CLINICAL

IMMUNOLOGY
 Hypersensitivity
● Hypersensitivity (also called hypersensitivity reaction or intolerance)
is an abnormal physiological condition in which there is an undesirable
and adverse immune response to antigen.

● It is an abnormality in the immune system that causes immune diseases

including allergies and autoimmunity.
 Types of hypersensitivity
The Gell and Coombs classification of hypersensitivity is the most widely
used, and distinguishes four types of immune response

▪ Type 1 (IgE mediated immediate reaction)

▪ Type 2 (antibody-mediated reaction mainly involving IgG or IgM)
▪ Type 3 (immune complex-mediated reaction involving IgG)
▪ Type 4 (cytotoxic, cell-mediated, delayed hypersensitivity reaction
involving T cells)
 TYPE 1 HYPERSENSITIVITY

● Type I hypersensitivity (or immediate hypersensitivity) is

an allergic reaction provoked by re-exposure to a specific type
of antigen referred to as an allergen.

● Exposure may be by ingestion, inhalation, injection, or direct contact.

 Type 1 (IgE mediated immediate reaction)
Alternative Name

• Allergy
• Immediate
• Anaphylactic

Antibodies or Cell Mediator

Antibody IgE

Immunologic Reaction
• Fast response which occurs in minutes, rather than multiple hours or days. Free
antigens cross link the IgE on mast cells and basophils which causes a release
of vasoactive biomolecules. Testing can be done via skin test for specific IgE
 ALLERGIES

❑ Allergies arise if the body's immune system

overreacts to certain foreign substances
(allergens) that are normally harmless in
most people.

❑ Allergen – exogenous antigens usually

harmless substance capable of triggering a
response that starts in the immune system
and results in an allergic reaction.
 Allergens
▪ pollens
▪ fungal spores
▪ house-dust mites
▪ animal epithelial materials
▪ drugs
▪ biologic products
▪ insect venoms
There are two stages to type 1 hypersensitivity: the sensitization
stage and the effect stage

• During the sensitization stage, the person encounters the antigen

but does not experience any symptoms.

• During the effect stage, the person has exposure to the antigen
again. As the body now recognizes the antigen, it is able to produce a
response that results in the symptoms that people typically experience
with an allergic reaction.
 Pathophysiology

● TH2 is involved in Type 1 Hypersensitivity.

● The activation of TH2 and the binding to the B

cells stimulates the B cells to undergo class
switching; that is, The B cells that are capable
of producing IgM and IgG, upon stimulation by
TH2 cells, switch to produce Ig E antibody.
The B cells produce a specific IgE to the
exposed allergen.
● In type I hypersensitivity, B cells are stimulated
(by CD4+ Th2 cells) to produce IgE antibodies
specific to an antigen. During sensitization, the
IgE antibodies bind to FcεRI receptors on the
surface of tissue mast cells and blood basophils.

● Mast cells and basophils coated by IgE

antibodies are "sensitized". Later exposure to
the same allergen cross-links the bound IgE on
sensitized cells, resulting in anaphylactic
degranulation, which is the immediate and
explosive release, of histamines and lipid
mediators

● The principal effects of these products

are vasodilation and smooth-muscle contraction.
 ● Within minutes of exposure to an
antigen, the immediate
hypersensitivity occurs, releasing
histamines and lipid mediators which
are responsible for the initial allergic
reaction response.

● The reaction may be either local or

systemic. Symptoms vary from mild
irritation to sudden death
from anaphylactic shock.
 Allergic Reaction Phases
● Early Phase
● The early phase of an allergic
reaction occurs within minutes
of an allergen exposure. This is a
result of histamine release from
mast cells, which causes
vasodilation, edema and
congestion.
Late Phase

● The late Phase of allergic reaction

occurs 2 to 24 hours after the
allergen exposure. This is an
inflammatory process in which
eosinophils, neutrophils and T cells
infiltrate the area. A cough and
wheezing may persist in the patient,
along with swelling and redness of
the skin.
 Allergic rhinitis
● Allergic rhinitis, also called hay fever, is an allergic reaction that causes
sneezing, congestion, itchy nose and watery eyes. Pollen, pet dander, molds
and insects can lead to hay fever symptoms.
 Antihistamines
● Antihistamine medications are available with a prescription or
over the counter (OTC). They work by blocking the histamine
that your body releases during an allergic
response. Antihistamines come as pills, liquids, eye drops,
nasal sprays and inhalers. They include:
• Loratadine (Claritin®).
• Cetirizine (Zyrtec®).
• Fexofenadine (Allegra®).
• Levocetirizine (Xyzal®).

