Transcript SPECIFIC DEFENSES OF THE HOST:THE IMMUNE RESPONSE …

NONSPECIFIC
DEFENSES
OF THE HOST
Innate Immunity
(Non-Adaptive Immunity)
(Pre-existing immunity)
Immunity you are born with
Does not change/adapt
during life in response to infection
HOST IMMUNE SYSTEM
There are over 400 known pathogens of man
and each of us is likely to come into contact
with at least 150 of them within our life span
Include:
Viruses (10-20 nm)
Bacteria (1-2 um)
Protozoa (50-100um)
Fungi (10um-10cm)
Parasites (Worms & Flukes) (>10cm)
Why Do We
Need An Innate
Immune
System?
Replication rate
of extracellular
bacteria with an
average
doubling time
of 20 minutes
Dead within
24hrs !!!
= 2 x 1021
Innate Immune System comprises
of a
Cellular arm (cells)
and
a
Humoral arm (soluble factors)
IMMUNOLOGY
Study of how the body limits invasion by non-self and
recognises and eliminates altered self
- damaged cells and cancer cells
HAEMATOLOGY
Study of blood cells and their origins and
the homeostatic mechanisms that control coagulation
Most types of blood cell are components of the immune system
INFECTION
Differences between infectious agents and
their sites of replication necessitate
different immune mechanisms for their control
•VIRUSES (DNA & RNA, intracellular replication)
•BACTERIA (intracellular / extracellular replication)
•FUNGI
•PROTOZOA
•WORMS
DEFENCE AGAINST INFECTION
•Physical barriers
•Non-adaptive (Innate) immunity
•Adaptive immunity
NONSPECIFIC
RESISTANCE
• Defenses that protect the
host against ANY
pathogen
– Mechanical factors
– Chemical factors
Specific Resistance
Specific Resistance, or immunity is
based on antibody production
It is a defense against a particular
microorganism
Mechanical Factors
The intact skin consists of the dermis,
an inner thicker portion composed of
connective tissue, and the epidermis,
an outer, thinner portion consisting of
several layers of epithelial cells
The top layer of epidermal cells
contains the protein keratin
(remember—fungi produce keratinase)
• Dermis
– Inner thicker
portion
• Epidermis
– Outer, thinner
portion
• Keratin
(waterproofing)
SKIN
SKIN INFECTIONS
• Rare in unbroken skin
• Sweat washes microbes off
• Cuts and burns may get infected
–Subcutaneous infections
–Staphylococcus spp.
MUCOSAL SURFACES
• Epithelial layer
• Connective tissue
Bronchi
Intestine
MUCOSAL SURFACES
(cont.)
•Gastrointestinal tract
•Respiratory tract
•Urinary tract
•Reproductive tract
MUCOSAL SURFACES
(cont.)
• Mucus traps
microorganisms
• Physical barrier
• Cilia lower respiratory
tract
• Washing (sweat)
MUCOSAL SURFACES
(cont.)
• Mucosal irritation or
damage facilitates
infection (smoking)
• Substances produced by
pathogens
–Treponema pallidum
Flushing of Cavities
• Prevents colonization
–Tears (lysozyme—breaks
down NAG/NAM)
–Saliva
–Urine
–Feces
–Sebum (unsaturated fatty acids of
sebum inhibit growth of certain
pathogens)
CHEMICAL FACTORS
• Skin
–Sebaceous glands
•Unsaturated fatty acids
•pH 3-5
LYSOZYME
• Enzyme that degrades
peptidoglycans
–Gram positives more
susceptible than Gram
negatives
LYSOZYME (cont.)
