Lecture 21: Defenses against microorganisms and irregular cells
1) Introduction:
An animal must defend itself against dangerous
viruses, bacteria, and other pathogens in the air, in food, and in water.
It must also deal with abnormal body cells, which, in some cases, may develop into cancer.
Three cooperative lines of defense have evolved
to counter these threats.
The first line of nonspecific defense is
external, consisting of epithelial cells that cover and line our bodies and the
secretions they produce.
The second line of nonspecific defense is
internal, involving phagocytic cells and
antimicrobial proteins that indiscriminately attack invaders that penetrate the
bodys outer barriers.
The third line of defense, the immune system,
responds in a specific way to particular toxins, microorganisms, aberrant body
cells, and other substances marked by foreign molecules.
Specific defensive proteins called antibodies are produced by lymphocytes.
2) Non-specific defense
Microbes that penetrate the first line of
defense face the second line of defense, which depends mainly on phagocytosis,
the ingestion of invading organisms by certain types of white cells.
The phagocytic cells
called neutrophils constitute about 60%-70% of
all white blood cells (leukocytes).
Cells damaged by invading microbes release
chemical signals that attract neutrophils from the
blood.
The neutrophils enter
the infected tissue, engulfing and destroying microbes there.
The fixed macrophages in the spleen, lymph
nodes, and other lymphatic tissues are particularly well located to contact
infectious agents.
Interstitial fluid, perhaps containing
pathogens, is taken up by lymphatic capillaries, and flows as lymph, eventually
returning to the blood circulatory system.
Along the way, lymph must pass through numerous
lymph nodes, where any pathogens present encounter macrophages and lymphocytes.
3) Immune system (acquired defense)
The vertebrate body is populated by two main
types of lymphocytes: B lymphocytes (B cells) and T
lymphocytes (T cells).
Both types of lymphocytes circulate throughout
the blood and lymph and are concentrated in the spleen, lymph nodes, and other
lymphatic tissue.
Because lymphocytes recognize and respond to
particular microbes and foreign molecules, they are said to display specificity.
A foreign molecule that elicits a specific
response by lymphocytes is called an antigen.
Antigens include molecules belonging to viruses,
bacteria, fungi, protozoa, parasitic worms, and nonpathogens
like pollen and transplanted tissue.
B cells and T cells specialize in different
types of antigens, and they carry out different, but complementary, defensive
actions.
B and T cells recognize specific antigens
through their plasma membrane-bound antigen receptors.
Antigen receptors on a B cell are transmembrane versions of antibodies and are often referred
to as membrane antibodies (or membrane immunoglobins).
The antigen receptors on a T cell, called T
cell receptors, are structurally related to membrane antibodies, but are
never produced in a secreted form.
A single T or B lymphocyte bears about 100,000
receptors for antigen, all with exactly the same specificity.
The particular structure of a lymphocytes
receptors is determined by genetic events that occur during its early
development.
As an unspecialized cell differentiates into a B
or T lymphocyte, segments of antibody genes or receptor genes are linked together
by a type of genetic recombination, generating a single functional gene for
each polypeptide of an antibody or receptor protein.
This process, which occurs before any contact
with foreign antigens, creates an enormous variety of B and T cells in the
body, each bearing antigen receptors of particular specificity.
This allows the immune system to respond to
millions of antigens, and thus millions of potential pathogens.
The selective proliferation and differentiation
of lymphocytes that occur the first time the body is exposed to an antigen is
the primary immune response.
About 10 to 17 days are required from the
initial exposure for the maximum effector cell
response.
During this period, selected B cells and T cells
generate antibody-producing effector B cells, called plasma
cells, and effector T cells, respectively.
While this response is developing, a stricken
individual may become ill, but symptoms of the illness diminish and disappear
as antibodies and effector T cells clear the antigen
from the body.
A second exposure to the same antigen at some
later time elicits the secondary immune response.
This response is faster (only 2 to 7 days), of
greater magnitude, and more prolonged.
In addition, the antibodies produced in the
secondary response tend to have greater affinity for the antigen than those
secreted in the primary response.
Lymphocytes, like all blood cells, originate
from pluripotent stem cells in the bone marrow or
liver of a developing fetus.
Lymphocytes do not react to most self antigens,
but T cells do have a crucial interaction with one important group of native
molecules.
These are a collections
of cell surface glycoproteins encoded by a family of
genes called the major histocompatibility complex
(MHC).
