The Inflammatory &

Immune Systems
Lecture #3 & #4
 First Lines of Defense:
(external & nonspecific)
• The body’s first lines of defense:
– Skin
• Sebaceous glands-secrete
antibacterial & antifungal FAs,
and lactic acid (pH 3-5).
– Mucous membranes
• Respiratory system
• GI system
• GU system
• Sweat, tears & saliva all contain
an enzyme (Lysozyme), that
attack G+ bacteria.
 First Lines of Defense: (external & nonspecific)
• If an injurious chemical, foreign body, or
microorganism penetrates these defenses,
the body tries to eliminate it, by mechanical
clearance:
– Sloughed off with skin
– Coughed up / out; Sneezing
(cilia of respiratory tract)
– Vomited
– Flushed out from urinary tract
• Auxiliary defenses of body:
– Normal population of bacteria (i.e. on skin &
in vagina)
 INFLAMMATORY RESPONSE
• Once external barriers have been
compromised (penetration at the level of the
cells & tissues), the INFLAMMATORY
RESPONSE occurs.
– Occurs within seconds
– Internal & Non-specific
– Affected tissues are surrounded by cells &
fluids that isolate, destroy, and remove …
thereby promoting healing.
– Involves many different plasma systems
& cell types
 Inflammation Overview
• Biochemical &
cellular process
that occurs in
vascularized
tissues.
• S&S include:
• Redness
• Swelling
• Warmth / heat
• Pain
• Loss of fxn
 Inflammation Overview
Blood vessel dilation & Increased Blood
Flow to the affected area:
• Increased vascular permeability:
–Outward leakage of plasma from
blood stream
–This plasma seepage forms an
inflammatory exudate
–WBCs migrate to injury site (called
‘chemotaxis’)
 Acute Inflammatory Response (AIR)
• Begins after lethal / non-lethal cellular injury:
• Trauma
• O2 or nutrient deprivation
• Genetic or immune defects
• Chemical agents
• Microorganisms
• Temperature extremes
• Ionizing radiation
• Dead cells:
– Body’s own cells or microorganisms
– Begins Immediately ~ occurs within
seconds
 A.I.R.
• Arterioles near the site of injury
constrict briefly, then dilate:
–Increased blood flow & pressure
in microcirculation
–Increased exudation of plasma &
blood cells into the tissue spaces
–Therefore edema / swelling are
present
 A.I.R.
Leukocytes (WBCs) & Vascular Permeability
• Migration of WBC to blood vessel walls &
adherence to them
• Biochemical mediators stimulate endothelial cells
(line capillaries & venuoles) to RETRACT
– Creates spaces b/w cells
– Leukocytes move through to get to inflammatory site
• Once at site: WBCs & plasma proteins:
– Stimulate & control subsequent inflammatory
processes
– Interact with components of the Immune
System
Inflammatory Response
 Migratory Phase(s) of WBC
Types of WBC movement:
–Margination / Pavementing –
sticking to capillary / venule walls
–Diapedesis – emigration through
the retracted endothelial jxns
• Like an ‘amoeboid-type’ mvmt.
–Chemotaxis – progression to
inflammatory site
 Phagocytic Phase of WBC:
– Recognition of target & it’s adherence
– Engulfment (ingestion; endocytosis)
– Fusion with lysosome within phagocyte
– Destruction of target by lysosomal enzymes
• When phagocyte dies: (short-life cycle)
• It itself lyses - all contents spill out
• Lysosomal enzymes can digest connective
tissue matrix
– Causes tissue destruction associated with
inflammation
• Alpha-1 Antitrypsin (PP produced by the
liver) – inhibits the enzymes of dead
phagocytes
Other contents of
Lysosomes
promote:
• Increase
vascular
permeability
• Chemotaxis for
monocytes
• Breakdown of
connective
tissues
• Activation of
complement &
kinin systems
Our Inflammatory Example

