In the name of Allah

Hypersensitivity reactions
Basic Immunology Introduction:
The main role of the immune system is to discriminate between self & non self antigens. Although the
immune system is supposed to protect us from foreign harmful antigens, it can lead sometimes to diseases
and abnormal conditions due attack of the self. In general, one of the main dysfunctions in the
hypersensitivity reaction is that there is failure of the self- non self recognition; the immune system attacks
the self antigens; this may occur in all the types of hypersensitivity reaction. The term Sensitive relates to
the idea that being sensitive to something, being protected from it, being capable of responding against it,
and it started from being protected against the infectious agent, that is to say, you are sensitive to
something, you are capable to react against it, you are protected against it (Sensitive = Protected from
infectious agent). Hypersensitivity means that when there is Excessive / Aberrant / Uncontrolled Immune
Response against antigen. Allergy means altered sensitivity or altered response; sometimes harmless non self
recognition can also lead to a disease. Increased capillary permeability occurs in allergic conditions. The
affected area may be red and itchy (pruritic) because of the local histamine release and other inflammatory
mediators but, in contrast to inflammation, allergy is not painful.

This table shows Gell & Coomb`s classification of hypersensitivity reactions:

In 1975, Gell and Coomb's proposed the four types of hypersensitivity reactions. This classication is the
only hypersensitivity reactions classification that is universally accepted all over the world till now.
HYPERENSITIVITY is a term discovered 100 years ago. Hypersensitivity reactions are specific immune
response against an antigen; all the mechanisms in Gell and Coomp's classifications depended on
specific immune response, either humoral or cellular, types I, II, & III are humoral immune responses,
while type IV is cellular response (cell mediated immunity).

 Gell and Coomb's classifications depended on two criteria, the mechanism (exactly what gets involved in
the hypersensitivity reaction) and the time frame between the exposure to the antigen and the
occurrence/ onset of the disease.
Type I occurs immediately; within minutes after the exposure to the antigen, thats why it is called
immediate hypersensitivity reaction. It includes IgE antibodies and explosive events like mast cells
degranulation and histamine release. Eosinophiles and neutrophiles respond to this type of reaction.
Type IV includes cell mediated immunity that occurs 2-3 days after exposure; why? Because there has
to be cytokines production, DNA transcription and translation to produce proteins and cytokines. Since
it gets involved, there are no explosive events like mast cell degranulation and histamine release.
Lymphocytes and macrophages respond to this reaction.
From now on we are going to deal with the clinical aspects of hypersensitivity reactions:

Clinical examples:
Type I
Type II

Type III
Type IV

Bronchial asthma, Allergic rhinitis, Conjunctivitis, Eczema, Urticaria,

Food & drug allergies, Insect Bite, Anaphylaxis
Organ Specific Autoimmune Disease
e.g. Autoimmune Hemolytic Anemia, Thrombocytopenia, Graves'
disease, Myasthenia Graves , Food & drug allergies.
Organ Non specific Autoimmune Disease e.g. Rheumatoid Arthritis,
SLE, Food & Drug allergies
Granulomatous Disease, sarcoidosis, Food & Drug allergies

One should be aware that the food & drug allergies can cause all types of hypersensitivity reactions; if
somebody is hypersensitive to some foods or drugs, it could be type I, II, III or IV, and it is difficult to
differentiate whether it is type 1, 2, 3 or 4 in the clinical ground and you have to know and appreciate
the major examples of each type of them. In general, hypersensitivity reaction can be against three types
of antigens; self antigens, benign (harmless) foreign antigens, or infectious (harmful) foreign antigens.
What initiates the disease is the immune respond to such antigens.
Type I hypersensitivity or allergic reaction is the focus of the discussion in this lecture.

Type 1 Hypersensitivity reaction:

Type I Hypersensitivity reaction depends mainly on two factors; the genetic and environmental factors.
1. Genetic factors play an important rule, but they are difficult to trace because many genes are involved;
polygenes involvement (it is not only a single gene that causes the diseases; many of the common
diseases (DM, Hypertention) have what it is called familial tendency; there is grouping within families
which gives an indicator that certain genetic factors and genes are playing a role). Only few examples of
certain genes have been proposed and the most recent ones are considered under the category of gene
regulators. Atopy means the tendency for IgE production. Normally, when we get exposed to antigens,
our bodies produce IgG, IgM, or IgA, but there is a subset of humans who produce IgE when they are
get exposed to certain antigens; this is the atopic character and allergy.