● Antihistamines can cause drowsiness. Avoid alcohol when

taking antihistamines, especially if you’re going to drive
 Mode of action

● Antihistamines block the

effects of histamine in
your body by binding to
the H-1 receptor
 Decongestants
● These medications relieve congestion in your nose and sinuses. You can take
decongestants by mouth (in pill or liquid form) or use a nasal spray.

• Afrin® nasal spray.

• Phenylephrine nasal spray (Neo-Synephrine®).
• Pseudoephedrine (Sudafed®).

● Decongestants can increase blood pressure and cause headaches, trouble

sleeping and irritability. Nasal decongestants can be addictive when you use
them for longer than five days
 Allergic Asthma
● Type of asthma, allergic asthma is a condition where your airways tighten
when you breathe in an allergen. This can be something in the air — often
pollen, dander or mold spores.
● high amounts of IgE can cause your airways to tighten, making it difficult to
breathe.
● Asthma is a disease of the lungs that causes your airways to:
• Become swollen or irritated (called inflammation) specifically in the airway
linings.
• Produce large amounts of mucus that is thicker than normal.
• Narrow because the muscles around the airways tighten.
• Feeling short of breath.
• Coughing frequently, especially at
night.
• Wheezing (a whistling noise during
breathing).
• Experiencing chest tightness (feels
like something is pressing or
squeezing your chest)
 Hives

● Hives, also known as urticaria, is a kind

of skin rash with red, raised, itchy
bumps. Hives may burn or sting. The
patches of rash may appear on different
body parts, with variable duration from
minutes to days, and does not leave any
long-lasting skin change
 Causes (Allergens)
Medications
● Drugs that have caused allergic reactions evidenced as hives
include codeine, sulphate of morphia, dextroamphetamine,
aspirin, ibuprofen, penicillin, clotrimazole,
trichazole, sulfonamides, anticonvulsants, cefaclor, piracetam, vaccines,
and antidiabetic drugs
● Food
● The most common food allergies in adults are shellfish and nuts. The
most common food allergies in children are shellfish, nuts, eggs, wheat,
and soy. One study showed Balsam of Peru, which is in many processed
foods, to be the most common cause of immediate contact urticaria.
Another food allergy that can cause hives is alpha-gal allergy, which may
cause sensitivity to milk and red meat.
● Infection or environmental agent
● Hives including chronic spontaneous hives can be a
complication and symptom of a parasitic infection, such
as blastocystosis and strongyloidiasis among others.
 FOOD ALLERGY

● A food allergy is an abnormal immune

response to food. The symptoms of the
allergic reaction may range from mild
to severe. They may include itchiness,
swelling of the tongue, vomiting,
diarrhea, hives, trouble breathing, or
low blood pressure. This typically
occurs within minutes to several hours
of exposure. When the symptoms are
severe, it is known as anaphylaxis
● Common foods involved include cow's
milk, peanuts, eggs, shellfish, fish, tree
nuts, soy, wheat, and sesame.
● The common allergies vary depending on the
country. Risk factors include a family history
of allergies, vitamin D deficiency, obesity, and
high levels of cleanliness. Allergies occur
when immunoglobulin E (IgE), part of the body's
immune system, binds to food
molecules. A protein in the food is usually the
problem.This triggers the release of
inflammatory chemicals such as histamine
 Anaphylaxis
● Anaphylaxis is a severe allergic reaction that
needs to be treated right away.

● Anaphylactic shock results from a severe allergic

reaction. It causes blood pressure to drop and
narrows your airway, making breathing difficult

● If you have an anaphylactic reaction, you need

an epinephrine (adrenaline) shot as soon as
possible, and someone should call 911 for
emergency medical help. Left untreated, it can
be deadly.

● Epinephrine can reverse the symptoms within

minutes.
● You shouldn’t take an antihistamine for an
anaphylactic reaction.
 There 5 common types of allergens found in the Philippines.

These are the most common allergens in the Philippines.

● a. Molds: Molds grow during warmer months in moist and damp places.
● b. Dust Mites: These pests are found in beds, sofas, and even carpets. They tend to
multiply fast.
● c. Pollen: Pollen is responsible for seasonal allergies. It is a fine powdery substance made
up of pollen grains from the plants.
● d. Fish and Seafood: Fish is the most common food allergy in the Philippines.
● e. Pet Dander: Pet dander is the most common allergy from pets. It ranges from the pet’s
saliva, urine, and skin.
● Allergy tests are performed to help you pin down the specific cause of
your allergic reactions. The different types of allergy tests are:

● – Skin Prick Test

● – Intradermal Skin Test
● – Patch Test
● – Blood Test
● Testing

○ In-Vivo Tests - Skin tests

■ Small amount of allergen injected into skin

■ Look for wheal formation of 3mm or greater in

diameter

■ Simple, inexpensive, can screen for multiple

allergens.