Unsuccessful IV Start
 Cells of the A.I.R.:
Neutrophils, Monocytes & Macrophages
• Neutrophils are the 1st
phagocytic leukocytes to
arrive on scene:
– Ingest bacteria, dead cells
& cellular debris
– Quickly die & are
removed as pus through
epithelium or lymphatic
system
• Monocytes & Macrophages:
– Same fxn as neutrophils,
but for a longer duration
 Cells of the A.I.R.:
Eosinophils, Basophils & Platelets
• Eosinophils:
–Help control Inflammatory Response
–Act directly against parasites
• Basophils: found in blood stream
–Possible fxn of Mast Cells?
• Platelets:
–Cytoplasmic fragments that help stop
bleeding, if vascular injury occurs
• The preceding WBCs & platelets carry out
their specific fxn, with the help of:
– Complement System
– Clotting System
– Kinin System
– Immunoglobulins
• Actions by all these elements, prepares the
lesion for tissue regeneration & repair
(called : ‘RESOLUTION’)
• The AIR is a complex system of interactions
that begins with Mast Cell degranulation,
and ending with healing.
 The MAST Cell
• Cell containing
granules
• Resides in loose
connective tissue,
proximal to blood
vessels
ACTIVATOR OF
IMMUNE
RESPONSE
–Degranulation:
contents spill into
extracellular matrix
 Degranulation of the MAST Cell by …
• Physical injury:
• Heat; trauma; u/v light; X-rays
• Chemical Agents:
• Toxins; snake / bee venoms; tissue
proteases (enzymes); dextran;
cationic proteins released from
neutrophils
• Immunologic Agents:
• IgE
• Activation of complement
components
• Granules of the Mast Cell are preformed S
biochemical mediators which contain: h
• Histamine o
• Neutrophil Chemotactic factor (NCF) r
t
• Eosinophil Chemotactic Factor of Anaphylaxis (ECF-A)
t
• Leukotrines & Prostaglandins
e
• Serotonin is released from platelets r
m
Histamine & Serotonin are vasoactive
amines that cause: r
• Smooth muscle contraction & dilation of e
s
b.vessels
p
– Increasing blood flow in microcirculation &
o
increasing vascular permeability; by retracting n
endothelial cells lining the capillaries s
• Neutrophil & Eosinophil chemotaxis e
 Short term Response
• Chemotactic factor attracts a specific type
of leukocyte to the site of inflammation:
– NCF: attracts Neutrophils
Phagocytosis
– ECF-A: attracts Eosinophils
 Long term Response
• Leukotrines & Prostaglandins:
– mediators synthesized by Mast Cells
• Leukotrines (Slow-Reacting Substances of Anaphylaxis
[SRS-A]):
• Acidic, sulfur containing lipids that produce effects similar
to Histamine, but are more prolonged.
• Prostaglandins:long chained unsaturated FAs:
• Increase vascular permeability
• Neutrophil chemotaxis
• Induce pain
• Contracts smooth muscle
• Suppresses histamine release
• Suppresses lysosomal enzymes from neutrophils
• Classified into grps: E, A, F, B
ASA [NSAID]: block prostaglandin formation
 Protein Plasma Systems
• A) Complement
All assist in the
• B) Clotting Inflammatory
• C) Kinin Response

