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Medical Physiology – Blood Physiology
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IMMUNITY
Body Defense
Our bodies are exposed continually to bacteria, viruses, fungi, and parasites, all of which
occur normally and to varying degrees in the skin, the mouth, the respiratory passageways,
the intestinal tract, the lining membranes of the eyes, and even the urinary tract. Many of
these infectious agents are capable of causing serious abnormal physiologic function or
even death if they invade the deeper tissues. In addition, we are exposed intermittently to
other highly infectious bacteria and viruses besides those that are normally present, and
these can cause acute lethal diseases such as pneumonia, streptococcal infection, and
typhoid fever.
The human body has the ability to resist almost all types of organisms or toxins that tend
to damage the tissues and organs. This capability is called immunity. There are two types
of immunity or body defense systems:
I.
The innate (nonspecific) defense system responds immediately to protect the
body from all foreign substances.
II.
Acquired (specific) defense system [Immune system; a functional system rather
than an organ system] mount the attack against particular foreign substances.
Nonspecific Body Defense [In native Immunity]
The term nonspecific body defense refers to mechanical barriers that cover body surfaces
and the cells and chemicals that act on the initial internal protection of the body from
invading pathogens (harmful or disease-causing microorganisms).
Surface Membrane Barriers
The body’s first line of defense against the invasion of disease-causing microorganisms is
the skin and the mucous membranes. As long as the epidermis is unbroken, this heavily
keratinized epithelial membrane is a formidable physical barrier to most microorganisms
that swarm on the skin. Keratin is also resistant to most weak acids and bases and to
bacterial enzymes and toxins. Intact mucosae provide similar mechanical barriers within
the body. Besides serving as physical barriers, skin and mucous membranes produce a
variety of protective chemicals:
1. The acid pH of skin secretions inhibits bacterial growth, and sebum contains
chemicals that are toxic to bacteria. Vaginal secretions of adult females are also very
acidic.
2. The stomach mucosa secretes hydrochloric acid and protein-digesting enzymes. Both
kill pathogens.
3. Saliva and lacrimal fluid contain lysozyme, an enzyme that destroys bacteria.
4. Sticky mucus traps many microorganisms that enter digestive and respiratory
passageways.
The respiratory tract mucosae also have structural modifications that counteract potential
invaders. Tiny mucus-coated hairs inside the nose trap inhaled particles, and cilia on the
mucosa of the upper respiratory tract sweep dust and bacteria mucus toward the mouth,
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preventing it from entering the lower respiratory passages, where the warm, moist
environment provides an ideal site for bacterial growth.
Although the surface barriers are quite effective, they are broken from time to time by
small nicks and cuts, for example, when you brush your teeth or shave. When this happens
and microorganisms invade deeper tissues, the internal innate defenses come into play.
Cells and Chemicals
The body uses an enormous number of nonspecific cellular and chemical means to protect
itself, including:
1. Phagocytes
Phagocytes such as macrophages or neutrophils become phagocytic; engulfs particulate
matter much the way an amoeba ingests a food particle. Flowing cytoplasmic extensions
bind to the particle and then pull it inside, enclosed within a membrane-lined vesicle. The
vesicle then fuses with a lysosome and its contents are broken down or digested.
2. Natural Killer (NK) Cells
Natural killer (NK) cells are a unique group of defensive cells that can lyse and kill cancer
cells and virus-infected body cells before the acquired immune system is activated.
Unlike lymphocytes of the acquired immune system, which only recognize and react
against specific virus-infected or tumor cells, NK cells are far less picky. They attack the
target cell`s membrane release a lytic chemical called perforins.
3. Inflammation: Tissue Response to Injury
The inflammatory response is triggered whenever body tissues are injured by physical
trauma (a blow), intense heat, irritating chemicals, or infection by viruses, fungi, or
bacteria (figure 1). The four cardinal signs of, inflammation are redness, heat, swelling,
and pain.
The inflammatory process begins with a chemical “alarm”. When cells are injured, they
release inflammatory chemicals including histamine and kinins, that:
(1) Causes blood vessels in the involved area to dilate and capillaries to become leaky.
(2) Activate pain receptors.
(3) Attract phagocytes and white blood cells to the area. This phenomenon is called
chemotaxis because the cells are following a chemical gradient.
4. Antimicrobial Proteins
The body's most important antimicrobial proteins are:
I.
