HYPERSENSITIVITY REACTIONS TYPE IV- Delayed-Type Hypersensitivity

(DTH)
Hypersensitivity reactions are
exaggerated or inappropriate immune
responses that may develop in the
humoral or cell-mediated responses
Being sensitized, or immunized, is truly
beneficial but if the immune system is
aggressively triggered causing tissue
damage or complications NOT GOOD

DEFINITON OF TERMS

Allergy
Altered reaction to external
substances
Heightened reactivity of Immune
System in response to external
substances
Allergens TYPE I. IMMEDIATE OR ANAPHYLACTIC
Antigens that trigger allergic HYPERSENSITIVITY
reactions
Antibody involved: IgE
Atopy
Effector cells: Tissue Mast Cells and
Inherited tendency to respond to
circulating Basophils
naturally-occurring inhaled or
Mediators: Histamine, Heparin,
ingested allergens via continued
Eosinophil Chemotactic Factor (ECF)
production of IgE
Clinical States:
Anaphylaxis
Hay fever, asthma, food allergies,
Systemic hypersensitivity involving
anaphylactic shock
many organs
Most severe type of allergic PRODUCTION AND SUPPRESION OF IgE
response
Cells having high affinity for IgE are
4 TYPES OF HYPERSENSITIVITY REACTIONS those with FcE-RI which binds to Fc
portion of IgE
TYPE I- IgE mediated
Cells: Eosinophils, Basophils, Mast Cells
TYPE II- Antibody-Mediated (IgG and IgM) Suppresors of IgE production:
Th1 = secretes IFN-y
TYPE III- Immune Complex-Mediated
Macrophage = secretes IL12/ IL18

JKP, RLG, RRB Page 1

 Th2 responds to produce: TYPE I: IgE-MEDIATED HYPERSENSITIVITY
IL4, IL13- responsible for B cell
differentiation (IgE production)
IL5, IL9- Development of Eosinophils
IL4, IL9- Maturation of Mast Cells
IL4, IL9, IL13- Overproduction of
Mucus

EFFECTS OF HISTAMINE

Bronchial smooth muscle

Histamine causes contraction of
bronchial smooth muscle, thus
narrowing the airways =
manifestation of ASTHMA
Intestinal smooth muscle
Histamine activation of H1 receptors
produces constriction of intestinal
smooth muscle, which results in
increased bowel peristalsis and
diarrhea
Peripheral nervous endings
Histamine stimulates sensory nerve
endings, especially those mediating
pain and itchiness. This effect is
responsible for pain and itch after an
injury such as insect bite

JKP, RLG, RRB Page 2


TYPE II. CYTOTOXIC HYPERSENSITIVITY
Antibodies involved: IgG and IgM
Antigens: Cellular or Cell-bound
Reactions involved antibodies directed
to antigen on surface of specific cells or
tissues resulting to cytolysis
(complement activation)
CLINICAL STATES:
Hemolytic Transfusion Reactions,
(HTRs), Hemolytic Disease of the
Newborn (HDN), Goodpastures
Syndrome, Myasthenia Gravis,
Graves Disease
MECHANISMS OF CYTOLYSIS
Cell Lysis results due to:
1. Complement Fixation to antigen
antibody complex on cell surface.
The activated complement will lead
to cell Lysis (MAC).
2. Phagocytosis is enhanced by the
antibody (opsonin) bound to cell
antigen leading to opsonization of
the target cell.
JKP, RLG, RRB
3. Antibody Dependent Cell-mediated
Cytotoxicity (ADCC):
Antibody coated cells (e.g. tumor
cells, parasites, graft cells, or
infected cells)
The process is different from
phagocytosis and independent
of complement
Cells most active in ADCC are:
NK cells, macrophages, and
eosinophils
HEMOLYTIC TRANSFUSION REACTION
(HTR)
The most common cause of an acute
hemolytic transfusion reaction is the
transfusion of ABO group-incompatible
blood
Person who are transfused with the
wrong blood type will produce anti-
hemagglutinins causing complement
mediated lysis
Transfusion reactions can be delayed
(DHTR) or immediate but have different
isohemagglutinins
Associated with the infusion of
incompatible erythrocytes
DHTR = 7-10 days after
Page 3
 HEMOLYTIC DISEASE OF THE NEWBORN When drug is withdrawn the hemolytic
(HDN) anemia disappears

