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Evolution by Natural Selection is a Selfish Process
Things (units) that survive & reproduce relatively more
of self become relatively more common over time.
An important way to increase survival & reproduction
is to form cooperative coalitions.
In evolutionary theory, the main mechanisms that underpin cooperation
(by stabilizing against cheating) are reciprocity and kin selection.
By helping kin, a ‘unit’ helps reproduce copies of shared genes (replicators).
In diploid sexual species, full siblings share 1/2 of their genes by common descent.
All the cells within a body (vehicle) that descend from a fertilized egg
are a clone and share all genes (except for mutations, ex cancers) & kinship = 1;
this makes for a very cooperative coalition - a body.
Most cells in a clonal body don’t reproduce across generations;
they increase copies of shared genes in their ‘close kin’ - the gametes.
It is the job of the immune system
to stabilize this big cooperative coalition of cells
by making sure everyone is on the same team - the ‘self team.’
Fig 43.1:
An overview
of defenses
(antigen-independent)
Cells of the Immune System
Lymphoid stem cells
develop into lymphocytes.
… two major classes are
B cells and T cells.
Myeloid stem cells
develop into
granule-containing
inflammatory cells:
Basophils – release
histamines, prostaglandins
Chemokines, pyrogens, etc.
Eosinophils &
Natural Killer cells– ‘bombs’
Other Myeloid stem cells develop into phagocytes …
neutrophils – fast & brief
Monocytes become big persistent macrophages
(antigen-independent)
Beyond their role as a physical barrier,
the skin & mucous membranes
counter pathogens with chemical defenses.
In humans, for example, secretions from sebaceous and
sweat glands give the skin a pH ranging from 3 to 5;
acidic enough to prevent colonization by many microbes.
(Normal skin bacteria are adapted to acidic, relatively dry env.)
Microbial colonization is also inhibited by
the washing action of saliva, tears, and mucous secretions.
These secretions contain antimicrobial proteins,
like the enzyme lysozyme, which digests peptidoglycan (fig 27.5)
in the cell walls of many bacteria.
Mucus is also rich in phagocytes and IgA antibodies
Mucus traps microbes and other particles that contact it.
In the trachea, ciliated epithelial cells sweep out mucus with its
trapped microbes, preventing them from entering the lungs.
Most microbes in food or water or swallowed mucus
are destroyed by the highly acidic environment of the stomach.
However, Hepatitis A virus is one of many pathogens that survives
gastric acidity and enters to the body via the digestive tract.
Microbes that penetrate the first line of defense,
(antigen-independent)
face the internal nonspecific defense:
phagocytosis, ingestion by certain types of white cells.
Phagocytic neutrophils constitute 60-70% of all leukocytes.
Damaged cells release chemical signals that attract neutrophils
{proinflammatory cytokines like interleukin-8 (Il-8) – aka chemokines}.
The neutrophils enter the infected tissue, engulfing and destroying microbes.
http://www.cat.cc.md.us/courses/bio141/lecguide/unit1/bacpath/cytogn.html#neut
Lipopolysaccharide LPS (aka endotoxin) from the gram-negative bacterial cell wall
binds to LPS receptors on monocytes, macrophages and neutrophils.
The binding of LPS to the LPS (CD14) receptor and Il-8 to Il-8 receptors on neutrophils
stimulates them to release proteases and toxic oxygen radicals for extracellular killing.
All components of the non-specific immune system are modulated by products of
the specific immune system, such as interleukins, interferon-gamma, antibody, etc
(antigen-independent)
Phagocytic Monocytes (5% of leukocytes)
circulate in the blood for only a few hours,
then migrate into tissues, developing into
large macrophages ("big eaters") =
Macrophages, the largest phagocytic cells.
Fig 43.3
Phagocytosis: This micrograph shows
fibril-like pseudopodia of a macrophage
attaching to rod-shaped bacteria,
which will be ingested and destroyed.
A macrophage engulfs a microbe
in a vacuole that fuses with a lysosome (Fig 7.14).
The lysosome has two ways of killing the trapped microbe:
1) w/ toxic forms of oxygen like superoxide anion and nitric oxide,
2) w/ lysosomal enzymes, including lysozyme.
Some microbes have evolved mechanisms for evading phagocytic destruction.
Some bacteria have outer capsules to which a macrophage cannot attach.
Others, like Mycobacterium tuberculosis, are readily engulfed
{it binds to macrophage surface receptors for the sugar mannose}
but are resistant to lysosomal destruction
{it can inhibit phagosome-lysosome fusion; the exact mechanism is not known}
and can even reproduce inside a macrophage.