Complement proteins include 20 plasma proteins that circulate in the blood in
an inactive state. When complement becomes attached or fixed to foreign cells
and form complement fixation it is activated. One of this fixation results is the
formation of membrane attack complex (MAC) that produce lesion and holes in
the foreign cell's surface. These allow water to rush into the cell causing it to
burst.
II.
Interferon when viruses damage the body by entering tissue cells to regenerate
their ATP or to make proteins. The virus infected cells secrete small proteins
called interferon that diffuse to nearby cells and bind to their membrane
receptors, this binding hinders the ability of viruses to multiply within these
cells.
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5. Fever although high fevers are dangerous because excess heat scrambles enzymes
and other proteins, mild to moderate fever seems to be benefit to the body. Bacteria
require large amounts of iron and zinc to multiply, but during a fever the liver and
spleen gather up these nutrients. Also fever increase the metabolic rate of tissue
cells in general, speeding up repair process.
Fig.1 : Events of inflammation
Specific Body Defense [Acquired Immunity]
The adaptive immune system protects us from a wide variety of infectious agents, as well
as from abnormal body cells recognized as foreign molecules (antigens).
There are three important aspects of the adaptive immune response:
1. It is specific. It recognizes and targets particular pathogens or foreign substances
that initiate the immune response.
2. It is systemic. Immunity is not restricted to the initial infection site.
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3. It has “memory.” After an initial exposure, it recognizes and mounts even stronger
attacks on previously encountered pathogens.
Antigens
An antigens is any substance that can mobilize the acquired defenses and provoke an
immune response. Most antigens are large, complex molecules (both natural and synthetic)
that are not normally present in the body or nonself.
A huge variety of your protein molecules (self-antigens) are not foreign or antigenic to
you, but they are strongly antigenic to other individuals. (This is the basis of transfusion
reactions and graft rejection).
Cells of The Immune System
The cells of immune system are lymphocytes and macrophages. Lymphocytes exist in two
major types; the B lymphocytes (B cells), produce antibodies and oversee humoral
immunity, whereas the T lymphocytes (T cells), are non-antibody producing lymphocytes
that constitute the cell-mediated arm of immunity. Unlike the two types of lymphocyte,
macrophages do not respond to specific antigens but instead play an essential role in
helping the lymphocytes.
Lymphocytes
Like all blood cells, lymphocytes originate from hemocytoblasts in red bone marrow. The
immature lymphocytes released from the marrow are essentially identical. Whether
a given lymphocyte matures into a B cell or a T. T cells arise from lymphocytes that
migrate to the thymus, where they undergo a maturation process of 2 to 3 days, directed by
thymic hormones (thymosin and others). Within the thymus, the immature lymphocytes
divide rapidly and their numbers increase enormously, but only those maturing T
cells have the ability to identify foreign antigens. B cells develop immunocompetence in
bone
marrow,
but little is
known
about
the
factors
that regulate
B
cell maturation. After becoming immunocompetent, both T cells and B cells migrate to the
lymph nodes and spleen.
Macrophages
Macrophages, which also become widely distributed throughout the lymphoid organs
and connective tissues, arise from monocytes formed in the bone marrow. They act
as antigen presenters in the specific defense system.Macrophages also secrete cytokine
proteins, called monokines, that are important in the immune.
Humoral Immunity [Antibody-Mediated Response]
Immature B lymphocytes is stimulated to its development into a fully mature B cells
when an
antigen
binds
to its surface
receptors.
This
binding
event
sensitizes, or activates, the lymphocyte to undergo clonal selection.The lymphocyte begins
to grow and then multiplies rapidly to form cells all exactly like itself and bearing the
same antigen-specific receptors. The resulting is identical cells descended from
the same ancestor cell is called a clone, and clone formation is the primary humoral
response to that antigen. Most of the B cell clone members, or descendants,
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become plasma cells. After an initial lag period, these antibody-producing "factories" act
in producing the same highly specific antibodies at a rate of about 2000 antibody molecules per second. (The B cells themselves produce only very small amounts of
antibodies.) However, this flurry of activity lasts only 4 or 5 days; then the plasma cells
begin to die. Antibody levels in the blood during this primary response peak in about 10
days and then slowly decline.
