Surface Barriers or Mucosal Immunity
Terms the student should know are in blue.
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.
|
Normal Adult Blood Cell Counts |
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|
Red Blood Cells |
5.0*106/mm3 |
|
|
|
Platelets |
2.5*105/mm3 |
|
|
|
Leukocytes |
7.3*103/mm3 |
|
|
|
|
Neutrophil |
|
50-70% |
|
|
Lymphocyte |
|
20-40% |
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|
Monocyte |
|
1-6% |
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Eosinophil |
|
1-3% |
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Basophil |
|
<1% |
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.
Surface Barriers or Mucosal Immunity
- 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.
Objectives
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 Igs; differences between identifying self and non-self, innate and acquired
immunity, primary and secondary immunity, active and passive immunity; specificity
and cross-reactivity.
http://uhaweb.hartford.edu/BUGL/immune.htm