The human immune system is a truly
amazing constellation of responses to attacks from outside the body. It has
many facets, a number of which can change to optimize the response to these
unwanted intrusions. The system is remarkably effective, most of the time. This
note will give you a brief outline of some of the processes involved.
An antigen is any substance that elicits an
immune response, from a virus to a sliver.
The immune system has a series of
dual natures, the most important of which is self/non-self recognition. The
others are: general/specific, natural/adaptive = innate/acquired,
cell-mediated/humoral, active/passive, primary/secondary. Parts of the immune
system are antigen-specific (they recognize and act against
particular antigens), systemic (not confined to the initial
infection site, but work throughout the body), and have memory (recognize and mount an even
stronger attack to the same antigen the next time).
Self/non-self recognition is
achieved by having every cell display a marker based on the major
histocompatibility complex (MHC). Any cell not displaying this marker is
treated as non-self and attacked. The process is so effective that undigested
proteins are treated as antigens.
Sometimes the process breaks down
and the immune system attacks self-cells. This is the case of autoimmune
diseases
like multiple sclerosis, systemic lupus erythematosus, and some forms of
arthritis and diabetes. There are cases where the immune response to innocuous
substances is inappropriate. This is the case of allergies and the simple
substance that elicits the response is called an allergen.
There are two main fluid systems in
the body: blood and lymph. The blood and lymph systems are intertwined
throughout the body and they are responsible for transporting the agents of the
immune system.
The 5 liters of blood of a 70 kg
(154 lb) person constitute about 7% of the body's total weight. The blood flows
from the heart into arteries, then to capillaries, and returns to the heart
through veins.
Blood is composed of 52–62% liquid
plasma and 38–48% cells. The plasma is mostly water (91.5%) and acts as a
solvent for transporting other materials (7% protein [consisting
of albumins (54%), globulins (38%), fibrinogen (7%), and assorted other stuff
(1%)] and 1.5% other stuff). Blood is slightly alkaline
(pH = 7.40 ± .05) and a tad heavier than water
(density = 1.057 ± .009).
All blood cells are manufactured by
stem cells, which live mainly in the bone marrow, via a process called hematopoiesis. The stem cells produce
hemocytoblasts that differentiate into the precursors for all the different
types of blood cells. Hemocytoblasts mature into three types of blood cells: erythrocytes (red blood cells or RBCs),
leukocytes (white blood cells or WBCs), and thrombocytes (platelets).
The leukocytes are further
subdivided into granulocytes
(containing large granules in the cytoplasm) and agranulocytes (without granules). The
granulocytes consist of neutrophils (55–70%), eosinophils (1–3%), and basophils
(0.5–1.0%). The agranulocytes are lymphocytes (consisting of B cells and T cells) and monocytes. Lymphocytes circulate in the
blood and lymph systems, and make their home in the lymphoid organs.
All of the major cells in the blood
system are illustrated below.
There are 5000–10,000 WBCs per mm3
and they live 5-9 days. About 2,400,000 RBCs are produced each second and each
lives for about 120 days (They migrate to the spleen to die. Once there, that
organ scavenges usable proteins from their carcasses). A healthy male has about
5 million RBCs per mm3, whereas females have a bit fewer than 5
million.
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Normal Adult Blood Cell Counts
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Red Blood Cells
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5.0*106/mm3
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Platelets
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2.5*105/mm3
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Leukocytes
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7.3*103/mm3
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Neutrophil
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50-70%
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Lymphocyte
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20-40%
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Monocyte
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1-6%
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Eosinophil
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1-3%
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Basophil
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<1%
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The goo on RBCs is responsible for
the usual ABO blood grouping, among other things. The grouping is characterized
by the presence or absence of A and/or B antigens on the surface of the RBCs.
Blood type AB means both antigens are present and type O means both antigens are
absent. Type A blood has A antigens and type B blood has B antigens.
Some of the blood, but not red
blood cells (RBCs), is pushed through the capillaries into the interstitial
fluid.