B cell clone members that do not become
plasma cells become long
lived
memory cells capable of responding to the same antigen at later meetings with it. Memory
cells are responsible for the immunological "memory" mentioned earlier. These later
immune responses, called secondary humoral responses, are much faster, more prolonged,
and more effective because all the preparations for this attack have already been made
(fig.2). Within hours after recognition of the old antigen, a new army of plasma cells is
being generated, and antibodies begin to flood into the bloodstream. Within 2 to 3 days,
blood antibody levels peak (at much higher levels than seen in the primary response),
and their levels remain high for weeks to months.
Antibodies
However, upon entry of a foreign antigen, the lymphoid tissue macrophages phagocytize
the antigen and then present it to the adjacent B lymphocytes. In addition, the antigen is
also presented to T cells at the same time, and activated "helper" T cells then also
contribute to the activation of the B lymphocytes.
The Nature of the Antibodies
The antibodies are gamma globulins called immunoglobulins, and they have molecular
weights between approximately 150,000 and 900,000. Usually they constitute about 20
percent of all the plasma proteins.All the immunoglobulins are composed of combinations
of light and heavy polypeptide chains; most are a combination of two light and two heavy
chains, as illustrated in Figure (3). Some of the immunoglobulins, though, have
combinations of as many as ten heavy and ten light chains, which gives rise to the much
larger molecular weight immunoglobulins. Yet in all immunoglobulins, each heavy chain
is paralleled by a light chain at one of its ends, thus forming a heavy-light pair, and there
are always at least two such pairs in each immunoglobulin molecule.
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Table (1):Classes of the Antibodies
Figure (2): Primary and secondary responses.
Figure (3): Antibody structure:
(v): variable region of antibody chain, (C):
constant region of antibody chain
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Mechanisms of Action of Antibodies
Antibodies act mainly in two different ways to protect the body against invading agents:
(1) by direct attack on the invader and (2) by activation of the complement system that
then destroys the invader.
Direct Action of Antibodies on Invading Agents
Because of the bivalent nature of the antibodies and the multiple antigen sites on most
invading agents, the antibodies can inactivate the invading agent in one of several ways, as
follows:
1. Agglutination, in which multiple large particles with antigens on their surfaces,
such as bacteria or red cells, are bound together into a clump.
2. Precipitation, in which the molecular complex of soluble antigen (such as tetanus
toxin) and antibody becomes so large that it is rendered insoluble and precipitates.
3. Neutralization, in which the antibodies cover the toxic sites of the antigenic agent.
4. Lysis, in which some very potent antibodies are occasionally capable of directly
attacking membranes of cellular agents and thereby causing rupture of the cell.
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However, the direct actions of antibodies attacking the antigenic invaders probably, under
normal conditions, are not strong enough to play a major role in protecting the body
against the invader. Most of the protection comes through the amplifying effects of the
complement system.
The Complement System for Antibody Action
"Complement" is a collective term to describe a system of about 20 different proteins,
many of which are enzyme precursors. All these are present normally among the plasma
proteins and also among the plasma proteins that leak out of the capillaries into the tissue
spaces. The enzyme precursors are normally inactive, but they can be activated in two
separate ways:
1- The Classical Pathway
The classical pathway is activated by an antigen-antibody reaction. That is, when an
antibody binds with an antigen, a specific reactive site on the "constant" portion of the
antibody becomes uncovered, or activated, and this in turn binds directly with the C1
molecule of the complement system, setting into motion a "cascade" of sequential
reactions.
2- The Alternate Pathway
complement system sometimes is activated without the intermediation of an antigenantibody reaction. This occurs especially in response to large polysaccharide molecules
in the cell membranes of some invading microorganisms.
Cellular (Cell-Mediated) Immune Response
Like B cells, immunocompetent T cells are activated to form a clone by binding with a
"recognized" antigen. However, unlike B cells, the T cells are not able to bind with free
antigens. Instead, the antigens must be "presented" by macrophages, and a double
recognition must occur. The macrophages engulf the antigens, process them internally,
and then finally display parts of the processed antigens on their external surface in
combination with one of their own (self) proteins.
Apparently, antigen presentation is a major role of macrophages and is essential for
activation and clonal selection of the T cells. Without macrophage "presenters," the
immune response is severely impaired. Cytokine chemicals (monokines, particularly
interleukin 1) released by macrophages also play important roles in the immune
response.
