PROTECTION AND

HYPERSENSITIVITY MECHANISM
WHICH MANIFEST ON SKIN
FK UNIB 2013

PROTECTION
INNATE IMMUNITY
INFLAMMATION:

vascular and cellular changes, mediators (local and

systemic)
Acute and chronic

ADAPTIVE IMMUNITY

HYPERSENSITIVITY MECHANISM
Infectious
Non infectious

NATURAL/NONSPECIFIC/
INHERENT/INNATE IMMUNITY

Integumentary System
(skin)
All multicellular organisms have defense mechanisms

against microbial and viral infections

For vertebrates, immune defense can be divided into
innate immunity and adaptive immunity
Vertebrate innate immune elements are closely related
to components of immunity in invertebrates

 Consists of three major regions

Epidermis outermost superficial
region
Dermis middle region
these two together make up the
cutaneous
membrane.
Subcutaneous region ( Hypodermis or
superficial fascia) deepest region
Also includes all the accessory
structures found in the skin (hair,

Functions of skin
Protection
Excretion (salts, water, wastes)
Maintenance of body temperature
Metabolism (Vitamin D3)
Storage (lipids, blood reserve)
Detection of sensation
Note: skin keeps water in as well as keeping
it out

Hair shaft
Pore
Dermal papillae
(papillary layer
of dermis)

Epidermis

Meissner's corpuscle
Free nerve ending
Reticular layer of dermis
Sebaceous (oil) gland
Arrector pili muscle

Dermis

Sensory nerve fiber

Eccrine sweat gland
Pacinian corpuscle

Artery

Hypodermis
(superficial
fascia)
Hair root
Hair follicle
Eccrine sweat
gland

Vein
Adipose tissue
Hair follicle receptor
(root hair plexus)

Figure 5.1

Figure 5.2b

Parts of the Cutaneous

Membrane
Outer epidermis:
superficial epithelium (epithelial tissues)
Composed of keratinized stratified squamous
epithelium, consisting of four distinct cell types
and four or five layers
Cell types include keratinocytes, melanocytes,
Merkel cells, and Langerhans cells
Outer portion of the skin is exposed to the
external environment and functions in protection

Inner dermis:
connective tissues (what are they?)

Innate Immunity:
An Evolutionary View
All multicellular organisms have defense mechanisms

against microbial and viral infections

For vertebrates, immune defense can be divided into
innate immunity and adaptive immunity
Vertebrate innate immune elements are closely related
to components of immunity in invertebrates
Innate immunity retains importance as
A first line of defense, slowing growth of infectious
agents until adaptive immunity kicks in
A means of directing adaptive immunity (induction of
inflammation, activation of dendritic cells, and
production of cytokines that specialize immune
responses)

The Epithelial Layer:

The initial barrier to infection
All pathogens must develop a means of getting past the
epithelium and this route is typically characteristic of for a
particular pathogen
via the airways
via the gastrointestinal tract
via the genitourinary tract
via cuts in the skin (or burns)
via mosquito bites
via dirty needles, etc.

The Epithelial Layer:

The initial barrier to infection
1.

2.
3.
4.
5.

6.
7.

Physical barrier of the epithelial layer (toughness of

barrier varies by location due to other functions: air
exchange, nutrient uptake, etc.)
Mucus/cilia to remove particles (lung, intestines)
Acid pH of the stomach
Anti-microbial peptides secreted by some epithelial cells
(small intestines, small airways of lungs)
Commensal bacteria (compete with pathogenic bacteria)
Secretory IgA (adaptive immunity)
Intraepithelial lymphocytes (adaptive immunity)

Recognition mechanisms of
innate immunity
Microbes evolve rapidly, so innate immunity

must focus on broadly expressed molecules

characteristic of broad groups of microbes
(pathogen-associated molecular patterns
PAMPs); pattern recognition receptors
Molecules recognized tend to be structural
elements that are common to broad classes of
microbes and are very hard to change (only
useful to think of them as patterns in some
cases)