– Enzymes within these systems exist in the

form of Proenzymes (inactive forms).
– Once the 1st proenzyme becomes active, it
starts a cascade to SEQUENTIALLY
ACTIVATE other enzymes in the system
 Protein Plasma Systems:
Complement System
• 10 proteins
• ~10% of the serum proteins
• Once activated, its components participate in
virtually every inflammatory response
• Defend against bacterial & fungal infections
• How activated?
– Classic Pathway: antigen-antibody complex
containing IgM or IgG, interacting with C1
– Alternative Pathway: bacterial & fungal cell
wall polysaccharides (endotoxins)
 Protein Plasma Systems:
The Clotting System (Coagulation)
• Forms a fibrous exudate
(meshwork) at inflamed site:
– trapping exudates, micro-
organisms & foreign bodies
• Prevents spread of infection
& inflammation to adjacent
tissues
– Keeps microorganisms &
foreign bodies at the site of
greatest phagocytic activity
• Forms a clot that stops
bleeding & provides a
framework for future repair
& healing
 Protein Plasma Systems:
The Clotting System (Coagulation)
• The main substance in the meshwork is
FIBRIN:
– insoluble protein (end product of coagulation
cascade)
• How activated?
– Extrinsic Pathway: injured cell activates it
– Intrinsic Pathway: substances released during
tissue destruction & infection:
• Collagen
• Proteases
• Kallikrein
• Plasmin
• Bacterial cell wall endotoxins
 Protein Plasma Systems:
Kinin System
• Primary kinin is Bradykinin:
– Dilation of vessels
– Act with prostaglandins to promote pain
– Extravascular smooth muscle contraction
(similar to histamine)
– Increases vascular permeability
– Increases leukocyte chemotaxis
• How activated?
– Stimulation of the plasma kinin cascade
 Control & Interaction of Protein Plasma Systems:
• Activation involves the production of many POTENT
biologically active substances
– protect the body from infection
• Why is control necessary?
• Activation must be guaranteed- the
inflammatory response is vital! Therefore
there are many ways to activate it!
• Biological factors are so potent, they need to
be localized to ONLY the inflamed area
– otherwise healthy cells & tissues can be harmed
– Carboxypeptidase: inactivates components
of Complement System
– Histaminase: inactivates histamine
– Arylsulfatase-B: inactivates leukotrines
 Control & Interaction of Protein Plasma Systems:
• Control of Histamine:
– Controlled (in part) by receptors on the body’s cells:
• H1: promotes inflammation [i.e. Neutrophil
chemotaxis]
• H2: inhibits inflammation, by suppressing:
– Leukocyte fxn (suppress chemotaxis)
– Mast Cell degranulation
• ALL OF THE PPS interact . When one activates-
simultaneously activates the other systems:
• i.e. Plasmin: exists as Plasminogen (proenzyme; inactive)
– Controls clot formation
– Activates complement cascade
– Activates plasma kinin cascade
 Cellular Components of Inflammation
3 main classes of Leukocytes:
1. Granulocytes- have lysosomal enzyme
granules
• Neutrophils
• Eosinophils
• Basophils
2. Monocytes / Macrophages- (do not have
granules) but do have lysosomal
enzymes
• Monocytes= immature in blood
• Macrophages= mature cells in tissues
ALL ARE CAPABLE OF PHAGOCYTOSIS
 Cellular Components of Inflammation
3. Lymphocytes- produce soluble
mediators. Primarily involved in the
Immune Response
Platelets- cytoplasmic fragments
• Circulate in blood stream until there is
vascular injury
• Interact with components of the
coagulation cascade to stop bleeding
• Degranulate & release serotonin
• Serotonin’s effects-similar to histamine
 Cellular Components of Inflammation
• Neutrophils & Macrophages:
• Normally circulate in blood stream & stimulated
by inflammation to migrate thru the vessel walls
near an inflammatory lesion
• Becomes part of exudate & attracted to
inflammatory lesion by specific chemotactic factors
• Kept at the site by meshwork formed by the
fibrinous exudate
• They phagocytose (ingest) foreign or dead cells
until they themselves die.
• Dead phagocytes become part of the purulent
exudate (pus)
–Leave through lymphatics and/or
epithelium
Polymorphonuclear
Neutrophils (PMN)
• Predominant phagocytic
cell in the early
Inflammatory response.
• Enters site 6-12 hrs post
injury
• Attracted by chemotactic
factors (i.e. Complement
fragments)
• Short lived due to acidic
environment
• Primary role – removal of
debris & phagocytosis
 Monocytes & Macrophages:
– Largest of the blood cells (14-40 um)
– Appear 24hrs – 7days; & replace Neutrophils
– Produced in bone marrow
– Enter circulation & migrate to inflammatory site
– Long-term defense; loves acidic environment
– Can fuse together to phagocytose larger targets
• Responsive to Lymphokines secreted by T cells
(increases killing capacity)
• Activate Immune System by processing antigen, for
presentation to lymphocytes
• Produce CSF (colony-stimulating factor):
Stimulates growth & differentiation of granulocytes
& monocytes in bone marrow
• Secrete factors that promote regrowth of tissue
Granulocytes w/ Eosinophils
many lysosomes
containing:
– biochemical
factors that
control effects of
serotonin &
histamine
– a very caustic
protein that can
dissolve the
surface
membrane of
parasites
 OTHER … Cellular Products
Inflammatory Cytokines: act in a non-specific
manner to enhance the Immune Response:
– Tumor Necrosis Factor (TNF):
• produced by macrophages in response to
G- bacteria
• act on hypothalamus to induce fever
– IL-1:
• produced by macrophages
• acts on the hypothalamus to induce fever
– Migration Inhibitory Factor (MIF):
• produced by lymphocytes - prevents
macrophage migration from inflammatory
site
OTHER …Cellular Products
• Interferon:
• body’s defense
against viruses
• non-specific
viricidal protein
–IFN-Alpha
–IFN-Beta
• do not kill
viruses- prevents
them from
infecting healthy
body cells
 Resolution & Repair
Tissue destruction
followed by healing
• Tissue Resolution:
• regeneration by mitosis
• restoration of original
str. & physiological fxn
• Tissue Repair:
• when resolution is not
possible
• replacement of
destroyed tissue with
scar tissue (collagen)
 Immune Response
• The Immune Response:
• Last line of defense
• Body’s defense mechanism against invasion
• Slower than inflammatory response
• SPECIFIC – Target Oriented
• Permanent or Long-term protection
• Can be induced by vaccination or
inoculation
• Affected by:
–One type of serum protein
(immunoglobulin, or antibody)
–One type of blood cell (lymphocyte – the
immune system cell)
• Anatomy of the Immune System:
• Bone Marrow
• Lymphoid Tissues
–thymus, spleen, lymph nodes, tonsils,
adenoids
• Leukocytes are WBCs, that are active
in the inflammatory & immune
response. Three types:
–Granulocytes … from myeloid cells
–Monocytes … from myeloid cells
–Lymphocytes … from lymphoid cells
»B & T Lymphocytes
The Anatomy Of
The Immune
System
 Lymphocyte
• Must migrate through lymphoid tissue in order
to become mature / competent cell
• Lymphocytes that migrate through:
– Bone marrow = B Lymphocytes (or B Cells)
• secrete antibodies (responsible for humoral immunity)
– Thymus gland = T Lymphocytes (or T Cells)
• are capable of becoming sensitized to & recognizing specific
antigens, which they attack directly
• responsible for cell mediated immunity