Lymph is an alkaline
(pH > 7.0) fluid that is usually clear, transparent, and
colorless. It flows in the lymphatic vessels and bathes tissues and organs in
its protective covering. There are no RBCs in lymph and it has a lower protein
content than blood. Like blood, it is slightly heavier than water
(density = 1.019 ± .003).
The lymph flows from the
interstitial fluid through lymphatic vessels up to either the thoracic duct or
right lymph duct, which terminate in the subclavian veins, where lymph is mixed
into the blood. (The right lymph duct drains the right sides of the thorax,
neck, and head, whereas the thoracic duct drains the rest of the body.) Lymph
carries lipids and lipid-soluble vitamins absorbed from the gastrointestinal
(GI) tract. Since there is no active pump in the lymph system, there is no
back-pressure produced. The lymphatic vessels, like veins, have one-way valves
that prevent backflow. Additionally, along these vessels there are small
bean-shaped lymph nodes that serve as filters of the lymphatic fluid. It is in the
lymph nodes where antigen is usually presented to the immune system.
The human lymphoid
system
has the following:
- · primary
organs: bone marrow (in the hollow center of bones) and the thymus gland
(located behind the breastbone above the heart), and
- · secondary
organs at or near possible portals of entry for pathogens: adenoids,
tonsils, spleen (located at the upper left of the abdomen), lymph nodes
(along the lymphatic vessels with concentrations in the neck, armpits,
abdomen, and groin), Peyer's patches (within the intestines), and the
appendix.
The innate immunity system is what
we are born with and it is nonspecific; all antigens are attacked pretty much
equally. It is genetically based and we pass it on to our offspring.
- The first and, arguably, most
important barrier is the skin. The skin cannot be penetrated by most
organisms unless it already has an opening, such as a nick, scratch, or
cut.
- Mechanically, pathogens are
expelled from the lungs by ciliary action as the tiny hairs move in an
upward motion; coughing and sneezing abruptly eject both living and
nonliving things from the respiratory system; the flushing action of
tears, saliva, and urine also force out pathogens, as does the sloughing
off of skin.
- Sticky mucus in respiratory
and gastrointestinal tracts traps many microorganisms.
- Acid pH (< 7.0) of
skin secretions inhibits bacterial growth. Hair follicles secrete sebum
that contains lactic acid and fatty acids both of which inhibit the growth
of some pathogenic bacteria and fungi. Areas of the skin not covered with
hair, such as the palms and soles of the feet, are most susceptible to
fungal infections. Think athlete's foot.
- Saliva, tears, nasal
secretions, and perspiration contain lysozyme, an
enzyme that destroys Gram positive bacterial cell walls causing cell
lysis. Vaginal secretions are also slightly acidic (after the onset of
menses). Spermine and zinc in semen destroy some pathogens.
Lactoperoxidase is a powerful enzyme found in mother's milk.
- The stomach is a formidable
obstacle insofar as its mucosa secrete hydrochloric acid
(0.9 < pH < 3.0, very acidic) and
protein-digesting enzymes that kill many pathogens. The stomach can even
destroy drugs and other chemicals.
Normal flora are the microbes, mostly bacteria, that live in and on the
body with, usually, no harmful effects to us. We have about 1013
cells in our bodies and 1014 bacteria, most of which live in the
large intestine. There are 103–104 microbes per cm2
on the skin (Staphylococcus aureus, Staph. epidermidis, diphtheroids, streptococci, Candida, etc.). Various bacteria live in
the nose and mouth. Lactobacilli live in the stomach and small intestine. The
upper intestine has about 104 bacteria per gram; the large bowel has
1011 per gram, of which 95–99% are anaerobes (An anaerobe is a microorganism that can live
without oxygen, while an aerobe requires oxygen.) or bacteroides.
The urogenitary tract is lightly colonized by various bacteria and
diphtheroids. After puberty, the vagina is colonized by Lactobacillus aerophilus that ferment glycogen to maintain
an acid pH.
Normal flora fill almost all of the
available ecological niches in the body and produce bacteriocidins, defensins,
cationic proteins, and lactoferrin all of which work to destroy other bacteria
that compete for their niche in the body.