The phenomenon of allergy is studied in the basis of epigenetics/epigenomics, in that, there are other
modifiers of how genes are regulated and may be not specifically these genes but other genes that
regulate them can lead to the atopic character.
Presence of specific HLA alleles
Polymorphism of FcRI
Polymorphism of IL-4 family of cytokines gene.
Polymorphism CD-14 receptor
2. Environmental factors: In Africa and some poor countries, most of the people rarely have any allergic
reaction, why? Because they have been exposed to various antigens from their environment in their
early life. However, improving environmental conditions such as adopting the western way of life like
having carpet, bed sheet, windows and shades, receiving vaccination (and thus few infections during life;
decreased incidence of infection), better medical care, use of antibiotic in the first few years of life,
excessive hygiene and having few sibling might lead to more tendency for allergic reactions and shift
toward IgE production rather than IgG, IgM or IgA; this is called hygiene hypothesis. One should
conclude that allergies are diseases of the modern world; the rate of allergy is much lower in poor and
limited living countries.
Atopy is a genetically determined state of hypersensitivity to environmental allergens in which the

patient has an increased tendency for IgE production. So when genetic & environmental factors
interplay with each others, an atopic phenomenon ensues. For example, when a normal person is
exposed to penicillin, he forms IgG, but if somebody is atopic, instead of making IgG against the
penicillin, he will make IgE; this is the core feature of type I hypersensitivity reaction, which is the IgE
production.
Defect in the target barrier organs, skin, GI tract and RS tract, is an important additional factor that
may influence the immune response against harmless antigens. For example, in the GI tract, the large
molecules (proteins), which are considered as antigens, dont reach circulation unless they are
completely digested into smaller groups and molecules (the amino acids & others), which are not
allergic. Defect in GI tract barrier will give that chance that large molecules (which are antigenic and
allergic) can penetrate and escape into the circulation and get exposed to the immune system and get
more immune phenomena and events. The result of the allergic reaction depends on the site of and the
reactivity to the IgE production (bronchial airways, skin, or gut).
There are many triggers of atopic reactions, such as: most of patients have silent diseases, but when
they expose to a triggering event, the disease ensues.
Infections: mainly viral infections; for example, if somebody has allergic condition like bronchial
asthma in his airways, number one trigger worldwide for exacerbation of the patient's bronchial
asthma is the Upper Respiratory Infection, viral infections; which leads through immune mechanism,
neurological mechanisms or secretions to exacerbation of the bronchial asthma.
Exposure to allergens if you have anybody who has asthma, most likely he will complain and get
irritated when he smell perfumes, chlorex, and others. The exacerbation of the bronchial asthma due
to exposure to these triggers is not immune mediated.
Tobacco smoking
Indoor or outdoor pollutants

1. Exposure to the allergen for the first time leads to its uptake by dendritic cells (Antigen Presenting
Cell),
2. The allergens will be presented to T-helper 2 cells,
3. TH2 cells release cytokines, e.g. IL-3, IL-4 & IL-5.
4. Interleukins 3 & 5 stimulate mast cells,
5. IL-4 leads B cells to be changed into plasma cells, which are IgE producers.
6. The IgE binds to mast cells (in the tissue) and basophiles through FcRI;
7. So now, the mast cells are ready for the second exposure to the antigen.
8. The second exposure to the antigen (allergen), which can be after a week or a period of time, will
cause cross linking of the IgE with mast cells, causing mast cells degranulation; this is an explosive
event that involves the release of mediators (histamine, leukotriens, Platelet activating factor,
prostaglandins, and other cytokine mediators IL-4, IL-5 (IL-5 has main action on eosinophiles, at the
sites of allergies seen in biopsies we often see degranulated eosinophiles).
9. This will lead to the allergic problem.
Remember: hypersensitivity type 1 reaction is a specic immune response that needs at least two exposures
to the antigen for the allergy reaction to starts; you can never have a specific immune response against
something from the first exposure.
Some clinical diseases mediated by type I hypersensitivity reaction:
1.
2.
3.
4.
5.

Allergic responses to aeroallergens: includes bronchial asthma, allergic rhinitis & conjunctivitis.
Dermatologic responses: includes eczema, urticaria, & angioedema.
Food and drug allergies
Insect sting allergies
Anaphylaxis (most dangerous and severe)

Aeroallergens:
A- Bronchial asthma is a triad of three symptoms: cough, wheeze & SOB. There are two types of asthma;
cardiac asthma (patients with pulmonary edema will have cough, wheeze & SOB, so when u hear a
wheeze, it doesn't always mean bronchial asthma or COPD) or bronchial asthma. The bronchial asthma
is characterized by chronic airway inflammation & chronic bronchial hyper-responsiveness. Some books
classify asthma into extrinsic (intermittent; allergy to cats, olive pollens (in March, April, May)) and
intrinsic (continuous; no clear extrinsic factor), but since these terms are not useful clinically, nobody
uses them anymore.