• Sweat
• Saliva
• Tears
• Nasal
secretions
GASTRIC JUICE
• Hydrochloric acid (pH 1.2 to 3)
–Helicobacter pylori
•Neutralizes acidic pH
• Enzymes
• Mucus
BLOOD
• Iron-binding proteins
–Lactoferrins
–Transferrins
• Iron unavilable for pathogens
DEAD TISSUE leads to INFECTION
Mechanical, chemical or thermal injury
Debride wounds
Interruption of blood supply –
infarction
DEFENCE AGAINST INFECTION
•Physical barriers
•Non-adaptive (Innate) immunity
•Adaptive immunity
A variety of immune mechanisms utilising
proteins and cells that act in concert
to control and eradicate infection
Immune mechanisms are targeted by
molecular recognition of micro-organisms
INNATE IMMUNITY
•Mast cells
increase blood flow and vascular permeabilitybring
components of immunity to site of infection
•Phagocytes
engulf (phagocytose) and destroy micro-organisms
•Complement
activate mast cells, attract phagocytes, opsonize
and lyze micro-organisms
•Acute phase proteins
activate complement and opsonise
SPECIFIC IMMUNITY
For each different antigen there is a specific receptor
1011 different antigens
1
2
3
4
1011 different receptors
1
3
2
4
Exposure to infection
Resistance to infection
•Climate
•Vectors
•Population
•Housing
•Water / sewage
•Public health
•Mutation
•Age
•Previous exposure
•Vaccination
•Nutrition
•Disease
•immunodeficiency
PHAGOCYTOSIS is the
body’s second line of
defense
• Ingestion of particulated matter by
a cell
–Phagocytes (white blood cells)
–Phagocytosis derived from the
Greek work “to eat” and “cell”
Formed Elements in Blood
--Blood fluid is called plasma
--Cells and cell fragments of the blood
are the formed elements
--Most important ones in Immunology
are the leukocytes (WBC)
--Decreased leukocyte counts are called
leukopenia (I.e.Thrombocytopenia)
A differential white blood count detects
leukocyte number changes
Leukocytes are subdivided into three
categories
GRANULOCYTES---have granules in their
cytoplasm (neutrophils, basophils, eosinophils)
LYMPHOCYTES (are note phagocytic—occur
in lymphoid tissue)
MONOCYTES (lack granules & are phagocytic
only after maturing into MQ)
PHAGOCYTES
• Neutrophils (60-70%)
–Initial phagocytic cells
• Monocytes/Macrophages (38%)
–Final phagocytic cells
Granulocytes
Eosinophil
(0-2%)
Neutrophils
(45-74%)
In Blood
Eosinophils Target – Worms and flukes
Filarial Nematode Larvae
Wucheria bancrofti
Migrates within tissues
Granulocytes are mostly neutrophils
that wander in the blood and can pass
through capillary walls to reach trauma
sites
MQ are highly phagocytic cells called
wandering MQ’s b/c of their ability to
migrate
Fixed MQ’s (histiocytes) enter
tissue/organs and remain there (I.e.
Kupffer cells in the liver)
PHAGOCYTOSIS
• Chemotaxis
• Adherence
• Ingestion
• Digestion
Avoiding Contact with
Phagocytes
• Bacteria can avoid the attention of phagocytes
in a number of ways
• Pathogens may invade or remain confined in
regions inaccessible to phagocytes. Certain
internal tissues (e.g. the lumens of glands, the
urinary bladder) and surface tissues (e.g. the
skin) are not patrolled by phagocytes.
• Some pathogens are able to avoid provoking
an overwhelming inflammatory response.
Without inflammation the host is unable to
focus the phagocytic defenses.
Some bacteria or their products
inhibit phagocyte chemotaxis
For example, Streptococcal
streptolysin suppresses neutrophil
chemotaxis, even in very low
concentrations
Fractions of Mycobacterium
tuberculosis are known to inhibit
leukocyte migration.
• Some pathogens can cover the surface of the bacterial
cell with a component which is seen as "self" by the
host phagocytes and immune system. Such a
strategy hides the antigenic surface of the bacterial
cell.
• Phagocytes cannot recognize bacteria upon contact
and the possibility of opsonization by antibodies to
enhance phagocytosis is minimized.
• Staphylococcus aureus produces cell-bound
coagulase which clots fibrin on the bacterial surface
• Treponema pallidum, the agent of syphilis, binds
fibronectin to its surface.
• Group A streptococci are able to synthesize a capsule
composed of hyaluronic acid. Hyaluronic acid is the
CHEMOTAXIS
• Chemical attraction of
phagocyte to microorganism
–Microbial products
–Damaged tissue
–White blood cell
components
ADHERENCE & ENGULFMENT
(INGESTION)
• Attachment of phagocyte plasma
membrane to microorganism
INGESTION
• Pseudopods extend from
phagocyte plasma
membrane and engulf the
microorganism forming
the phagosome
A pathogen is only a pathogen if
it “tricks” the immune
system’s defense missiles
(phagocytes)
Inhibition of Phagocytic
Engulfment
• Some bacteria employ strategies to avoid
engulfment (ingestion) if phagocytes do make
contact with them
• Many important pathogenic bacteria bear on
their surfaces substances that inhibit
phagocytic adsorption or engulfment
• Clearly it is the bacterial surface that matters
• Resistance to phagocytic ingestion is usually
due to a component of the bacterial cell
surface (cell wall, or fimbriae, or a capsule).