The resident bacteria can become
problematic when they invade spaces in which they were not meant to be. As
examples: (a) staphylococcus living on the skin can gain entry to the body
through small cuts/nicks. (b) Some antibiotics, in particular clindamycin, kill
some of the bacteria in our intestinal tract. This causes an overgrowth of Clostridium difficile, which results in pseudomembranous
colitis, a rather painful condition wherein the inner lining of the intestine
cracks and bleeds.
A
phagocyte is a cell that attracts (by chemotaxis), adheres to,
engulfs, and ingests foreign bodies. Promonocytes are made in the bone marrow, after
which they are released into the blood and called circulating monocytes, which eventually mature into macrophages (meaning "big eaters",
see below).
Some macrophages are concentrated
in the lungs, liver (Kupffer cells), lining of the lymph nodes and spleen,
brain microglia, kidney mesoangial cells, synovial A cells, and osteoclasts.
They are long-lived, depend on mitochondria for energy, and are best at attacking
dead cells and pathogens capable of living within cells. Once a macrophage
phagocytizes a cell, it places some of its proteins, called epitopes, on its
surface—much like a fighter plane displaying its hits. These surface markers
serve as an alarm to other immune cells that then infer the form of the
invader. All cells that do this are called antigen
presenting cells
(APCs).
The non-fixed or wandering macrophages roam the blood vessels and can
even leave them to go to an infection site where they destroy dead tissue and
pathogens. Emigration by squeezing through the capillary walls to the tissue is
called diapedesis
or extravasation. The presence of histamines at the infection site attract
the cells to their source.
Natural
killer cells
move in the blood and lymph to lyse (cause to burst) cancer cells and
virus-infected body cells. They are large granular lymphocytes that attach to
the glycoproteins on the surfaces of infected cells and kill them.
Polymorphonuclear neutrophils, also called polys for short, are phagocytes that
have no mitochondria and get their energy from stored glycogen. They are
nondividing, short-lived (half-life of 6–8 hours, 1–4 day lifespan), and have a
segmented nucleus. [The picture below shows the
neutrophil phagocytizing bacteria, in yellow.] They constitute 50–75% of
all leukocytes. The neutrophils provide the major defense against pyogenic
(pus-forming) bacteria and are the first on the scene to fight infection. They
are followed by the wandering macrophages about three to four hours later.
The complement
system
is a major triggered enzyme plasma system. It coats microbes with molecules
that make them more susceptible to engulfment by phagocytes. Vascular
permeability mediators increase the permeability of the capillaries to allow more
plasma and complement fluid to flow to the site of infection. They also
encourage polys to adhere to the walls of capillaries (margination) from which they can squeeze
through in a matter of minutes to arrive at a damaged area. Once phagocytes do
their job, they die and their "corpses," pockets of damaged tissue,
and fluid form pus.
Eosinophils are attracted to cells coated with
complement C3B, where they release major basic protein (MBP), cationic protein,
perforins, and oxygen metabolites, all of which work together to burn holes in
cells and helminths (worms). About 13% of the WBCs are eosinophils. Their
lifespan is about 8–12 days. Neutrophils, eosinophils, and macrophages are all
phagocytes.
Dendritic
cells
are covered with a maze of membranous processes that look like nerve cell
dendrites. Most of them are highly efficient antigen presenting cells. There
are four basic types: Langerhans cells, interstitial dendritic cells,
interdigitating dendritic cells, and circulating dendritic cells. Our major
concern will be Langerhans cells, which are found in the epidermis and mucous membranes,
especially in the anal, vaginal, and oral cavities. These cells make a point of
attracting antigen and efficiently presenting it to T helper cells for their
activation. [This accounts, in part, for the
transmission of HIV via sexual contact.]
Each of the cells in the innate immune system bind to
antigen using pattern-recognition
receptors. These receptors are encoded in
the germ line of each person. This immunity is passed from generation to
generation. Over the course of human development these receptors for
pathogen-associated molecular patterns have evolved via natural selection to be
specific to certain characteristics of broad classes of infectious organisms.
There are several hundred of these receptors and they recognize patterns of
bacterial lipopolysaccharide, peptidoglycan, bacterial DNA, dsRNA, and other
substances. Clearly, they are set to target both Gram-negative and
Gram-positive bacteria.