Recognition of an infection once it

gets past the epithelial barrier
Soluble innate immune recognition elements
(complement)
Sentinel innate immune cells of tissues:
tissue macrophages, mast cells and immature dendritic
cells, which induce inflammation (1st two) and trigger
adaptive immunity (DCs)

or mast cell

Inflammatory mediators:
Cytokines, chemokines
and lipids
TNF

New Science Press Ltd. 2000

Inflammation
A local physiological response to tissue

injury
It is not in itself a disease, but is usually a
manifestation of disease.
May have beneficial effects:
destruction of invading microorganisms
and walling of an abscess cavity,
prevention infection spreading.
Classified into:
Acute: initial and often transient series of
tissue reaction to injury
Chronic: subsequent and prolonged tissue
reaction following initial response

Sign of inflammation
1.

Color (heat caused by blood flow)

2.

Rubor (redness caused by dilation of vessels)

3.

Tumor (swelling due to an extravascular

accumulation of fluid)

4.

Dolor (pain due to increased pressure exerted

by the accumulation of interstitial fluid and to
mediators such as bradykinin)

5.

Functio laesa (loss of function)

Inflammation
Acute
Initial response to tissue injury
Vascular component: dilatation of vessels
Exudative component: vascular leakage to protein-rich

fluid
Neutrophil polymorph is the characteristic cell
recruited to the tissue
Outcome may be resolution, suppuration (abscess),
organisation/progression to chronic inflammation

Acute inflammation (1)

Cause of inflammation
Microbial infection : pyogenic, bacteria, viruses
Hypersensitivity reactions: parasites, tubercle
bacilli
Physical agents: trauma, ionising radiation,
heat, cold
Chemicals: corrosives, acids, alkalis, reducing
agents, bacterial toxins
Tissue necrosis: infarction

Involves several processes

Vascular component hyperemia
Exudative comp. vascular leakage of protein

rich-fluid
Cellular component recruitment of

leukocytes, mainly pmn

Proliferative comp. tissue regeneration,

granulation and healing

Early stages
oedema fluid, fibrin and pmn in extracellular

spaces of damaged tissue

Involves 3 processes
(1) Changes in vessel calibre flow
(2) vascular permeability n formation of
exudate
(3) Formation of cellular component
emigration of
pmn into extravascular space

Vascular dilatation
Normal: most of
capillary bed closed
down
Acute inflammation:
sphincters open,
causing blood to flow
through all capillaries

Vascular changes:
Alteration in vessel calibre (transient

vasoconstriction) resulting in blood flow

(vasodilatation) and engorgement of downstream capillary beds erythema/warm
structural changes that permit plasma proteins
to leave circulation ( vascular permeability):
protein rich fluid to extravascular tissue
blood cells more concentrated blood
viscosity slowing circulation numerous
dilated small vessels packed with Erythrocytes
(stasis)
Neutrophils begin to settle out of flowing blood,
accumulate along endothelial surface

Cellular events :
emigration of pmn from microcirculation and
accumulation in the focus of injury (cellular
recruitment and activation)
Margination and rolling
Adhesion and transmigration,
Chemotaxis and activation (later stage)

 New Science Press Ltd. 2004

Phagocytes
Macrophages are the chief phagocytic cells
Free macrophages wander throughout a region in
search of cellular debris
Kupffer cells (liver) and microglia (brain) are
fixed macrophages

Figure 21.2a

Phagocytes A key weapon

Neutrophils become phagocytic when
encountering infectious material
Eosinophils are weakly phagocytic, but defend
against parasitic worms
Mast cells bind and ingest a wide range of
bacteria

Mechanism of Phagocytosis
Microbes adhere to the phagocyte
Pseudopods engulf the particle (antigen) into a
phagosome
Phagosomes fuse with a lysosome to form a
phagolysosome
Invaders in the phagolysosome are digested by
proteolytic enzymes
Indigestible and residual material is removed by
exocytosis

1 Microbe adheres to phagocyte.

2 Phagocyte forms pseudopods that
eventually engulf the particle.

Lysosome

Phagocytic vesicle
containing antigen
(phagosome).
3 Phagocytic vesicle is
fused with a lysosome.
Phagolysosome

Acid
hydrolase
enzymes

4 Microbe in fused vesicle

is killed and digested by
lysosomal enzymes within
the phagolysosome, leaving
a residual body.
Residual body
5 Indigestible and
residual material
is removed by
exocytosis.