■ Stop anti-histamines 24-72 hours before test.

■ Danger of systemic reaction

■ Not for children under 3

 Type I (Immediate) Hypersensitivity
The reactions shown here demonstrate allergic response.
 Type 2 hypersensitivity reaction
● Type II hypersensitivity, in the Gell and Coombs
classification of reactions, is an antibody mediated process in
which IgG and IgM antibodies are directed against antigens on
cells (such as circulating red blood cells) or extracellular
material (such as basement membrane).
● This subsequently leads to cell lysis, tissue damage or loss of
function through mechanisms such as

1. Complement system activation

2. Antibody-dependent cellular cytotoxicity or
3. anti-receptor activity
These reactions usually take between 2 and 24 hours to develop
 Cytotoxic Reaction Etiology
Cytotoxic reactions cause cellular toxicity via structural damage or lysis of cells in the body.
 Triggered by antigens found on cell surfaces
 Altered self antigens
 Heteroantigens (Foreign antigens)

• The antibodies induce cytotoxic reactions when they adhere to antigens on the surface of
healthy cells in the body and flag them for destruction by aggressive effector cells. Type II
hypersensitivity reactions are known as antibody-dependent cytotoxicity reactions
because IgG and IgM antibodies bind to self-antigens, targeting them for other cells to
destroy.
 Complement activation
• The binding of an IgG or IgM to an antigen can activate the complement system and
cause the lysis of the antigen by the membrane attack complex (MAC) or by
Phagocytosis.

• The activation of the complement system results in opsonization, the agglutination

of red blood cells, cell lysis, and cell death.
 Opsonization and Phagocytosis
• The antibody binds to the antigen and makes it a target for Phagocytosis, a process
known as opsonization.
• Antibody coats cell surface promotes phagocytosis – macrophages, neutrophils and
eosinophils have Fc receptors to bind to antibody on target cell.

Fc receptors bind to antibodies that are

attached to infected cells or invading
pathogens.
Antibody-dependent cellular cytotoxicity
(ADCC)
An IgG binds to the surface antigen on the infected cell. The NK cells recognize and
kill the antibody coated infected cell. Natural Kill cells have Fc receptors, bind to
antibodies, results in cytotoxicity
 Anti-receptor activity
Type II hypersensitivity reactions cause a type of autoimmune reaction in which
antibodies bind to cell receptors in a way that causes dysfunction.
Ex. Antibodies bind to receptors on the thyroid causing over-expression of thyroid
hormone
Three Examples of Type II Hypersensitivity
Reactions
• Transfusion Reactions
• Occurs with ABO blood antigen groups

• Complement mediated lysis

• Hemolytic Disease of the Newborn

• Grave’s Disease
 Transfusion reactions
 Hundreds of different antigens expressed on RBCs
 Antibodies can be produced naturally or through exposure, transfusion or
pregnancy
 Most well known example due to ABO incompatibility.
 Individuals form potent antibodies against ABO antigens not present on their red
blood cells.
 Group O individuals have anti-A and if transfused with group A blood will have an
immediate, and possibly fatal, reaction
 Other blood groups may cause delayed reaction or acute reactions.
Red blood cell antigens determine your blood group:
The antigens expressed on the red blood cell determine an individual's blood group.
The main two blood groups are called ABO (with blood types A, B, AB, and O) and
Rh (with Rh D-positive or Rh D-negative blood types).
-The differences in human blood types, are due to the presence or
absence of certain molecules called antigens which are present on the
surface of the RBCs.

-The antigens are located on the surface of the red blood cells.

- The antibodies, are in the blood plasma to attack foreign antigens,

resulting in clumping (agglutination).

-Antigens are also found in a wide variety of tissues and biological

fluids such as saliva, milk , seminal fluid, urine , and gastric juice.
 Agglutination
• The blood will agglutinate (clump) if the antigens in the patient's blood match the
antibodies. A antibodies attach to A antigens - they match like a lock and key -
and thus form a clump of red blood cells.