Classical examples of antiphagocytic
substances on the bacterial surface
include
• Polysaccharide capsules of S. pneumoniae,
Haemophilus influenzae, Treponema pallidum
and Klebsiella pneumoniae
• M protein and fimbriae of Group A
streptococci
• Surface slime (polysaccharide) produced as a
biofilm by Pseudomonas aeruginosa
• O polysaccharide associated with LPS of E.
coli
• K antigen (acidic polysaccharides) of E. coli or
the analogous Vi antigen of Salmonella typhi
DIGESTION
• Within cytoplasma the
phagosome fuses with
lysosome (digestive enzymes)
forming the phagolysosome
LYSOSOME CONTENTS
• Lysozyme • Hypochlorous acid
• Lipases
• Toxic O2
• Proteases • Nucleases
Survival Inside of Phagocytes
• Some bacteria survive inside of phagocytic
cells, in either neutrophils or macrophages
• Bacteria that can resist killing and survive or
multiply inside of phagocytes are considered
intracellular parasites
• In this case, the environment of the phagocyte
may be a protective one, protecting the
bacteria during the early stages of infection or
until they develop a full complement of
virulence factors
• The intracellular environment guards the
bacteria against the activities of extracellular
bactericides, antibodies, drugs, etc.
BACTERIAL INTRACELLULAR PATHOGENS
Organism
Disease
Mycobacterium tuberculosis
Tuberculosis
Mycobacterium leprae
Listeria monocytogenes
Salmonella typhi
Shigella dysenteriae
Yersinia pestis
Brucella species
Legionella pneumophila
Leprosy
Listeriosis
Typhoid Fever
Bacillary dysentery
Plague
Brucellosis
Pneumonia
Typhus; Rocky Mountain Spotted
Fever
Chlamydia; Trachoma
Rickettsiae
Chlamydia
• Many intracellular parasites have special
(genetically-encoded) mechanisms to get themselves
into host cells that are nonphagocytic
• Intracellular pathogens such as Yersinia, Listeria,
Salmonella, Shigella and Legionella possess
complex machinery for cellular invasion and
intracellular survival
• These systems involve various types of non-toxin
virulence factors
• Sometimes these factors are referred to as bacterial
invasins
• Still other bacteria such as Bordetella pertussis and
Streptococcus pyogenes, have recently been
discovered in the intracellular habitat of epithelial
cells
• Intracellular parasites survive
inside of phagocytes by virtue
of mechanisms which interfere
with the bactericidal activities
of the host cell.
PREVENTION OF
PHAGOSOME AND
LYSOSOME
• Replicate inside phagocyte
• Shigella
• Mycobacterium
• Mycobacteria (including M.
tuberculosis) have waxy,
hydrophobic cell wall and
capsule components (mycolic
acids), which are not easily
attacked by lysosomal
enzymes
• In Salmonella typhimurium, the pH
that develops in the phagosome after
engulfment actually induces bacterial
gene products that are essential for
their survival in macrophages.
KILLING OF
PHAGOCYTE
• Toxins
• Staphylococcus
–Actinobacillus
• B. abortus and Staphylococcus
aureus are vigorous catalase and
superoxide dismutase producers,
which might neutralize the toxic
oxygen radicals that are generated
by systems in phagocytes
• S. aureus produces cell-bound
pigments (carotenoids) that
"quench" singlet oxygen produced
in the phagocytic vacuole
• Escape from the phagosome
• Early escape from the
phagosome vacuole is essential
for growth and virulence of
some intracellular pathogens
• This is a clever strategy employed by
the Rickettsiae
• Rickettsia enter host cells in
membrane-bound vacuoles
(phagosomes) but are free in the
cytoplasm a short time later, perhaps
in as little as 30 seconds
• A bacterial enzyme, phospholipase A,
may be responsible for dissolution of
the phagosome membrane.
