Allergy &

Hypersensitiviti
es,
 Learning Outcomes

Compare and contrast the

four types of
Hypersensitivity-
Be able to identify clinical
diseases associated with
the four hypersensitivity.
Four types of
hypersensitivity reactions
Type
I
Allergy: A type I
hypersensitivity
reaction
IgE antibodies are responsible for
type I hypersensitivity
Allergies are initiated by an interaction
between an IgE antibody and a
multivalent antigen
Free circulating IgE is usually very, very
low in concentration in blood serum
IgE only should be produced in response
to parasitic infections…BUT
Atopic individuals produce IgG
against common
environmental Ags…
Birds & Bees
 Allergy: A type I
hypersensitivity
reaction
 Atopic individuals produce IgG against
common environmental Ags
 Most are proteins or glycoproteins
 Most possess many antigenic
sites (epitopes) per
molecule
 Often have intrinsic enzymatic
properties
 May contain potential PAMPs,
stimulating innate immunity
 Many allergens enter the host via mucosal tissues at very low
concentrations, which tend to predispose the individual to generate
TH2 responses, leading to B-cell secretion of IgE
Allergy: A type I
hypersensitivity
reaction
The High-Affinity IgE
Receptor, FcεRI on
Mast cells and
Basophils
Responsible
for the
clinical
manifestatio
ns of type I
hypersensiti
vity
.
 Type I
Mediators
 Innate immune cells produce molecules responsible for
type I hypersensitivity symptoms
Innate immune cells: e for
responsibl
type I hypersensitivity
symptoms
Histamine
Formed by decarboxylation of the
amino acid histidine,
Major component of mast-cell
granules, accounting for about 10% of
granule wt.
Histamine binds one of four
different histamine receptors,
 H1contraction of intestinal and bronchial
smooth muscles
Innate immune cells: responsible
type I hypersensitivity
for
symptoms
 Leukotrienes and prostaglandins
 As secondary mediators, the leukotrienes and
prostaglandins are not formed until the mast cell
undergoes degranulation
 For example
 Asthmatic response, the initial contraction of human
bronchial and tracheal smooth muscles is at first
mediated by histamine; however, within 30 to 60
seconds, further contraction is signaled by leukotrienes
and prostaglandins.
 eukotrienes are approximately 1000 times more
effective at mediating bronchoconstriction than
is histamine
Innate immune cells:
responsible for type I
hypersensitivity
symptoms
Cytokines and chemokines
Mast cells and basophils also
release several varieties of these
signaling molecules
 IL-4 and IL-13 stimulate TH2 responses to
increase IgE production by B cells
 IL-5 recruits and activates eosinophils
 TNF-α may contribute to shock in
systemic anaphylaxis
 IL-8 acts as a chemotactic factor,
 Reactions…

Systemic
anaphylaxis
 Often initiated by an
injected or gut-absorbed
allergen
 Bee sting venom,
penicillin, seafood, nuts are
examples

 Symptoms include:
 Labored respiration
 Precipitous drop in blood pressure leading to
anaphylactic shock
 Contraction of smooth muscles leading to
defecation, urination, and bronchiolar constriction
 May lead to death by asphyxiation
 Epinephrine is the immediate treatment

 Epinephrine, the drug of choice for treating systemic

 Categories of type I
hypersensitivity
reactions
 Food allergies: a common type of atopy on the
rise
 Food allergens are
often water-soluble
glycoproteins stable
to heat, acid, and
proteases
 Can cause vomiting and
diarrhea due to smooth
muscle contraction
and gut vasodilation
Genetic Basis for Type I

Allergy-linked genes
include:
 Proteins involved in generation and regulation of
immune responsiveness
 Innate immune receptors
 Cytokines/chemokines and their receptors
 MHC proteins

Airway remodeling
genes
 Growth factors
 Proteolytic enzymes
Hyposensitizatio
n
 Diagnostic tests and
treatments are available
for type I hypersensitivity
reactions
 Hyposensitization
 Repeated low-dose
exposures may
induce
an increase in
regulatory T cells
and
their
cytokines
 May also induce
competitive IgG subtypes
 IgE receptor signaling
is tightly regulated

IgE receptor signaling is tightly

regulated
Co-clustering with inhibitory
receptors
Mast cells express both FcεR1 (activating)
and FcγRIIB (inhibiting) Ig receptors
 If a cell binds IgE and IgG, the
inhibiting signal induced by IgG
binding wins out
This is partially why inducing IgG in
Type
II
 Antibody-mediated
Type II

Transfusion reactions are an example of type

II hypersensitivity
 Involve Ab-mediated destruction of cells by non-IgE
Ab
 Blood group Ag are carbohydrates
 Adults possess antibodies to the blood type they
do NOT have
 If they receive a transfusion of the “wrong” type
of blood, their antibodies will quickly attach to
the donor blood cells and trigger complement
proteins
Type II
Antibody Antigen
Complexes
 Antibody bound to a cell-surface antigen can induce death of
the antibody-bound cell by three distinct mechanisms
 activate the complement system
 cell destruction by antibody-dependent cell-mediated
cytotoxicity (ADCC), Via Fc receptors on cytotoxic to Fc of AB
targeted cell
 Opsonins

 Tissue Specific
Type II
 Tissue Specific

 Ab finds an Ag in the tissue

 Inflammation
 Neutrophil damage
 Complement damage

 Clinical Disease
 Graves Disease hyper thyroidism TSH mimicing
Ab.
Type
III
Immune Complex-Mediated
(Type III) Hypersensitivity
 Occurs when immune complexes are
inefficiently cleared and may be deposited
in the blood vessels or tissues…
(1) the presence of antigens capable of
generating particularly extensive
antigen- antibody lattices,
(2) a high intrinsic affinity of antigens
for particular tissues,
(3) the presence of highly charged
antigens (which can affect immune
complex engulfment)
(4) a compromised phagocytic system
Arthriti
s
 The total cost of arthritis in the US was an estimated
$128 billion,
 split between $81 billion in direct medical expenses
and
$47 billion in related losses of productivity and
care management.