(antigen-independent)
About 1.5% of all leukocytes are eosinophils.
Their main contribution is against larger parasitic invaders,
such as the blood fluke Schistosoma mansoni.
Eosinophils position themselves against the external wall of a parasite
and discharge destructive enzymes from cytoplasmic granules.
These cells have only limited phagocytic activity.
Nonspecific defense also includes natural killer (NK) cells.
NK cells do not attack microorganisms directly;
instead, they destroy virus-infected body cells
(as well as abnormal & cancerous cells).
NK cells are not phagocytic; rather,
they mount an attack on the cell's membrane,
causing the cell to lyse (burst open).
www.bio.ic.ac.uk/ research/dmd/
NK cells require the order of a minute or two to survey a target cell.
A lack of such accumulation of MHC I protein (HLA-C)
signifies to the Natural Killer cell that something is abnormal in
the cell, e.g. it is virally infected, and it should be killed.
Phagocyte function is intimately associated with
an effective inflammatory response and also with certain antimicrobial proteins.
Cellular Mediators of Inflammation - http://web.indstate.edu/nurs/mary/PATHOPHY.htm
Neutrophils and Monocytes are drawn by the chemotactic chemicals,
Neutrophils are highly phagocytic leukocytes …
contain lysosomal granules (enzymes) which digest substances that they engulf.
Monocytes are large immature forms of a macrophage …
Chemical Mediators of Inflammation - http://web.indstate.edu/nurs/mary/PATHOPHY.htm
Histamine: In response to injury, granulated leukocytes known as
mast cells (fixed in the body organs) and basophils (flowing in blood stream)
release histamine which causes dilation of local blood vessels …
bronchial constriction (smooth muscle) and mucus production,
{antihistamines fill receptor cell ‘locks’ w/o turning the key - preempt histamine keys;}
Bradykinin: … which causes increases heart rate & vascular permeability …
The kinins are also responsible for pain.
Prostaglandins: … attract neutrophils, increase platelet aggregation to help clotting.
cause redness (increase vasodilation and permeability)
pain (increase sensitivity of nerve endings)
Leukocytes also release molecules called pyrogens,
which set the body's thermostat at a higher temperature – fever:
phagocytized bits of bacterial pyrogens (cell wall etc)
increase the production of interleukin-1 in phagocytes.
IL-1 (endogenous pyrogen or leukocyte pyrogen) increases the local production of
prostaglandins in the anterior hypothalamus, increasing the temperature set-point.
Fever can be reduced by aspirin which inhibits
the cyclooxygenase enzyme necessary for the synthesis of prostaglandins.
Certain bacterial infections can induce an
an overwhelming systemic inflammatory response known as septic shock .
Characterized by high fever and low blood pressure,
septic shock is the most common cause of death
in U.S. critical care units.
http://www.mnwelldir.org/docs/immune/immune1.htm
There are many types of interferons, and
their name derives from their function: the ability to interfere with viral infections.
When a cell is attacked by a virus, though it cannot save itself,
it can create an interferon that will warn other cells of an impending infection.
Having been warned, the uninfected cells arm themselves with antiviral substances
that keep the virus from replicating (reproducing themselves) in the uninfected cells.
{the actual mechanisms are complex & not well known, see
http://www.bio.indiana.edu/studies/ugrad/M430/INTERFERON.html }
Some interferons act as chemokines, attracting & activating phagocytes.
Interferons are not virus specific.
The complement system - later.
This strain has a gene that
interferes w/ interferon!
& prevents infected cells
from signaling for
immune response.
Lethal H5N1 influenza viruses escape host anti-viral cytokine responses
Seo SH, Hoffmann E, Webster RG NATURE MEDICINE 8 (9): 950-954 SEP 2002
http://www.thebody.com/step/immune.html
The Organs of the Immune System
Bone Marrow -- All the cells of the immune system
are initially derived from the bone marrow …
bone marrow-derived stem cells differentiate into …
B cells, natural killer cells,
granulocytes and immature thymocytes,
in addition to red blood cells and platelets.
Immature thymocytes … leave the bone marrow
and migrate into the thymus.
Thymus -- The function of the thymus is to produce mature T cells.
Through a maturation process sometimes referred to as thymic education,
T cells that are beneficial to the immune system are spared, while
T cells that evoke a detrimental autoimmune response are eliminated.
The mature T cells are then released into the bloodstream.
In immature lymphocytes, genes for immunoglobulins mutate like crazy,
creating zillions of mutant ‘locks,’ each w/ a different key to its ignition.