• Listeria monocytogenes relies on several
molecules for early lysis of the
phagosome to ensure their release into the
cytoplasm
• These include a pore-forming hemolysin
(listeriolysin O) and two forms of
phospholipase C
• Once in the cytoplasm, Listeria induces
its own movement through a remarkable
process of host cell actin polymerization
and formation of microfilaments within a
comet-like tail
Killing Phagocytes Before
Ingestion
• Many Gram-positive pathogens,
particularly the pyogenic cocci,
secrete extracellular enzymes that
kill phagocytes
• Many of these enzymes are called
hemolysins because their activity
in the presence of red blood cells
results in the lysis of the RBC
• Extracellular proteins that
inhibit phagocytosis include
the Exotoxin A of
Pseudomonas aeruginosa
which kills macrophages
• bacterial exotoxins (Bacillus
anthrax toxin EF & Bordatella
pertussis toxin AC) which
decrease phagocytic activity
INFLAMMATION
• A localized protective response
of the body to tissue injury
–Pain
–Heat
–Redness
–Swelling
–Loss of function
INFLAMMATION
FUNCTIONS
• To destroy invading agents
• Walling off invading agents
• Repair or replace damaged
tissue
Vasodilatation & Increased Permeability
of Blood Vessels
-Vasodilatation is the 1st stage of inflammation
-It involves an increase in blood vessel
diameters  more blood flow to the injured area
-Responsible for the redness, heat, edema
(swelling), & pain of inflammation
-Histamine is released by injured cells &
increases permeability of immune system cells
to the site of injury
THE COMPLEMENT
SYSTEM
part II
COMPLEMENT SYSTEM
• 30 different serum proteins
involved in:
–Lysis (destruction) of foreign
cells
–Inflammation
–Phagocytosis
Blood
Serum
Blood clot
COMPLEMENT SYSTEM
• Two cascade activation paths:
–Classical (immune system)
•Antibodies
–Alternative
•Interaction with Polysaccharides
(mostly bacterial)
•Protein C3 activates both the
alternative & the classical pathway
•Major components of the classical
pathway are C1 and C9
Classical pathway is initiated by the
binding of AB’s to Ag
Alternative pathway is initiated by the
interaction of foreign particle with the
protein factors (important in combating
enteric G- MO)
Classical pathway
Alternative pathway
•Endotoxin (Lipid A) trigger the
alternative pathway
•The alternative pathway is often
known as the lectin pathway
•MQ interacting w/ the foreign
particle stimulate the liver to
secrete lectin, which assists in the
opsonization of MO
What is opsonization?
• Increases the susceptibility of
microorganisms to ingestion by
phagocytes
Complement system &
inflammation
•C5a is the most potent complement protein
triggering inflammation
•It causes mast cells to release vasodilators such as
histamine so that blood vessels become more permeable
•it increases the expression of adhesion molecules on
leukocytes and the vascular endothelium so that
leukocytes can squeeze out of the blood vessels and
enter the tissue (diapedesis)
•it causes neutrophils to release toxic oxygen radicals
for extracellular killing; and it induces fever
COMPLEMENT SYSTEM FUNCTIONS
• Cytolysis
–Formation of membrane attack
complexes by the complement proteins
–Damage of plasma membrane
• leakage and death of the cell
COMPLEMENT SYSTEM
FUNCTIONS
• Inflammation
–Triggers histamine release
• Increased blood vessel
permeability
• Promotes migration of cells to
site of inflammation
(Humoral) classical pathway
Alternative pathway
SPECIFIC DEFENSES OF
THE HOST: THE IMMUNE
RESPONSE
IMMUNITY
• Specific response to
foreign microorganisms or
substances
–Antibodies
–Specialized
lymphocytes (B and T)
ANTIGENS
• Foreign substances or
microorganisms that
provoke an immune
response
Types of immunity
Acquired immunity
Natural
Active
Passive
Artificial
Active
Passive
Infection Colostrum Vaccines Antiserum
COLOSTRUM
• Fluid rich in protein and
immune factors, secreted
by the mammary glands
during the first few days
of lactation
SERUM
• Fluid remaining after
blood has clotted
• Fluid where most
antibodies are found
–Antiserum
Blood
Serum
Blood clot
SEROLOGY
• The study of antibodies
and antigens
IMMUNE SYSTEM
• Humoral or antibodymediated
–B lymphocytes
• Cell-mediated
–T lymphocytes (TH & TC)
HUMORAL IMMUNE
RESPONSE
• Against:
–Bacteria
–Bacterial toxins
–Viruses outside of cells
CELLULAR IMMUNE
RESPONSE
• Against:
–Intracellular agents
–Fungi
–Protozoa
–Helminths
–Viruses inside cells
ANTIGENS
• Proteins
• Polysaccharides
• Lipids and nucleic acids
only if combined with
proteins or
polysaccharides
EPITOPES OR ANTIGENIC
DETERMINANTS
• Antibodies specifically combine
with a small segment of the
antigen called the antigenic
determinant or epitope to form
an antigen-antibody complex
• The antigen-antibody reaction
is characterized by specificity
HAPTEN
• Small molecule that needs a large molecule carrier
to behave as an antigen
• Drugs and pesticides are low molecular weight
molecules and can be treated as haptens
• By conjugation to larger carrier molecules
(albumin), low molecular weight drugs and
pesticides can be made antigenic
• Not antigenic unless attached to a carrier molecule
– Penicillin
– Penicillin binding to certain blood proteins
(albumin) can become antigenic  Penicillin
allergy
ANTIBODIES OR
IMMUNOGLOBULINS
(Igs)
• Y-shaped proteins made
in response to an antigen
• Antibodies specifically
bind to that antigen by
two antigen-binding sites
Receptor for
macrophages
CLASSES OF
IMMUNOGLOBULINS
• IgG
• IgM
• IgA
• IgD
• IgE
IMMUNOGLOBULIN G
(IgG)
–80% of all Igs
–Cross blood vessels and
enter tissue fluids
–Cross human placenta
IMMUNOGLOBULIN G
(IgG) (cont.)