Two main classes of MHC molecules mark body cells as self.
The immune system can mount two types of
responses to antigens: a humoral response and a cell-mediated response.
Humoral immunity involves B cell
activation and results from the production of antibodies that circulate in the
blood plasma and lymph.
Circulating antibodies defend mainly against
free bacteria, toxins, and viruses in the body fluids.
In cell-mediated immunity, T lymphocytes
attack viruses and bacteria within infected cells and defend against fungi,
protozoa, and parasitic worms.
They also attack nonself
cancer and transplant cells
To review, the immune responses of B and T lymphocytes
exhibit four attributes that characterize the immune
system as a whole: specificity, diversity, memory, and the ability to
distinguish self from nonself.
A critical component of the immune response is
the MHC.
Proteins encoded by this gene complex display a
combination of self (MHC molecule) and nonself
(antigen fragment) that is recognized by specific T cells
The humoral immune response is initiated when B
cells bearing antigen receptors are selected by binding with specific antigens.
3) Immunity and Disease
Immunity conferred by recovering from an
infectious disease such as chicken pox is called active immunity because
it depends on the response of the infected persons own immune system.
Active immunity can be acquired naturally or
artificially, by immunization, also known as vaccination.
Vaccines include inactivated toxins, killed
microbes, parts of microbes, and viable but weakened microbes.
These no longer cause disease, but they can act
as antigens, stimulating an immune response, and more important, immunological
memory.
A vaccinated person who encounters the actual
pathogen will have the same quick secondary response based on memory cells as a
person who has had the disease.
Routine immunization of infants and children has
dramatically reduced the incidence of infectious diseases such as measles and
whooping cough, and has led to the eradication of smallpox, a viral disease.
Unfortunately, not all infectious agents are
easily managed by vaccination.
For example, although researchers are working
intensively to develop a vaccine for HIV, they face many problems, such as
antigenic variability.
The major histocompatibility
complex (MHC) is responsible for stimulating the rejection of tissue grafts and
organ transplants.
Because MHC creates a unique protein fingerprint
for each individual, foreign MHC molecules are antigenic, inducing immune responses
against the donated tissue or organ.
To minimize rejection, attempts are made to
match MCH of tissue donor and recipient as closely as possible.
In the absence of identical twins, siblings
usually provide the closest tissue-type match.
Allergies are hypersensitive (exaggerated)
responses to certain environmental antigens, called allergens.
One hypothesis to explain the origin of
allergies is that they are evolutionary remnants of the immune systems
response to parasitic worms.
The humoral mechanism that combats worms is
similar to the allergic response that causes such disorders as hay fever and
allergic asthma.
Sometimes the immune system loses tolerance for
self and turns against certain molecules of the body, causing one of many
autoimmune diseases.
In systemic lupus erythematosus
(lupus), the immune system generates antibodies against all sorts of
self molecules, including histamines.
Lupus is characterized by skin rashes, fever,
arthritis, and kidney dysfunction.
Rheumatoid arthritis leads to damage and
painful inflammation of the cartilage and bone of joints.
In insulin-dependent diabetes mellitus,
the insulin-producing beta cells of the pancreas are the targets of autoimmune
cell-mediated responses.
Healthy immune system function appears to depend
on both the endocrine system and the nervous system.
For example, hormones secreted by the adrenal
glands during stress affect the number of white blood cells and may suppress
the immune system in other ways.
Similarly, some neurotransmitters secreted when
we are relaxed and happy may enhance immunity.
Physiological evidence also points to an immune
system-nervous system link based on the presence of neurotransmitter receptors
on the surfaces of lymphocytes and a network of nerve fibers that penetrates
deep into the thymus.
In 1983, a retrovirus, now called human immunodeficiency
virus (HIV), had been identified as the causative agent of AIDS.
There are two major strains of the virus, HIV-1
and HIV-2.
HIV-1 is the more widely distributed and more
virulent.
Both strains infect cells that bear CD4
molecules, especially helper T cells and class II MCH-bearing antigen-presenting
cells, but also macrophages, some lymphocytes and some brain cells.
CD4 functions as the major receptor for the
virus.
The immune system engages in a prolonged battle
against HIV.
(1) The immune response diminishes the initial viral load,
but HIV continues to replicate in lymphatic tissue.
(2) Viral load gradually rises as HIV is released from
lymphatic tissue and helper T cell levels decrease.
(3) This results in extensive loss of humoral and
cell-mediated immunity.