(b)
Figure 21.2b

Later stages
Chemotaxis of neutrophils (pmn)
Chemical mediator of acute inflammation

spread of acute inflammation.

Histamine and thrombin release cause by
original infl.stim up regulation P-selectin and
PAF (platelet- activating actor) on endothel
Adhesion molecules appear on cell surface

Chemical mediators released from cells:

Histamine
Lysosomal compounds
Prostaglandins
Leukotrienes5-hydroxyryptamine (serotonine)
Chemokines (eg. IL-8)

Plasma factors
Coagulation system (Hageman factor/F. XII)
Kinin system
Fibrinolytic system
Complement system

Mediators of Inflammation
Pro-inflammatory cytokines (TNF, IL-1) signal to

endothelial cells to make them:

Leaky to fluid (influx of plasma; containing antibodies,
complement components, etc.)
Sticky for leukocytes, leading to influx of neutrophils first,
then monocytes, lymphocytes
Systemic effects: fever, acute phase response
ACUTE PHASE RESPONSE: cytokines induce production of
particular proteins by the liver, response to severe infection

Mediators
Can be circulating in plasma or produced locally
Plasma derived mediator: complement, kinin, coagulation

factors circulate as an inactive precursors and must

undergo proteolytic cleavage.
Induce their effect by binding to specific receptors on
target cells
May stimulate target cells to release secondary effector
molecules.
May act on only one/very few targets or have widespread
Function is usually tight regulated. Once activated and
released from cell, inactivated, then eliminated or
inhibited

Local mediators (cellular)

(1)
Preformed mediators in secretory granule
histamine (mast cell, basophils, platelet),
Serotonin (platelets),
lysosomal enzymes (neutrophils, macrophages)

Newly synthesized
Prostaglandins (leukocytes, platelets, ECs)
Leukotrienes (leukocytes)
Platelet activating factors (leukocytes, EC)
Activating oxygen species (leukocytes)
Nitric oxide (macrophages)
Cytokines (lymphocytes, macrophage, ECs)

Systemic mediators
(plasma)
Factor XII (Hageman factor) activation
Kinin system (bradykinin)
Coagulation/fibrinolysis system

Complement activation
C3a (anaphylatoxin)
C5a (anaphylatoxin)
C3b
C5b-9 (membrane attack complex)

Complement system
A cascade of enzymatic proteins. Can be

activated during acute inflammatory

reaction in various ways;

in tissue necrosis: enzyme releases fr. dying

cells
During infection:

Formation of antigen-antibody complexes can activate

complement via classical pathways
Endotoxins of Gram-negative bacteria activate
coplement via alternative pathways

Products of kinin and fibrinolytic system can

activate complement

Acute dermatitis

Role of tissue
macrophages
Secrete numerous chemical mediators
Most important: IL-1 and TNF-

(stimulatory effects occurred after

histamine and thrombin)
E-selectin: adhesion mol binds and
activate neutrophils
IL-8
Epithelial derived neutrophil attractant 78

Role of lymphatics
Lymphatic channels dilated (drain away

oedema fluid of inflammatory exudate)

Role of neutrophil
polymorph
Movement
Adhesion to micro-organisms
Phagocytosis
Intracellular killing of micro-organism
Oxygen dependent mechanims
Release of lysosomal products

The role of mast cell

Important
Under stim by C3a/C5a, release inflammatory

mediator

cellulitis
Skin (lateral part): red (erythema) due to

vascular dilatation assoc w acute

inflammation

Components of acute and chronic inflammation

Chronic inflammation
Implies the process has extended oer a long

period of time
Cellular reactions acute
Lymphocyte, plasma cells and macrophage
predominate
Granulation or scar tissue also formed

Cause:
Primary chronic inflammation: transplant
rejection
Progression from acute inflammation
Recurrent episodes of acute inflammation

