Immune System

Defends against microbes and parasites

Removes dead and damaged cells and tissues
Allergies and autoimmune diseases
Chronic inflammation and heart disease and
cancer
Transplant tissue rejection
Septic shock and anaphylactic shock

Immune Defenses: Found in all life forms

Pathogens attack all
life forms
How can a bacteria
defend itself from a
virus?
Restriction enzymes

Immune Systems: Required for Multicellular life

Some immune defenses shared by plants and humans

Immune System and History

Infectious disease causes 1/3 of deaths today
Infectious disease is a major factor in history
for examplethe population of Native
Americans fell 95% after the Spanish landed in
North AmericaThey had no resistance to Old
World diseases. What would the world be like
today if they.like the Central Africans. had
been able to resist invasion by Europeans?

Immune System and History

The ancient Greeks were almost destroyed by
a plague that had symptoms that match no
known disease today.they said the plague
followed the Nile River from central Africa
Can new plagues appear today?

Infectious Diseases
Constantly Evolving and Invading new Hosts
HIV

Monkey Pox

Immune Systems
Innate
Fast

Specific or Adaptive
Slower

Recognizes many microbe Targets highly specific

molecules
molecular features
(antigens)
Stable genes in DNA
genome
Responds in same way
every time

Variable genes in DNA genome

Has memory and responds
differently to repeated
infection

Innate Defenses
-Physical barriers
-External chemical and
microbial barriers
Mucus
Normal bacteria
Defensins and lysozyme
-Internal molecules
Complement

----Phagocytic cells
Macrophages
Monocytes
Neutrophils
Natural Killer cells
----Inflammation and fever

Innate Defenses: Physical Barriers

Epithelial cell layers
---skin
---respiratory
---gastrointestinal
---urinary and vaginal

Epithelial cells bind to form barriers layers

Figure 19-40 Molecular Biology of the Cell ( Garland Science 2008)

Innate Defenses
Chemical barriers: Mucus
Some epithelial layers
secrete highly
hydroscopic molecules
to form mucus barriers
to trap and wash away
bacteria and viruses

Innate Defenses
Chemical barriers: Mucus
During pregnancy the
cervix forms a mucus
plug as a barrier to
maintain a sterile
uterus

Innate Defenses
Chemical and microbial barriers
Vaginal mucus secretions select
a community of bacteria
that cause the female
reproductive tract to be
highly acidthis limits the
growth of pathogens
The ears, skin, oral and
respiratory cavities intestines
have similar communities of
protective bacteria

Innate Defenses
Chemical barriers
Many epithelial tissues secrete antibacterial
molecules
Lysozyme
Dissolves bacterial cell wallsfound in tears
Defensins
Naturally produced antibiotic peptides

Defensins
Large family of antibiotic peptides found from
plants to humans
Also found as venoms in some poisonous snakes
Perhaps dozens of human genesnot all active
..difficult to study as the different defensins
overlap in functions

Defensins
Insert into membranes and form pores
May have intra-cellular cell toxic functions
Found in storage granules of leukocytes (White
blood cells) released by to kill other cells
Toxic to bacteria, fungi and some viruses
Some monkeys resistant to HIV have been
reported to have defensins that kill HIV

Some Viruses have cell-like membranes

Defensins:
Cationic and hydrophobic sides
Believed to form
membrane pores
May not function well
in Cystic Fibrosis
patients due to
altered ion channels
A future topical
microbiocide?

Non Specific Defenses:

Complement
Complement: Proteins
produced in liver
Classical pathway
.complements function
of antibodies
Alternative and Lectin
pathway
.Recognizes and binds
to bacterial and fungal
membranes

Stimulates function of other

parts of immune systems
Attracts Phagocytes by
chemotaxis
Coats bacteria and
facilitates phagocytosis:
Opsonization
Destroys target cell
Membrane Attack
Complexes

Complement Activation

Complement:
Membrane Attack Complex

Complement:
Membrane Attack Complex

Complement:
Membrane Attack Complex

Phagocytes

Phagocytes
Greek phagein: To eat
Innate immune system cells designed to devour
and destroy:
extracellular matrix material for tissue
remodling
foreign cells and microbes
abnormal cells (old Red Blood Cells)
can become highly active Respiratory Burst

Phagocytes
Macrophages: Found as resident cells within
tissues:
Microglial cells: found in CNS
..Kupffer cells: found in Liver
..Dust Cells: lung alveolar macrophages

Phagocytes: Kupffer cells

Liver specific macrophages
engulf bacteria, debris
and damaged RBCs.
One of two functional cell
types in liver---will
phagocytose India Ink

Phagocytosis
1.
2.
3.
4.
5.