Lymphocytes come in two major
types: B cells and T cells. The peripheral blood contains 20–50% of circulating
lymphocytes; the rest move in the lymph system. Roughly 80% of them are T
cells, 15% B cells and remainder are null or undifferentiated cells. Lymphocytes
constitute 20–40% of the body's WBCs. Their total mass is about the same as
that of the brain or liver. (Heavy stuff!)
B cells are produced in the stem cells of the bone marrow; they produce
antibody and oversee humoral immunity. T cells are nonantibody-producing
lymphocytes which are also produced in the bone marrow but sensitized in the thymus and constitute the basis of
cell-mediated immunity. The production of these cells is diagrammed below.
Parts of the immune system are
changeable and can adapt to better attack the invading antigen. There are two
fundamental adaptive mechanisms: cell-mediated immunity and humoral immunity.
Macrophages engulf antigens,
process them internally, then display parts of them on their surface together
with some of their own proteins. This sensitizes the T cells to recognize these
antigens. All cells are coated with various substances. CD stands for cluster of
differentiation
and there are more than one hundred and sixty clusters, each of which is a
different chemical molecule that coats the surface. CD8+ is read "CD8
positive." Every T and B cell has about 105 = 100,000
molecules
on its surface. B cells are coated with CD21, CD35, CD40, and CD45 in addition
to other non-CD molecules. T cells have CD2, CD3, CD4, CD28, CD45R, and other
non-CD molecules on their surfaces.
The large number of molecules on
the surfaces of lymphocytes allows huge variability in the forms of the
receptors. They are produced with random configurations on their surfaces.
There are some 1018 different structurally different receptors.
Essentially, an antigen may find a near-perfect fit with a very small number of
lymphocytes, perhaps as few as one.
T cells are primed in the thymus,
where they undergo two selection processes. The first positive selection process weeds out only
those T cells with the correct set of receptors that can recognize the MHC
molecules responsible for self-recognition. Then a negative selection process begins whereby T
cells that can recognize MHC molecules complexed with foreign peptides are
allowed to pass out of the thymus.
Cytotoxic or killer T
cells
(CD8+) do their work by releasing lymphotoxins, which cause cell lysis. Helper T
cells
(CD4+) serve as managers, directing the immune response. They secrete chemicals
called lymphokines
that stimulate cytotoxic T cells and B cells to grow and divide, attract
neutrophils, and enhance the ability of macrophages to engulf and destroy
microbes. Suppressor T cells inhibit the production of cytotoxic T cells once they are
unneeded, lest they cause more damage than necessary. Memory T
cells
are programmed to recognize and respond to a pathogen once it has invaded and
been repelled.
An immunocompetent but as yet
immature B-lymphocyte is stimulated to maturity when an antigen binds to its
surface receptors and there is a T helper cell nearby (to release a cytokine).
This sensitizes or primes the B cell and it undergoes clonal
selection,
which means it reproduces asexually by mitosis. Most of the family of clones
become plasma cells. These cells, after an initial lag, produce highly specific
antibodies at a rate of as many as 2000 molecules per second for four to five
days. The other B cells become long-lived memory
cells.
Antibodies, also called immunoglobulins or Igs [with
molecular weights of 150–900 Md], constitute the gamma globulin part of the blood proteins. They
are soluble proteins secreted by the plasma offspring (clones) of primed B
cells. The antibodies inactivate antigens by, (a) complement fixation (proteins attach to antigen
surface and cause holes to form, i.e., cell lysis), (b) neutralization (binding to specific sites to
prevent attachment—this is the same as taking their parking space), (c) agglutination (clumping), (d) precipitation (forcing insolubility and settling
out of solution), and other more arcane methods.
Constituents of gamma globulin are:
IgG-76%, IgA-15%, IgM-8%, IgD-1%, and IgE-0.002% (responsible for autoimmune
responses, such as allergies and diseases like arthritis, multiple sclerosis,
and systemic lupus erythematosus). IgG is the only antibody that can cross the
placental barrier to the fetus and it is responsible for the 3 to 6 month
immune protection of newborns that is conferred by the mother.