• This antibody-antigen reaction causes severe clumping (agglutination) of the

red blood cells. Agglutination tends to block blood vessels, resulting in brain and
kidney damage and, ultimately, death
ABO Blood Type System
 Importance of The ABO System

• Blood group antigens must be determined

to secure a safe practice of blood
transfusion.
• They are also useful in determining familial
relationships in forensic medicine.
Genetics of Blood Types

Codominance
is a condition in which the alleles of a gene
pair in a heterozygote are fully expressed
thereby resulting in offspring with
a phenotype that is
neither dominant nor recessive
 Rhesus Blood Group

• Is the second most significant blood group system in human transfusion.

• The D antigen (RhD)
• Rh(D) status of an individual, is normally described with a positive or negative suffix
after the ABO type. If it is present or absence on RBCs’ surface respectively.

• So, for example, some people in group A will have it, and will therefore be classed
as A+ (or A positive), while the ones that don't, are A- (or A negative). And so it goes
for groups B, AB and O.
 Rhesus (Rh)
• The positive or negative sign next to the blood groups is known as the Rhesus (Rh)
factor. The Rh factor is an inherited protein that can be found on the surface of the red
blood cell. Researchers applied the Rh designation after initially discovering the antigen
group in rhesus macaque primates.

• Unlike ABO blood type, no anti-Rh antibodies are present in Rh- individuals unless they
have been exposed to Rh antigens. If Rh+ blood is introduced into an Rh- individual, anti-
Rh antibodies will be produced against the Rh(+) blood
 Rh Blood Group Transfusion
• A person with Rh+ blood can receive blood from a person with Rh- blood without any
problems
• A person with Rh- blood can develop Rh antibodies in the blood plasma if he or she
receives blood from a person with Rh+ blood, whose Rh antigens can trigger the
production of Rh antibodies

Note: that the blood group ABO, should be considered along with Rh group.
 Principle Of Test

Type B Anti B Agglutination Hemolysis

blood gp antibodies

Seen as the
picture
Results
Transfusion reaction
Produced by mismatched blood types
Destroys foreign RBC by complement-mediated
lysis triggered by IgG
Produces fever, intravascular clots, lower back pain,
Hemoglobin (Hgb) in urine

Free Hgb produced has 2 fates:

passes to the kidneys – hemoglobinuria
Breaks down to bilirubin..can be toxic
 Hemolytic Disease of The Newborn (HDN)
• Also called, Erythroblastosis Fetalis
• Mother is Blood type Rh-, Father and fetus are Rh+
• First pregnancy = sensitization at delivery due to hemorrhage
• Second pregnancy = Mother produce anti-Rh IgG antibodies that
cross placenta to attack fetal RBCs leading to hemolysis
 HDN happens when an Rh negative mother
has a baby with an Rh positive father. If the
Rh negative mother has been sensitized to
Rh positive blood, her immune system will
make antibodies to attack her baby. When the
antibodies enter the baby's blood, they will
attack the red blood cells. This causes them
to break down.

• Exposure to Rh+ fetal RBC’s stimulates production

of memory/plasma
• Activation of memory cells in subsequent pregnancy
stimulate IgG Ab’s which can cross the placenta
• mild-severe hemolytic anemia ensues along with
bilirubin which affects the brain/CNS
• Treatment centers on anti-Rh antibodies (Rhogam)
• Mothers can be tested for anti-Rh antibodies
• Isolated fetal RBC’s can be checked for anti-Rh IgG
w/ Coombs test
 Grave’s Disease
● Graves’ disease is an autoimmune disorder that
can cause hyperthyroidism, or overactive
thyroid. The thyroid is a small, butterfly-
shaped gland in the front of your neck.
Thyroid hormones control the way your body
uses energy, so they affect nearly every organ
in your body, even the way your heart beats.
● With Graves’ disease, your
immune system attacks your
thyroid gland, causing it to
make more thyroid hormones
than your body needs. As a
result, many of your body’s
functions speed up.
Graves' ophthalmopathy.
 Pathophysiology
● Graves' disease is an autoimmune disorder, in
which the body produces antibodies that are
specific to a self-protein - the receptor for thyroid-
stimulating hormone. These antibodies cause
hyperthyroidism because they bind to the TSH
receptor and chronically stimulate it.

● The result of chronic stimulation is an abnormally

high production of T3 and T4. This, in turn, causes
the clinical symptoms of hyperthyroidism, and the
enlargement of the thyroid gland visible as goiter.
THYROID-STIMULATING antibodies
(TSAb) are IgG that bind to and activate
the TSH receptor.
● The three treatment options are radioiodine therapy, medications,
and thyroid surgery.Radioiodine therapy involves taking iodine-131 by
mouth, which is then concentrated in the thyroid and destroys it over
weeks to months.
Thank you for
listening!