• Protects against circulating
bacteria and viruses
• Neutralizes bacterial
toxins
• Trigger the complement
system
• Facilitates phagocytosis
IMMUNOGLOBULIN M
(IgM)
• 1st AB that appears in response to an
AG—however their conc. declines
rapidly
–Used for diagnosis
• 5-10% of all Igs
• Pentamer (5 “Y”s) joined by a j
chain
• Do not cross placenta b/c too big
IMMUNOGLOBULIN M
(IgM) (cont.)
• Predominant AB in the blood
typing process rx
• Hi IgM conc. Represents an active
disease
• Aggregates antigens
• Triggers the complement system
• Facilitates phagocytosis
• Antigen receptor of B cell
IgM
pentamer
“J” chain
IMMUNOGLOBULIN A
(IgA)
• 10 - 15% of all Igs
• Most common in mucous
membranes and body
secretions
–Mucus, saliva, tears and
milk
IMMUNOGLOBULIN A
(IgA) (cont.)
• Dimer (2 “Y”s) joined by
a j chain
• Prevents attachment
(adherence) of pathogens
to mucosal surfaces
IgA dimer
Secretory
component
“J” chain
IMMUNOGLOBULIN E
(IgE)
• 0.002% of all Igs
• Bind to mast cells and
basophils
• Involved in allergies
• Effective against parasitic
worms
IMMUNOGLOBULIN D
(IgD)
• Structurally similar to
IgG
• Unknown function in
serum
• Antigen receptor on B
cell surfaces
IgM
IgG
IgA
IgE
IgD
ANTIGEN-ANTIBODY
REACTION
• Neutralization
–Viruses and toxins
• Agglutination (clumping of AG
&AB so phagocytes can ingest
them better)
–Bacterial cells
• Precipitation
–Soluble antigens
viruses
(b) Neutralization of viruses by antibodies
No access to cell receptors
IMMUNE SYSTEM
• Humoral or antibodymediated
–B lymphocytes
• Cell-mediated
–T lymphocytes
B CELLS AND
HUMORAL IMMUNITY
• Stem cells in bone
marrow
–Adults
• Liver
–Fetuses
CLONAL SELECTION OF
B CELLS
Activated B cell (Lymphocyte)
Memory
cells
Plasma cells
(Igs-producing)
CLONAL DELETION
• During fetal development,
clones of lymphocytes that
react with self antigens are
eliminated (self-tolerance)
PLASMA CELLS
• Secrete antibodies (Igs)
against specific antigens
• Short lived
• Produce 2000 antibodies
per second
T-CELL MEDIATED
IMMUNITY
• Derived from stem cells
–Adults
•Bone marrow
–Fetuses
•Liver
T-CELL MEDIATED
IMMUNITY (cont.)
• Mature and differentiate
in thymus
• Mature T cells migrate to
lymphoid organs
T-CELL MEDIATED
IMMUNITY (cont.)
• Clonal selection determines
proliferation of T cells that
carry out cell-mediated
immunity
• Respond only to antigens
presented by macrophages
TYPES OF T CELLS
• Cytotoxic (TC) CD8
–Kill altered cells
• Helper (TH) CD4
–Activate B, TH, and TC
cells
TYPES OF T CELLS (cont.)
• Delayed Hypersensitivity
(TD) CD4 and CD8
–Anti-cancer, allergies
• Suppressor (TS) CD4 and
CD8
– Suppress immune
response
NATURAL KILLER (NK)
CELLS
• Non-T lymphocytes
• Not specific
• Kill altered cells
CYTOKINES
(INTERLEUKINS)
• Chemical messengers of
the immune system
–Interleukin-1
•Stimulates TH cells
–Interleukin-2
•Proliferation of TH cells