IgM is the dominant antibody
produced in primary immune responses, while IgG dominates in secondary immune
responses. IgM is physically much larger than the other immunoglobulins.
Notice the many degrees of
flexibility of the antibody molecule. This freedom of movement allows it to
more easily conform to the nooks and crannies on an antigen. The upper part or
Fab (antigen
binding)
portion of the antibody molecule (physically and not necessarily chemically)
attaches to specific proteins [called epitopes]
on the antigen. Thus antibody recognizes the epitope and not the entire
antigen. The Fc region is crystallizable and is responsible for effector
functions, i.e., the end to which immune cells can attach.
Lest you think that these are the
only forms of antibody produced, you should realize that the B cells can
produce as many as 1014 conformationally different forms.
The process by which T cells and B
cells interact with antigens is summarized in the diagram below.
In the ABO blood typing system,
when an A antigen is present (in a person of blood type A), the body produces
an anti-B antibody, and similarly for a B antigen. The blood of someone of type
AB, has both antigens, hence has neither antibody. Thus that person can be transfused with any type
of blood, since there is no antibody to attack foreign blood antigens. A person
of blood type O has neither antigen but both antibodies and cannot receive AB,
A, or B type blood, but they can donate blood for use by anybody. If someone
with blood type A received blood of type B, the body's anti-B antibodies would
attack the new blood cells and death would be imminent.
All of these of these mechanisms
hinge on the attachment of antigen and cell receptors. Since there are many,
many receptor shapes available, WBCs seek to optimize the degree of confluence
between the two receptors. The number of these "best fit" receptors
may be quite small, even as few as a single cell. This attests to the specificity of the interaction. Nevertheless,
cells can bind to receptors whose fit is less than optimal when required. This
is referred to as cross-reactivity. Cross-reactivity has its limits. There are many receptors
to which virions cannot possibly bind. Very few viruses can bind to skin cells.
The design of immunizing vaccines
hinges on the specificity and cross-reactivity of these bonds. The more
specific the bond, the more effective and long-lived the vaccine. The smallpox
vaccine, which is made from the vaccinia virus that causes cowpox, is a very
good match for the smallpox receptors. Hence, that vaccine is 100% effective
and provides immunity for about 20 years. Vaccines for cholera have a
relatively poor fit so they do not protect against all forms of the disease and
protect for less than a year.
The goal of all vaccines is promote
a primary immune reaction so that when the organism is again exposed to the
antigen, a much stronger secondary immune response will be elicited. Any
subsequent immune response to an antigen is called a secondary
response
and it has
- a shorter lag time,
- more rapid buildup,
- a higher overall level of
response,
- a more specific or better
"fit" to the invading antigen,
- utilizes IgG instead of the
large multipurpose antibody IgM.
Immunity can be either natural or artificial, innate or acquired=adaptive, and either active or passive.
- Active natural (contact with
infection): develops slowly, is long term, and antigen specific.
- Active artificial
(immunization): develops slowly, lasts for several years, and is specific
to the antigen for which the immunization was given.
- Passive natural
(transplacental = mother to child): develops immediately, is
temporary, and affects all antigens to which the mother has immunity.
- Passive artificial (injection
of gamma globulin): develops immediately, is temporary, and affects all
antigens to which the donor has immunity.
Know:
antigen, overall properties of the immune system, allergen; major fluid systems
of the body; hematopoiesis occurs in stem cells of the bone; erythrocytes,
leukocytes, and thrombocytes; types of white blood cells; lymphoid system and
lymph nodes; mucosal immunity and types of surface barriers to infection;
normal flora; phagocytes, macrophages, antigen presenting cells, neutrophils, B
cells and T cells are produced in the bone marrow and T cells are primed in the
thymus, CD4+ and CD8+ cells, helper cells, memory cells, cytotoxic cells,
suppressor cells; priming and clonal selection; antibody and Ig's; differences
between identifying self and non-self, innate and acquired immunity, primary
and secondary immunity, active and passive immunity; specificity and cross-reactivity
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