 Arthritis affects 23 percent of adults in the US, or 41

million people, and is expected to rise to 78 million
cases by 2040.
 Arthritis also occurs with other chronic conditions as
many patients are unsure on how to manage their
own symptoms.
Mechanism..
Immune
complexes bind
to mast cell,
neutrophils &
macrophages
Via Fc…
 Immune Complex-Mediated
(Type III) Hypersensitivity

 Immune Complex formation in Blood then

gets trapped
 Deposition of MEDIUM size complexes
 Kidneys filtration high blood pressure
pushing through
 Blood vessel walls usually targets small
blood vessles
 Joints – have filter in joints and the
complex forms
May trigger release of
inflammatory mediators
and vasoactive mediators
Proteases released may
damage connective tissues
Clots may form as
complexes activate
platelets
 Symptoms include fever, rashes,
joint pain, lymph node
enlargement, and protein in the
urine
Vasculitis if in blood vessel
Glomerulonephritis if in kidney
Type
III
Type IV
 Delayed-type (type
IV) hypersensitivity
(DTH)
 Purely cell-mediated rather
than Ab mediated

 Initiated by T cells

 Requires a delay for the reaction

to develop

 Characterized by recruitment of
macrophages at inflammation site

 Poison ivy contact dermatitis is the

most common example
Poison Ivy
Reaction….
Type IV
Hypersensitivi
ty
 Delayed-type
(type IV)
hypersensitivi
ty (DTH)

 The effector phase of a classical DTH response is induced by

second exposure to a sensitizing Ag
 A prolonged inability to clear Ag (as seen in TB cases) can
result in formation of destructive
 Multinucleate giant cells
 Granulomas
 Type IV
 Cell Mediated
 CD* or CD4
 Tissue Destruction

 Delayed

 Examples of Disease
 Crohns Disease – attaches the gastroinstestinal
 Multiple Scherosis- attacks mylein sheaths and
 Jouvanile Diabetes – attacks the beta cells can nto make
insulin
 Hashimoto Disease – T-cells destroy the thyroid
Transplant Rejection
Transplant Rejection
 LEADS TO VASCULAR DAMAGE AND DEATH
OF THE ORGAN

 Cyclosporin used to fight this rejection

 Cyclosporin blocks IL-2 – without this can
not be effectors or developm memory
cells
Delayed-type (type
IV) hypersensitivity
(DTH)DTH reaction can be detected by
The
a skin test
 By injecting a small amount of Ag under the skin
 If a red, slightly swollen, firm lesion develops in 48–72 hours,
the test is positive
 This indicates the individual has a population of sensitized
TH1 cells against the Ag
 This does NOT indicate if an active infection is occurring or if
the individual already overcame an infection (leaving memory
cells)
 Commonly used in the United States to test for
tuberculosis exposure
Delayed-type (type
IV) hypersensitivity
(DTH)
 Contact dermatitis is a type IV
hypersensitivity response
 Sensitization can occur if a reactive
chemical compound binds to skin proteins
 Modified proteins are then presented to T
cells
 Could be induced by pharmaceuticals,
cosmetics, industrial chemicals, metal ions, etc.
 Can cause strong cell-mediated responses
against skin cells, inducing blister-like lesions and
rashes
Intracellula …
r
 Chronic

Inflammatio
n
Chronic
inflammatio
n
Chronic inflammation
 Infections can cause chronic inflammation
 Continual microbial invasion can induce
chronic inflammation
 Gum disease
 Unhealed wounds
 Failure of tolerance mechanisms to gut
microbes
 Some microbes are ineffectively cleared,
inducing chronic inflammation
 Certain fungal and mycobacterial infections
Chronic
inflammation
 There are noninfectious causes of
chronic inflammation
 Damage-associated molecular patterns
(DAMPs)
 Self Ag released by certain conditions
associated with damage
 Tumors
 Autoimmune diseases
 Atherosclerosis and heart disease
 Obesity
 Each capable of inducing long-term inflammation
Chronic
inflammation
 Obesity is associated with chronic inflammation
 Visceral adipocytes are secretors of
proinflammatory cytokines
 TNF-α
 IL-6
 May trigger other disease states associated
with chronic inflammation
Chronic
Inflammation
 Chronic inflammation can cause systemic
disease
 
Chronic inflammation
TNF-α/IL-6 and insulin
induce signaling resistance
cascades that inhibit ability of
insulin receptors to function
 Greater obesity linked to greater Type 2 diabetes
 Lose the fat, get insulin response back (sometimes)
 Chronic inflammation and susceptibility to other diseases
 Inflammation can drive blood vessel production and wound
repair mechanisms
 Too much can lead to excessive tissue scarring (fibrosis)
 Could also promote tumor formation and enhance production
of feeding blood vessels in tumors
Summar
y
 Hypersensitivities are examples of a good
thing gone wrong
 Each type represents an immune response
initiating harm rather than help
 Each has slightly different triggers and outcomes,
but each is potentially very serious
 Understanding each type allows clinicians to
intervene more effectively, alleviating
symptoms