (p. 422-423)
Granulocytes account for 75% of all leukocytes (white blood cells) and contain large granules or
compartments that store pre-formed chemicals such as histamine, leukotrienes and
prostaglandins. Granulocytes include: eosinophils, neutrophils, basophils and mast cells.



Eosinophils (2-4%) are non-specific immune cells (granulocytes) involved in eliminating
allergens and parasites. Eosinophils primarily attack parasitic wormsby attaching to their
surface. Eosinophils then release digestive enzymes, such as peroxidase, lysozyme, and
perforin, which act to break down the large parasite into smaller parts that can be consumed by
macrophages. Eosinophilia, an abnormally high number of eosinophils in the blood, is often an
indication that the patient has a parasitic infection.

Basophils account for 0.5-1% of all leukocytes (white blood cells). Found circulating in the
blood, basophils release histamine in response to injury, infection and allergic responses. The
release of histamine causes vasodilation of the blood vessels, which results in increased blood
flow and the recruitment of WBCs into the infected or injured tissue. Although similar in
function to basophils, mast cells are found in the tissues where they release histamine in
response to injury, infection and allergens.



Neutrophils are non-specific immune cells that patrol the borders of our body. Always on the
lookout for foregin invaders, neutrophils are the 1st cells to arrive at the site of injury or
infection. The primary function of the neutrophil is to eat and digest invading microbes by
phagocytosis (amateur eaters). Although neutrophils account for 55-65% (25 billion cells) of all
white blood cells (WBCs), they are short-lived and only survive 3-8 days before dying and
forming pus. Substances that induce pus formation are called pyogens. For
example, Streptococcus pyogenes, causes the formation of white nodules at the back of the
throat.
Non-Specific Immune Cells: Agranulocytes (p. 423-424)
Agranulocytes do not appear to have granules when viewed under a light
microscope. Agranulocytes include: monocytes, macrophages, dendritic cells, T-lymphocytes,
and B-lymphocytes.




Monocytes & Macrophages (p. 432-433)
Monocytes are agranular, non-specific immune cells that circulate in the blood and mature into
macrophages when they migrate into tissues.Macrophages perform 3 important functions
within the non-specific immune system: 1) phagocytosis (professional eaters); 2) release
chemical messengers to alert other immune cells; and 3)present information about the foreign
microbes (antigens) to the T cells, which are the generals of the immune army.












Macrophages that migrate into specific tissues are named for their location in the body. For
example, alveolar macrophages are found in the lungs, Kuppfer cells are found in the
liver, dendritic cells are found in the skin and mucous membranes, and microglia are found in
the brain.






Chemical Messengers: Cytokines & Interleukins (p. 428-429)
Immune cells communicate using chemical messengers called cytokines. Cytokines are small,
regulatory proteins essential for communication between cells. Cytokines are produced by
many types of cells including, monocytes, macrophages, lymphocytes, fibroblasts, mast cells,
platelets, and endothelial cells. Cytokines have several different functions within the body: 1)
they can mediate non-specific immune reactions such as inflammation, fever, and phagocytosis;
2) they regulate the growth and activation of the specific immune system lymphocytes; 3)
stimulate hematopoiesis in the bone marrow; amd 4) they can either expand (vasodilate) or
constrict (vasoconstrict) blood vessels.
Interleukins are a special class of cytokine that allow immune cells (leukocytes) to
communicate with each other and the rest of the body. For example,interleukin-1 (IL-1) is
produced by macrophages in response to infection. This chemical messenger activates the
hypothalamus and induces fever.Histamine is a vasoactive chemical messenger produced by
mast cells and basophils, that causes vasodilation and increased vascular
permeability.Leukotrienes also increase vascular permeability. Prostaglandins, which can be
produced by most body cells, can trigger inflammation and pain.










2nd Line of Defense: Fever (p. 431-432)
Fever is an increase in body temperature induced by endogenous (interleukin-1, IL-1) or
exogenous (Lipopolysaccharide found on Gram-negative bacterial cells) pyrogens. Fever is
induced when chemical messengers such as IL-1 stimulate the hypothalamus to raise body
temperature. Fever acts to slow down microbial metabolism while, at the same time, ehances
immune cell function.