Local inflammation:
acute and chronic
Acute
Stimulus: transient
Duration: brief
Phagocyte: neutrophils
Characterized by
heat, redness,
swelling and pain
Formation of pus

Chronic
Stimulus: persistent
Duration: prolonged
Phagocyte:
macrophages
Characterized by cell
proliferation
Formation of
granuloma,
macrophage, fibrotic
wall

Cells involved in chronic

inflammation

Chronic inflammation
Inflammation of prolonged duration in which active inflammation,
tissue destruction and attempts at repair occur simultaneously
Causes
Persistent damage
Persistent infection
Prolonged
exposure to toxic
agent
Autoimmunity
Significant damage
Key cells are different
MACROPHAGES
LYMPHOCYTES
NO exudate
Special types
GRANULOMATOUS

Granulomatous inflammation
What is a
granuloma? - an
aggregate of
macrophages
What causes
granulomatous
inflammation?
Infection TB
Foreign material
Reaction to tumours
Immune diseases
(sarcoid, crohns)

Failure of the barrier

Eczema
Immersion

eczema

eczema
Inflammatory skin condition have a great variety

of precipitating factors
A reaction pattern, not a single disease, several
causes, varied clinical pattern, swelling of
epidermis, characterised by inflammation and
spongiosis (due to separation of keratinocytes and
fluid accumulation

NON-INFECTIOUS
INFLAMMATORY DISEASES
Urticaria

A reaction pattern, basic lesion is oedema, clinically

characterized by itching n swelling

Lupus erythematosus
Autoimmune disease affecting connective tissue, systemic form
can involve kidneys, skin lesiohs involve epidermis n adnexa
Psoriasis
Genetically determined diseas, silvery grey scales of
parakeratosis, polymorphs enter epidermis but abscesses are
sterile
Lichen planus
No genetic/precipitating factors, drug eruptions (?) Polygonal,
itchy papules, band-like chronic inflammatory infiltrate, centred
on dermo-epidermal junction

psoriasis
Strong genetic tendency, silvery scales of

parakeratosis n bleeding when scratched superficially.

Predilection: extensor surfaces, uncommon to the face

psoriasis
Acanthotic, dermal papillae onlly covered by thin

layer ot epidermis (2-3), bleeding point,

maturation incomplete, accumulation of abn
keratin

Lichen planus
Violaceous, flat-topped and polygonal. White lines

Lupus erithematosus

Lupus erithematosus

Tuberculosis cutis

Tuberculosis cutis

Type I (IgE-mediated)
Type II (Fc and complement-mediated)
Type III (Immune complex-mediated)
Type IV (Delayed-type hypersensitivity)

An immunologic reaction which

produces tissue damage on
reexposure to antigen.

Allergic rhinoconjunctivitis (hay fever)

Asthma
Eczema (atopic dermatitis)
Acute urticaria
Anaphylaxis

Histamine
Produced almost exclusively by basophils and
mast cells (3-8 pg/cell)
Immediate pharmacologic effects:

pruritus (H1)
vascular permeability/vasodilatation
(H1)
smooth muscle contraction (H1)
gastric acid secretion (H2)

Mast Cell Mediators

Preformed
Vasoactive amines: histamine
Neutral proteases: tryptase, chymase
Acid hydrolases: -hexoseaminidase
Proteoglycans: heparin, chondroitin sulfate
Newly formed
Eicosanoids: PGD2, LTC4
Cytokines: TNF, IL-4, IL-5, IL-6

Mast Cell Tryptase

Tetrameric serine protease
Found only in mast cells, not basophils
Peaks in 1 hour and remains elevated 4-6

hours in serum following release in

anaphylaxis
Alpha isoform is predominant in blood:
most mastocytosis patients with systemic
disease have total tryptase levels that are
elevated (> 20 ng/ml) and are at least 10fold > than their tryptase level.