Most of these mutant immunoglobulins are ‘ignited’ by self-antigens (95%).
Self-tolerance results from clonal deletion:
maturing lymphocytes that react intensely in Bone or Thymus
are convinced to commit suicide (apoptosis, Fig 21.18)
http://www.thebody.com/step/immune.html
Cells of the Immune System
T-Cells are divided into two major subsets.
The TH helper subset, also called CD4+ T cell coordinates immune regulation.
The main function of the TH helper cell is to augment immune responses
by the secretion of {chemokines - interleukins} that activate other white blood cells.
T cells interact with cell surface glycoproteins encoded by
a family of genes called the major histocompatibility complex (MHC).
In humans, MHC glycoproteins are known as HLA (Human Leukocyte Antigens).
Through a process known as antigen presentation, an MHC molecule
cradles a 9 amino acid fragment of an intracellular protein antigen in its groove,
carries it to the cell surface, and "presents" it to an antigen receptor on a T cell.
{see Falk et al 2002. Nature 348,248-251}
(a) Class I MHC molecules found on almost all nucleated cells in the body
present to Cytotoxic T cells (TC), which then kill the presenter.
(b) Class II MHC molecules are made by only a few cell types,
chiefly macrophages and B cells (called antigen-presenting cells (APCs))
that ingest bacteria (and viruses) and then destroy them.
Class II MHC molecules in these cells collect peptide remnants of this degradation
and present them to helper T cells, which send out chemical signals
that incite other cell types to fight the pathogen
MHC-dependent mate preferences in humans.
Wedekind et al. 1995. Proc. Roy. Soc. Lond. B 260: 245-249.
…each female student was asked to rate
the odours of six T-shirts.
Oooohh he smells so …
different!
They scored male body odours as more pleasant
when they differed from the men in their MHC {II}
than when they were more similar.
http://www.thebody.com/step/immune.html
Cells of the Immune System
The cytotoxic TC killer subset or CD8+ T cell.
… directly kill certain tumor cells,
viral-infected cells and sometimes parasites.
perforin, a protein that forms pores in the target cell's membrane.
http://www.thebody.com/step/immune.html
Cells of the Immune System
B Cells -- The major function of B lymphocytes
is the production of antibodies in response to
foreign proteins of bacteria, viruses, and tumor cells.
Antibodies are specialized proteins that specifically
recognize and bind to one particular protein.
Antibody … binding to a foreign substance or antigen,
often is critical as a means of signaling other cells
to engulf, kill or remove that substance from the body.
http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm
Antibodies {& membrane-bound receptors}
Each antibody is made up of
two identical heavy chains and
two identical light chains,
shaped to form a Y.
… the tips of the Y's arms = the variable region =
the antigen-binding site … allow the antibody
to recognize a matching antigen,
much as a lock matches a key.
The stem of the Y links the antibody to
other participants in the immune defenses.
This area is identical in all antibodies of the same class …
http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm
Antibody Genes
Scientists long wondered
how all the genetic information needed
to make millions of different antibodies
could fit in a limited number of genes.
The answer is that antibody genes are pieced together
from widely scattered bits of DNA,
and the possible combinations are nearly endless.
As this gene forms, it assembles segments
that will determine the variable-V,
joining-J, and constant-C segments
of this antibody molecule …
http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm
Antibodies belong to a family of large protein molecules
known as immunoglobulins.
IgG, the major immunoglobulin in the blood,
is also able to enter tissue spaces;
it works efficiently to coat microorganisms,
IgD is inserted into the membrane of B cells,
where it somehow regulates the cell's activation.
IgE is normally present in only trace amounts,
but it is responsible for the symptoms of allergy {it triggers
mast cells in mucous membranes to release histamines}.
IgA—a doublet—
concentrates in body fluids such as tears, saliva,
and the secretions of the respiratory and
gastrointestinal tracts {snot}.
It is, thus, in a position to guard the entrances to the body.
IgM usually combines in star-shaped clusters.
It tends to remain in the bloodstream,
where it is very effective in killing bacteria.
http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm
Complement
The complement system consists of a series of proteins
that "complement" the work of antibodies in destroying bacteria.
Complement proteins circulate in the blood in an inactive form.
The so-called "complement cascade" is set off when
the first complement molecule, C1, encounters
antibody bound to antigen in an antigen-antibody complex.
The end product is a cylinder that punctures the cell membrane and,
by allowing fluids and molecules to flow in and out, dooms the target cell.
http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm
Immunity: Short- and Long-Term Cell Memory
Whenever T cells and B cells are activated,
some become "memory" cells.