What Causes Chills?
If the thermostat (hypothalamus) has been set by the pyrogen (interleukin-1 or LPS) at 102F,
but the blood temperature is only at 99F, then the muscles are stimulated to contract or shiver
to produce heat. At the same time, vessels in the skin constrict (become smaller) and the
piloerector muscles in the skin cause "goosebumps" to form. In contrast, when the thermostat
is reset to 98.6F, but the blood is still at 102F, the body will cause the vessels to dilate
(expand) and the body will sweat in an attempt to release heat and lower the body's
temperature.
2nd Line of Defense: Inflammation (p. 426-431)
Inflammation is a non-specific response to tissue injury or infection that limits the spread of
pathogens, removes damaged cells or tissues, destroys pathogens, and stimulates tissue repair.
4 Signs of Inflammation
Inflammation is characterized by 4 signs: rubor, calor, tumor, and dolor.

Inflammation begins when injured or infected tissues release chemical distress signals, such
as histamine, that cause vasodilation. Vasodilation leads toincreased blood flow and
the recruitment of non-specific immune cells to the site of injury. Non-specific immune cells
migrate in response to the chemical distress signal released by infected or injured cells via a
process called chemotaxis and leave the blood vessel to enter the tissue via diapedesis.



Steps in Inflammation
1. Mast cells release chemical messengers (histamine and leukotrienes) in response to tissue
injury or infection. These factors create a "chemical trail" for the immune cells to follow to the
site of injury or infection via a process called chemotaxis.

2. Histamine causes vasodilation or expansion of the blood vessels. This causes redness (rubor)
and increased heat (calor) in the affected region. Leukotrienes make the blood vessel walls
more permeable or leaky.



3. Neutrophils & macrophages crawl out of the blood vessels by diapedesis. This causes swelling
(tumor) in the affected tissue.Neutrophils and macrophages remove microbes or damaged
tissue by phagocytosis (eating) and pus is formed.

4. Tissue damage is repaired and scars can form if fibroblasts are involved.
Inflammation can either be acute or chronic. Acute inflammation is a localized response that
develops immediately upon injury and lasts for a short period of time. Acute inflammation is
typically beneficial and results in the destruction of microbes and tissue repair. Chronic
inflammation is a more slow-progressing form of inflammation that persists for a longer period
of time (months to years). Chronic inflammation can cause damage to surrounding host tissues.



Both steroidal (corticosteroids) and non-steroidal anti-inflammatory drugs (NSAIDs) can be
used as anti-inflammatory drugs to reduce pain and swelling. NSAIDS, which include drugs like
aspirin and ibuprofen, prevent prostaglandins from being synthesized. They achieve this by
inhibiting the cyclooxygenase (COX) enzyme. In contrast, other products, such as Tylenol
(acetaminophen) can be used to reduce pain (analgesic), but cannot reverse the effects of
inflammation.



2nd Line of Defense: Phagocytosis (p. 432-434)
Phagocytosis involves: 1) chemotaxis; 2) attachment to the microbe; 3)endocytosis; 4)fusion
with a lysosome; 5) digestion of the microbe; 6) formation of residual waste; and 7) release of
waste by exocytosis.

Antimicrobial Secretions: Interferon (p. 434-435)
Non-specific immune cells produce and secrete a variety of antimicrobial substances including
interleukins, lactoferrins, peroxides, free radical, lysins, complement and interferon. These
substances act to destroy the invading microbe or inhibit microbial metabolism. Interferon is
an anti-viral cytokine produced by virally infected cells that helps prevent the spread of
infection to neighboring cells.


Antimicrobial Secretions: Complement (p. 435-438)
The complement system is a series of 9 blood proteins that are activated in response to
microbial invasion. When activated, these proteins either bind to pathogens or antibody-
pathogen complexes to target them for destruction by phagocytosis or form a membrane
attack complex to lyse the invading cell. Complement proteins C3a &
C5a induce chemotaxis and inflammation. Complement protein C3b coats or opsonizes the
surface of microbes to enhance phagocytosis (cellular eating) by macrophages. Complement
proteins C5-9 form the membrane attack complex (MAC) and induce lysis of the microbe.



Preview of Specific Immunity (Chapter 15)
The 3rd line of defense involves the activation of the specific or acquired immune system.
Once activated, the specific immune system mounts a defense that is specific to the invader,
global, and long-lasting. The specific immune response is mediated by B- and T-lymphocytes,
which work together but utilize different mechanisms to destroy the microbial invader. Only B-
or T-cells