Injection of Histamine in
the Skin: The Triple
Local erythema - H (and some H )-mediated
Response
arteriolar dilatation
1

More widespread flare from antidromic

release of Substance P from sensory nerves

Wheal produced by increased vascular
permeability

Acute Phase Allergic Reaction:

Occurs within seconds to minutes of IgE

receptor activation (mast cell mediator release)

and resolving within an hour
Intense pruritus, edema, erythema
Almost all effects can be replicated with
histamine

Late Phase Allergic Reaction:

A delayed inflammatory response (peaking at 4-

8 hrs and persisting up to 24 hrs) following an

intense acute phase reaction
Skin: erythema, induration, burning
Lungs: airway obstruction poorly responsive to

bronchodilators
Nose/eyes: erythema, congestion, burning

Histology: mast cell degranulation followed by

influx of first neutrophils and eosinophils followed

by mononuclear cells
Major portion of effects replicated by TNF

Therapy of Allergic
Disease
Inhibition of IgE synthesis: Immunotherapy
Inhibition of IgE binding to receptor:

Monoclonal anti-IgE (Xolair (Omalizumab)

Inhibition of mast cell mediator release:

Topical corticosteroids
Cromolyn, nedocromil

Inhibition of mediator action:

Antihistamines
Leukotriene receptor antagonists
Topical and systemic corticosteroids

Type II Hypersensitivity
Examples of Type II HS:
Transfusion reactions
To ABO blood groups
To other RBC blood groups

Hemolytic disease of the newborn

(erythroblastosis fetalis)
Drug-induced hemolytic anemia (penicillin)

Type III Hypersensitivity

Immune Complex Disease
Antibody (IgG) / attaching to soluble antigen
leads to complex formation
Immune complexes may deposit in:
Blood vessel walls (vasculitis)
Synovial joints (arthritis)
Glomerular basement membrane
(glomerulonephritis)
Choroid plexus

Type III Hypersensitivity

Damage occurs due to:
Anaphylatoxin release due to complement

activation (C3a, C5a) which then attracts

neutrophils, and causes mast cell degranulation

Neutrophils have trouble phagocytosing stuck

immune complexes so they release their granule

contents leading to more inflammation

Platelet aggregation also results from complement

activation

These effects are also known as the Arthus reaction

Type III Hypersensitivity

Localized reactions
edema and redness (erythema) and tissue
necrosis of the affected tissue
Can occur in the skin following insect bites
Can occur in the lungs

E.g. farmers lung from inhaling particles from

moldy hay

Type III Hypersenstivity

Generalized reactions:
Serum sickness (following treatment with
antiserum to a toxin)
Autoimmune diseases
SLE
Rheumatoid arthritis

Drug reactions (penicillin)

Infectious diseases

Meningitis, hepatitis, malaria, mono etc.

Type IV Hypersensitivity
Delayed type hypersensitivity (DTH)
TH cells that have been sensitized by an

antigen develop a TH1 and (sometimes a TC

response) leading to macrophage recruitment
and activation.
First noticed with reaction to tuberculosis
bacteria (tuberculin reaction)
Hallmarks of type IV is the large number of
macrophages at the reaction site, and that it
takes an average of 24 hrs to manifest after
repeat exposure.

Immunopathology
Definition: Type IV reaction
The Type IV (delayed-type) reaction
does not require antibody.
Macrophages (epithelioid histiocytes) present antigen to

T-cells. The activated T-cells then release cytokines (IL12), which cause cell proliferation and recruit additional
inflammatory cells to the site.

A variant of type IV hypersensitivity is via

cytotoxic T lymphocytes (CTLs).

These CD8+ cells kill target cells (tumor cells or virus

infected cells) by recognizing foreign antigens on the cell

surface complexed with MHC Class I & kill via perforins,
very similar to the way complement kills cells with the
MAC

Type IV Hypersensitivity
(Delayed)
CD4+ T lymphocytes
mediated
- Granulomatous
diseases
- Tuberculin skin reactions
- Transplant rejection
- Contact dermatitis

Cytotoxic T lymphocyte
(CTL) mediated
- Neoplastic cell lysis
- Transplant rejection
- Virus-infected cell lysis

Type IV Reaction Contact Dermatitis