This is where maternal IgG antibodies

specific for fetal blood group antigens
cross the placenta and destroy fetal
RBCs
Erythroblastosis fetalis- Severe
hemolytic disease of newborns
Most commonly develops when an
Rh+ fetus expresses an Rh antigen on
its blood that and Rh- mother
doesnt
PERNICIOUS ANEMIA

PA is caused by a deficiency of vitamin

B12 that results from the patients
inability to secrete Intrinsic Factor
Stomach
Parietal Cell- HCl
and Intrinsic
Factor (IF) for
absorption of
vitamin B12
(cobalamin)
Chief Cell-
pepsinogen---HCl-
--pepsin-protein
digestion
DRUG-INDUCED HEMOLYTIC ANEMIA
Antibody to parietal
(DIHA)
cells lysis-
This is where certain antibiotics can
decreased IF and
absorb nonspecifically to the proteins
decreased B12
on RBC membranes
IF-blocking antibodies
Examples: methyldopa, penicillin,
streptomycin
Sometimes antibodies form inducing
complement-mediated lysis and thus
progressive anemia

JKP, RLG, RRB Page 4

 MACROCYTIC CELLS (MEGALOBLASTIC
ANEMIA)

AUTOIMMUNE IDIOPATHIC
THROMBOCYTOPENIC PURPURA (AITP)

GOODPASTURES SYNDROME

JKP, RLG, RRB Page 5


Idiopathic Thrombocytopenic Purpura
(ITP) is an autoimmune disorder that
results to increased platelet destruction
or shortened platelet survival due to
presence of antibody bound to platelets
TYPE III. IMMUNE COMPLEX
HYPERSENSITIVITY
Antibodies involved: IgG and IgM
Antigen is soluble
Affects organs where antigen-antibody
reactions are deposited
CLINICAL STATES:
Arthus Reaction, Rheumatoid
Arthritis, SLE, Glomerulonephritis,
Serum Sickness
TYPE III- IMMUNE COMPLEX-MEDIATED
HYPERSENSITIVITY
Reaction with antibodies create immune
complexes
Failure to clear off immune complex by
phagocytosis
Large amounts of immune complexes
can lead to deposition and tissue
damage (Type III reaction)
JKP, RLG, RRB
The magnitude depends on the
quantity of immune complexes and
their distribution
RHEUMATOID ARTHRITIS
Presence of autoantibodies against
citrullinated proteins in Rheumatoid
Arthritis (RA) patients
Arginine in protein is converted into
citrulline during inflammation
Serologically looking for the presence
of: anti-cylic citrullinated protein (anti-
CCP) Abs
ARTHUS REACTION
The Arthus reaction is a type of local
type III hypersensitivity reaction which
involves deposition of antigen/antibody
complexes mainly in the vascular walls,
serosa (pleura, pericardium, synovium)
and glomeruli.
Injection of an Antigen( live-attenuated
vaccines):
Can lead to an acute Arthus reaction
within 4-8 hours
Page 6
 Localized tissue and vascular GLOMERULONEPHRITIS
damage result from accumulation of
fluid (edema) and RBC (erythema)
Severity can vary from mild swelling
to redness to tissue necrosis

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

SLE is an autoimmune disease in which

the bodys immune system mistakenly
attacks healthy tissue.
IN THE LAB TEST FOR:
ANA (Antinuclear antibody)
SERUM SICKNESS
Anti-DSDNA
A systemic immune complex
phenomenon
Injection of large doses of foreign serum
(from animals)
Resulting in formation of large amounts
antigen-antibody complexes
Immune complexes are deposited in
various sites
10 days after injection:
Fever
Urticaria
Athralgia
Lymphadenopathy
Splenomegaly
Glomerulonephritis