Immune Response Success: depends upon the

interactions between the humoral & cell-
mediated responses
Mature Lymphocyte:
– Small & Round
– WBC (6-10 um)
• Originates in the:
– Liver
– Spleen
– Bone marrow
… of the developing
fetus & child; as
lymphocyte
precursors or stem
cells
 Immune Response
• Recognizes substances that are:
– “self” & “non-self” / foreign (ANTIGENS)
• Antigens can be located on infectious &
non-infectious agents:
• Viruses, bacteria, fungi or parasites
• Pollen
• Foods / Rxs
• Transfusions
• Transplanted
tissues
 Immune Response
• Body’s response to Antigenic Challenge
–B Lymphocytes (B cells)
• make antibodies (Immunoglobulin)
–T Lymphocytes (T cells)
• attack antigen directly
• These cells are specific:
– each cell recognizes only one specific antigen
• Carry a special ‘memory’ for the antigen. If
it ever attacks again - Immune Response is
MUCH quicker!
 IMMUNITY
Therefore the Immune
System possesses
MEMORY &
SPECIFICITY,
creating long-lasting
protection against
specific antigens.
This is termed
IMMUNITY
 Natural vs. Acquired Immunity
• Natural Immunity (aka ‘native’
or ‘innate resistance’)
–non-specific
–not produced by the Immune
System
–present from birth
–species / host dependent
• i.e. humans for canine distemper or
cowpox
 Natural vs. Acquired Immunity
Acquired Immunity: gained after birth as a result
of the Immune Response.
– Active: produced by host after exposure to antigen or
immunization (vaccination)
– Passive: preformed antibodies or T Lymphocytes are
transferred / transfused to the recipient, yielding
TEMPORARY immunity

i.e. 1: Gamma Globulin

i.e. 2: Immune Serum
i.e. 3: Passage of immunity
via the placenta
 Response to Invasion
When the body is invaded, it
has 3 ways to defend itself:
1. The Phagocytic Immune
Response
2. The Humoral (or Antibody)
Immune Response
3. The Cellular Immune
Response
1. The Phagocytic Immune Response
• 1st line of defense
• involves:
– granulocytes &
macrophages
which ingest
foreign particles
 2. The Humoral (or Antibody) Immune Response
• Begins with B cell
– transform themselves into PLASMA
CELLS, which make antibodies
– antibodies are then circulated, find
antigen & binds with it
• The part of the pathogen that
stimulates antibody production is the
ANTIGEN (or Immunogen)
– it is a protein marker, on the surface of
the particle / pathogen
 2. Antibodies
• Antibodies are large proteins called
Immunoglobulins. Each Ig has 2 subunits,
each of which contain a light & heavy
peptide chain.
– Each subunit has a portion that serves as a
binding site for a a specific antigen, called the
Fab Fragment
• this portion ‘locks-on’ to the specific antigen
– Another portion of the antibody is the Fc
Fragment
• this allows the Ig to take part in the
Complement System
Fab Fragment