Chemotaxis and adherence to microbe

Surround and ingest (eat) microbe
Formation of phagosome
Fusion with lysosomes to form phagolysome
Digestion/destruction of microbe by enzymes
and molecules produced by enzymes
NO, HOCL, H2O2, Hydroxyl radicals

6. Processing or discharge of digest

Phagocytes: Monocytes
Monocytes are produced by bone marrow
stem cells
Migrate into blood and follow signals
released at infection sites
Differentiate into macrophages at sites of
infection
Bone marrow production increases during
infection when more macrophages are
needed

Phagocytes: Neutrophils
Neutrophils: also known as
Polymorphonuclear leukocytes
Produced by bone marrow stem cells
Travel in blood: attracted to sites of infection
First additional cells to arrive at infection site
Fast acting.but live for short time
Dead neutrophils make up most of Pus

Innate Immune System

Recognition of Microbes
Complement bind to bacteria and fungi and
their binding stimulates phagocytosis by
macrophages
Many cell surface receptors for bacterial and
fungal molecules Toll Like Receptors (TLR)
Several families of internal sensors of
microbes... NOD family most well known
NOD proteins also found in plants and insects

Natural Killer Cells

Natural Killer Cell are produced from bone
marrow stem cells
Have cell surface receptors that scan cells for
abnormal cells and evidence of intracellular
infection by bacteria and viruses
Kill cells showing evidence of infection
Also stimulates macrophages

Natural Killer Cells

Immunological Surveillance
Natural Killer cells (NK cells) Attack cells with
abnormal membrane molecules OR when MHC
I of the adaptive immune sys. disappears
Destruction of:
--bacteria, fungus and some enveloped virus
--infected cells
--cancerous cells

Natural Killer cells

Cell Killing
1. NK cells contact and recognizes abnormal cell
2. Golgi apparatus moves like turret of a tank
and vesicles of Perforins released towards cell
3 Perforins diffuse into target cell membrane and
form complexes and create pores
4 Target cell membrane leaks and dies
5 Also, adds proteins to attacked cell that stimulates
apoptosis

NK cells: Perforin

Innate Immune System

Inflammation
Damaged cells release prostaglandins and
various proteins, potassium ions
The body interprets the altered interstitial
fluid composition as an infection or wound.
and responds with inflammation

Innate Immune System: Inflammation

Inflammation: designed to signal infection is
underway and to limit the infection
Factors released from dying cells can trigger
Mast cells release of histamine as signaling
molecule for inflammation:
Cascade of signals: prostaglandins play a major
role in promoting inflammation

Inflammation

Dilation of blood vessels: swelling

Capillary permeability increases
Phagocytes attracted to area
Fibrin from blood clot cascade forms fibers
around wound area to trap bacteria
Chemokines released

Inflammation
Chemokines released to act to attract
phagocytes following chemokine concentration
gradient
Locally, blood vessel endothelial cells respond
to inflammation factors by expressing
glycoproteins in cell surface: Selectins
Remotely, bone marrow reserves respond by
releasing neutrophils and monocytes

Emigration from blood:

Monocytes and Neutrophils
The leukocytes begin to stick to blood vessel
walls and roll along: margination
Local presence of chemokines causes the
leukocytes to adhere tightly and begin migrating
thru enlarged capillary pores: diapedesis
Leukocytes migrate to site of chemokine release

Inflammation
Role in many diseases
Chronic inflammation may have roles in heart
many diseases including heart disease,cancer
and autoimmune diseases
Aspirin blocks prostaglandin synthetase .
some doctors in US recommend a childs
aspirin every day for those at risk of heart
disease or colon cancer
C-Reactive protein used as a measure of
systemic inflammation

Inflammation:
Endometriosis
Endometriosis: the most common cause of
female sterility in the developed world
Believed to result from abnormal inflammation
response in the endometrium lining of uterus
Why would the uterus have such sensitivity to
inflammation?
How has this sensitivity been used in
medicine?

Septic Shock
Septic shock, or sepsis, results from the
massive release of endotoxins such as LPS
(Lipopolysccharide)
These compounds are recognized throughout
the body as a sign of infection: This results in
a systemic inflammation response of
vasodilatation and loss of fluid from capillaries
The death rate of sepsis is about 50% results
from circulatory collapse

Lipopolysccharide-LPS-Endotoxin

Anaphylaxis
Anaphylaxis results from a systemic response
to a circulating antigen such as a drug one has
become allergic to
The response is similar to septic shock but can
happen very, very quickly after taking a
medicine or getting a sting from an insect
Can quickly cause death from circulatory
collapse: Anaphylactic shock

Innate Immune System

Interferons
Small protein signal molecule released by
virally infected cells responding to presence of
dsRNA or unmethylated CpG DNA
Acts as hormone to normal cells and by 2nd
messenger system triggers expression of over
300 genes.to make them poor viral hosts
Generally shuts down cellular viral production
antiviral
Can lead to infected cell apoptosis

Interferon:
Dicer: RNA interference
Cells respond interferon by production of the
protein Dicer
Dicer degrades dsRNA into small fragments of
about 21-25 nucleotides
Then, it degrades any mRNA these fragments
will bind to
This system has been used to great effect to
silence genes by adding small RNAi molecules

Innate Immune System

Interferon

Currently used as drug for

Hepatitis B and C
Also used for some cancers
Mixed successsometimes
doesnt help
Toxic to cells with
prolonged use

Innate Immune System

Fever
Fever: a metabolically elevated body
temperature
Can be induced by the hypothalamus
Often induced by pyrogens such as
lipopolysaccharides or (LPS).
The body recognizes the presence of this
molecule as a sign of bacterial infection and
fever begins as part of the non-specific
immune response

Innate Immune System

Fever
Increased leukocytes mobility and
phagocytosis
Enhanced effects of the specific immune
responses
Cells move faster and enzymatic reactions are
quicker @ higher temperatures
Some pathogens may not function well at high
temp. i.e. soil dwelling bacteria

Fever:
Metabolic functions are temperature sensitive

Body Responses to Bacterial Infection

Figure 2224