JKP, RLG, RRB Page 7

TYPE IV. CELL-MEDIATED/DELAYED-TYPE
HYPERSENSITIVITY

Reaction involves sensitized T cells and

release of its lymphokines as mediators
and amplifiers
Mediated by cells rather than antibodies
no Ab involvement
CLINICAL SITES:
Contact dermatitis, GVHD
reactions, Transplant rejection, PPD
(Tuberculin Test for MTB)

TYPE IV HYPERSENSITIVITY

A.K.A. cell mediated hypersensitivity or

delayed type hypersensitivity
A hypersensitive response mediated by
sensitized TDH cells, which release
various cytokines and chemokines
Generally occurs 2-3 days after TDH cells
interact with antigen
An important part of host defense
against intracellular parasites and
bacteria

PHASES OF DTH RESPOSNE

Sensitization phase: occurs 1-2 weeks

after primary contact with Ag What happens if the DTH response is
What happens during this phase? prolonged?
TH cells are activated and clonally o A granuloma develops
expanded by Ag presented together Continuous activation of
with class II MHC on an appropriate macrophages
APC, such as macrophages or induces the
Langerhans cell (dendritic epidermal macrophages to
cell) adhere closely
Generally CD4+ cells of TH1 subtype to one another,
are activated during sensitization assuming an
and designated as TDTH cells epithelioid

JKP, RLG, RRB Page 8

 shape and sometimes fusing
together to form giant,
multinucleated cells

SKIN TESTING/MANTOUX TEST

The Mantoux Test or Mendel-Mantoux

Test (also known as Mantoux screening
test, tuberculin sensitivity, Pirquet test,
or PPD test for purified protein
derivative) is a screening tool for
pulmonary tuberculosis
DIABETES MELLITUS TYPE I

In insulin-dependent (type 1) diabetes, T

cells respond to pancreatic islet cell
antigens, damaging the islets and
eventually preventing insulin secretion.

JKP, RLG, RRB Page 9

CONTACT DERMATITIS SICCA/ SJOGRENS SYNDROME

HYPERSENSITIVITY PNEUMONITIS

Allergic disease of the lung parenchyma

characterized by inflammation of the
alveoli and interstitial spaces
Caused by chronic exposure to allergens
Seen mostly in men aged 30-50 years
old
TYPE V HYPERSENSITIVITY REACTION
STIMULATORY REACTION
Other names: farmers lung, pigeon
breeders disease, and humidier lung Activation/ Inhibition
disease Mediated by antibodies (IgG)
Involving dust cells/ alveolar Subtype of Type II
macrophage Examples:
Allergens: moldy hay, compost, pigeon DM II
droppings, infested flour, moldy Myasthenia gravis
tobacco, moldy cheese Graves Disease

JKP, RLG, RRB Page 10

MYASTHENIA GRAVIS DIABETES MELLITUS TYPE II

A condition causing abnormal weakness

of certain muscles
A rare chronic autoimmune disease
marked by muscular weakness without
atrophy, and caused by a defect in the
action of acetylcholine at
neuromuscular junctions

GRAVES DISEASE

JKP, RLG, RRB Page 11

Parameter Type 1 Type 2 Type 3 Type 4 Type
5
Antibody IgE IgG and IgM IgG and IgM None
Antigen Soluble Cellular antigen Soluble Both
Chemical Histamine Complement- Complement- Cytokines
Mediator C3b C3b
Cell Mast Cells Macrophage Macrophage T Cells
Mediator Phagocytes Phagocytes Macrophage
Response 15-30 Minutes Minutes-Hours 3-8 Hours 48-72 Hours
Time
Outcome/ Effect of Cell Destruction Tissue Recruitment of
Endpoint Histamine Destruction T-cell &
macrophage
Other Immediate Cytotoxic Immune- Delayed-Type
Names Hypersensitivity Hypersensitivity Complex Hypersensitivity
Hypersensitivity
Examples Asthma HTR SLE Contact
Hay Fever HDN Arthus Dermatitis,
Food Allergies DIHA Serum Sickness Type I DM,
Etc. PA Etc. Sjogren
GD
GS
Etc.

JKP, RLG, RRB Page 12