Fc
 2. Antibodies
• Antibodies defend against pathogens in
several ways, and the type of defense
depends on the structure & composition of
both the antigen and antibody.
• Agglutination- clumping of antigens
together for phagocytosis
• Opsonization- coating of a sticky
substance over the antigen/Ig complex
for phagocytosis
• Promote release of vasoactive
substances:
»Histamine
»Slow-reacting Substance (Leukotrines)
 2. Types of Immunoglobulins
• IgM: (10%)
• First Ig present
• Activates Complement
• Bacterial & viral infections
• IgA: (15%)
• Body fluids (saliva, tears, breast milk)
• IgD: (0.2%) - Unclear Role
• IgG: (75%)
• Activates Complement
• Enhances phagocytosis
• Crosses Placenta
• IgE: (0.004%)
• Allergic & hypersensitivity Rxn; Parasitic
infections
 Primary Immune Response
• Initial antigenic challenge is
followed by a latent period.
• No signs of antibodies [Ig]
• after ~ 5days IgM detected in
bloodstream
–with lower levels of IgG
IgM dominates! The Immune
System is now “primed”
 Secondary Immune Response
• If there is a second challenge
by the same antigen:
–more rapid production of
larger amounts of antibodies,
than the first time (titers)
• due to the ‘memory’ feature
Increased IgG
compared to IgM
 3. The Cellular Immune Response
• Involves the T
Lymphocytes:
– many different
types
– attack pathogen
directly
– Responsible for the
Cellular Immune
Response
– Mediated in same
response as B cell
• Killer T Cells:
– attack pathogen
directly to cause lysis
• Suppressor T Cells:
– Decrease B Cell
production
• Method of control
• Memory T Cells:
– Establish memory
for future attack by
same pathogen
 Helper T (CD4):
Stimulates & orchestrates immune system by
secreting cytokines & lymphokines:
IL-2
Interferon-gamma
TNF
… that attract & activate:
– B Cells
– Killer T Cells
– Macrophages
– Other Defense Mechanism Cells
Four Stages of the Immune Response
• a) Recognition:
–recognize as foreign or non-self:
• Macrophages
• Lymph nodes
• Lymphocytes (B &T)
–are all used for surveillance
–some lymphocytes can circulate for
decades!
• Some for the lifetime of the
individual!
• b) Proliferation:
– circulating lymphocyte returns to the
nearest lymph node
– the ‘sensitized’ lymphocyte stimulates
dormant B & T Cells to:
• enlarge
• divide
• proliferate
– T cells differentiate:
– B cells differentiate:
–Plasma Cells - secrete antibody
–Memory B Cells
• c) Response:
– The differentiated lymphocytes
participate in:
• Humoral Immune Response (HIR)
–Plasma cells - secrete antibody
–Memory cells
• Cellular Immune Response (CIR)
– Involves T cells {Viral antigens (rather
than bacterial) induce the CIR}
– Most Immune Responses involve both,
but usually one dominates:
– i.e. Transplanted organ rejection; MONO; HIV:
CIR dominates
– i.e. Bacterial PNE & Sepsis: HIR dominates
• d) Effector Phase:
– Antigens are
destroyed or
neutralized through
the action of:
• Antibodies
• Complement
• Macrophages
• Cytotoxic (Killer)
T cells
 Factors that Affect Immunity
• Exogenous:
– trauma; Dx; pollutants; radiation; UV
light; Rxs
• Endogenous:
– age; gender; nutritional status; genetics;
reproductive status
Therefore the quality & intensity
of the Immune Response … is
the sum of ALL these factors
• Sometimes the Immune
Response is not in the
best interest of the
organism & needs to be
suppressed.
– i.e.1: transplanted organs
- need pharmacologic
suppression.
– i.e.2: Allergic Rxn - the
host’s Immune System is
hypersensitive to the
antigenic properties of
substances in the
environment.
 Vaccines
• Do not cause
disease
–killed
–made less
infectious
(attenuated)
• Illicits Immune
Response