The next time that an individual encounters that same antigen,
the immune system is primed to destroy it quickly.
Long-term immunity can be stimulated not only by infection
but also by vaccines
made from infectious agents that have been inactivated
or, more commonly, from minute portions of the microbe.
Short-term immunity can be transferred
passively via antibody-containing serum;
similarly, infants are protected by antibodies
they receive from their mothers
(IgG antibodies cross the placenta, IgA antibodies are passed in breast milk).
Note the use of passive immunity w/ IgG to Rh factor at 1st birth
preempt Rh- mom from developing active memory & strong attack on 2nd child.
http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm
Disorders of the Immune System: Allergy
Allergies such as hay fever and hives
are related to the antibody known as IgE.
The first time an allergy-prone person is exposed to
an allergen—for instance, grass pollen—
the individual's B cells make large amounts
of grass pollen IgE antibody.
These IgE molecules attach to granule-containing cells
known as mast cells, which are plentiful in the lungs, skin,
tongue, and linings of the nose and gastrointestinal tract.
The next time that person encounters grass pollen,
the IgE-primed mast cell releases {histamines} that cause
the wheezing, sneezing, and other symptoms of allergy.
To Desensitize the person to the antigen - (allergy shots)
Give repeated small doses of the antigen intramuscularly.
This leads to a build up of IgG, {circulating in blood & lymph}
which clears out the antigen
before it gets to the IgE on the Mast cells.
Not 100% effective, but it does help some.
http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm
Disorders of the Immune System: Autoimmune Disease
{See: http://www.montana.edu/wwwwami/523/Reading11.htm}
Sometimes the immune system's recognition apparatus breaks down,
and the body begins to manufacture antibodies and T cells
directed against the body's own cells and organs.
… type I or juvenile-onset diabetes is due to the combined
attack of T cells and antibodies directed against the ß cells
of the pancreas that normally produce insulin
People w/ systemic lupus erythematosus …
have developed an immune response to their own DNA,
and the presence of anti-DNA antibodies in their serum
is one mechanism of diagnosis lupus …
Rheumatoid Arthritis:
Some people produce the rheumatoid factor
which is an IgM autoantibody.
This auto IgM binds to the Fc part of IgG,
forming immune complexes, which lodge in the joints
and cause inflammation of the joint.
{see Vinuesa & Goodnow 2002. Nature 416,595-598}
Disorders of the Immune System:
AIDS
is an immunodeficiency disorder
caused by {HIV},
a virus that destroys helper T cells.
CD4 molecules on helper T cells
enhance the binding w/ class II MHCbearing antigen-presenting cells.
HIV binds to CD4 & helper T cells
are highly susceptible to infection.
The AIDS virus splices its DNA
into the DNA of the cell it infects;
the cell is thereafter directed
to churn out new viruses.
http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm
Immunity and Cancer
When normal cells turn into cancer cells,
some of the antigens on their surface change.
These altered antigens flag immune defenders, including
cytotoxic T cells, natural killer cells, & macrophages.
According to one theory, patrolling cells of the immune system
provide continuing bodywide surveillance, spying out and
eliminating cells that undergo malignant transformation.
Tumors develop when
the surveillance system breaks down or is overwhelmed
{or when the immune system is suppressed, ex by stress}
Social stress in laboratory rats - Behavior, immune function, and tumor metastasis.
Stefanski V. PHYSIOLOGY & BEHAVIOR 73 (3): 385-391 JUN 2001
Abstract:
… in subdominant males
after 2 days of continuous social confrontation …
elevated plasma concentrations of adrenal hormones …
lower numbers of blood CD4 and CD8 T cells as well as
reduced activity levels of T cells and natural killer (NK) cells …
A 10-fold lower tumor clearance in subdominant males demonstrates
suppression of the animals' capacity to prevent metastatic development. …
Immune responses and latent herpesvirus reactivation in spaceflight.
Stowe et al. Aviation Space and Environmental Medicine 72 (10): 884-891 OCT 2001.
Abstract:
Background: Increased frequency and severity of herpesvirus infections
are common in individuals with impaired cellular immunity …
This study investigated immune responses and latent herpesvirus reactivation
during a 9-d spaceflight. …
Conclusions: … spaceflight and associated stresses reactivate latent herpesviruses
… acute changes in neuroendocrine hormones mediate these changes
in part by downregulating cellular immunity. …
http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm
The Immune System and the Nervous System
Biological links between the immune system and the nervous system
exist at several levels.
{ Think Happy Thoughts – ‘humoral immunity’! }