The different classes of T cell clones are:
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I- Cytotoxic (killer) T cells, cells that specialize in killing virus-infected, cancer, or
foreign graft cells. One way they accomplish this is by binding to them and inserting a
toxic chemical (perforin or others) into the foreign cell's plasma membrane.
II- Helper T cells are the T cells that act as the "directors" or "managers" of the
immune system. Once activated, they circulate through the body, recruiting other cells
to fight the invaders. For example, helper T cells interact directly with B cells (that have
already attached to antigens), prodding them into more rapid division (clone
production) and then signaling for antibody formation to begin. They also release a
variety of cytokine chemicals called lymphokines that act indirectly to rid the body of
antigens by (1) stimulating cytotoxic T cells and B cells to grow and divide; (2)
attracting other types of protective white blood cells, such as neutrophils, into the area;
and(3) enhancing the ability of macrophages to engulf and destroy microorganisms.
III- Suppressor Tcells, releases chemicals that suppress the activity of both T and B
cells. Suppressor T cells are vital for winding clown and finally stopping the immune
response after an antigen has been successfully inactivated or destroyed. This helps
prevent uncontrolled or unnecessary immune system activity
VI- memory cells; most of the T cells enlisted to fight in a particular immune response
are dead within a few days. However, a few members of each clone are long-lived
memory cells that remain behind to provide the immunological memory for each
antigen encountered and enable the body to respond quickly to its subsequent
invasions.
Vaccination
process of vaccination has been used for many years to cause acquired immunity against
specific diseases. A person can be vaccinated by injecting dead organisms that are no
longer capable of causing disease but which still have their chemical antigens. This type
of vaccination is used to protect against typhoid fever, whooping cough, diphtheria, and
many other types of bacterial diseases.
Also, immunity can be achieved against toxins that have been treated with chemicals so
that their toxic nature has been destroyed even though their antigens for causing immunity
are still intact. This procedure is used in vaccinating against tetanus and other similar toxic
diseases. And, finally a person can be vaccinated by infection with live organisms that
have been "attenuated." That is, these organisms either have been grown in special culture
media or have been passed through a series of animals until they have mutated enough that
they will not cause disease but do still carry the specific antigens. This procedure is used
to protect against poliomyelitis, yellow fever, measles, smallpox, and many other viral
diseases.
Passive Immunity.
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All the acquired immunity has been active immunity. That is, the person's body develops
either antibodies or activated lymphocytes in response to invasion of the body by a
foreign antigen. However, temporary immunity can be achieved in a person without
injecting any antigen whatsoever. This is done by infusing antibodies, activated T cells,
or both from someone else or from some other animal that has been actively immunized
against the antigen. The antibodies will last for 2 to 3 weeks, and during that time the
person is protected against the invading disease. Activated T cells will last for a few
weeks if transfused from another person, and for a few hours to a few days if transfused
from an animal. The transfusion of antibodies or lymphocytes to confer immunity is
called passive immunity.
Allergy
One of the important side effects of immunity is the development, under some
conditions, of allergy. There are several different types of allergy, some of which can
occur in any person, and others that occur only in persons who have a specific allergic
tendency.
An Allergy that Occurs in Normal People; Delayed-reaction Allergy
This type of allergy frequently causes skin eruptions in response to certain drugs or
chemicals, particularly some cosmetics and household chemicals, to which one's skin is
often exposed. Delayed-reaction allergy is caused by activated T cells and not by
antibodies.
Allergies in the "Allergic" Person
Some persons have an "allergic" tendency. Their allergies are called atopic allergies
because they are caused by a non ordinary response of the immune system. The allergic
tendency is genetically passed on from parent to child, and it is characterized by the
presence of large quantities of IgE antibodies.
Autoimmune Diseases
When the immune system loses its ability to distinguish self-antigen while stile recognize
and attack foreign antigens, the body produces antibodies (auto antibodies) and sensitized
cells that attack and damage its own tissues. Most common immune diseases are: type I
diabetes mellitus which destroys pancreatic beta cells, and Rheumatoid arthritis which
systematically destroys joints.
Immunodeficiency
The most important acquired immunodeficiency is acquired immune deficiency syndrome
[AIDS] which is caused by a virus transmitted in blood, semen, vaginal secretions, and
saliva. The virus named HIV (human immunodeficiency virus), specifically targets and
destroys helper T cells, resulting in depression of cell-mediated immunity.
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