B- Allergic rhinitis: characterized by nasal blockage, rhinorrhea (watery white to yellow secretion (yellow to
green suggest infection mainly) from the nose); "runny nose", decrease smell of sensation, sneezing &
nasal itching.
A very characteristic phenomenon for
those who have allergic rhinitis is the
allergic salute (rubbing the nose by the
palm of the hand causing a crease across
the bridge to appear, this elevation may
make breathing more easily for them).
30% of those with bronchial asthma have allergic rhinitis and vice versa.
C- Allergic conjunctivitis " : characterized by redness, itching, tetany sensation (the patient
feels like a small stone in his eyes), photophobia, watery secretions and tearing of the eyes (epiphora).
The allergens in these three diseases(A, B, & C) are usually in the air; the uniting factor for these diseases is
that they are allergic to something in the air; thats why they are called aeroallergens. When you approach
to the patient ask is the allergy seasonal? At which season it occurs? Or is the allergy perennial (lasting
throughout the whole year), what time of the year usually the allergy occurs? Is it during day or night gets
worse, what do you feel if there is any certain time that you get to feel worse?. These three diseases
(aeroallergens) depend on where the patient is living; where we have different types of aeroallergens in
different region; e.g. Northern Jordan is different from southern Jordan which differ from saudia arebia and
Syria and so on. So it seems that every region or country has got its own aeroallergens; aeroallergens
depend on the locality. In USA, ragweed is the major source of aeroallergen (it occurs in august, September,
October and November; up to the first frost). In Jordan, the olive trees are the major source of
aeroallergens (it occurs in early spring from the mid of March up to the end of May).
So allergy could be:
Seasonal allergy occurs in certain seasons, occurs in the day more than in night, aeroallergens are

usually outdoor e.g. pollens, grass, trees, wheat, certain fungi, or occupational exposure. Or
Perennial allergy occurs all the year round, occurs at night more than during the day, aeroallergens

usually are indoor; the most common indoor aeroallergen worldwide is the dust mite. Other indoor
aeroallergens include cat aeroallergen, cockroaches, certain fungi and other sources.
Dust mite is the feces, of a small insect, that get accumulated on the carpet, pillows, mattress,
etc.. This insect is known as a dermatophagoides pteronyssinus; it is called dermatophagoides
because it eats the scale that fall from the human skin, the allergen for these is their feces that
usually can be founded in the air or on the furniture. Dust mite can be best seen when the sun
light enters the room; when you slam on a couch or a pillow, you will see fine large particles in
the air that are flying but they tend to settle down after a period of time.
Different aeroallergens have different aerodynamics. For example, the dust mite have large
molecular weight, huge in size (can be seen), heavy (so they tend to settle down) and mainly
seen on the ground and furniture, whereas, the cat aeroallergen is usually very fine and much
smaller and they continue to float in the air; they never settle down.

By far, the most common aeroallergen worldwide is the dust mite (indoor, perennial); one study in northern
Jordan showed that, 60% of those who have bronchial asthma and allergy had the dust mite being the
major/commonest antigen/ aeroallergen, olive pollens (outdoor, seasonal) were the second in Jordan.

These patients need to be diagnosed and their allergens need to be identified in order to control and treat
their conditions. One way of reaching good diagnosis is to take full detailed history from the patient. Each
patient with bronchial asthma or any allergic disease, at least once in life, should have a skin test to confirm
what s/he is allergic against.

1- Skin test (Prick Skin test Challenge or Intradermally Skin test Challenge; done in vivo): Put the antigens
of interest in the skin (vivo) (this done either by prick test; the skin is scratched in the presence of
glycerin dissolved allergen, or intradermally; introduction of the allergen in a soluble solution).
This test has to be standardized, means that, we have to put +ve and ve controls; histamine is used as
a +ve control, while saline is used as a ve control. The +ve control (histamine) leads to redness and
swelling of the skin; if somebody is allergic to a certain antigen, a similar reaction occurs in the area
where that antigen presents. The ve control (saline) doesnt induce reaction, similarly, if somebody is
not allergic to a certain antigen, no reaction results in the area where that antigen presents. So after 15
minutes of putting the antigen of interest in the skin, the result is either +ve or ve. If someone is
allergic to something, a wheal (site where the skin is elevated and tips, American system concentrates
on the wheal to say if somebody is ve or +ve) & flare (site where the skin is red; it's around the wheal,
European system concentrates on the flare to say if somebody is allergic or not) reaction ensues, which
is +ve. The +ve reaction indicates that there is antigen specific IgE antibody. So by doing the skin test,
we can demonstrate the presence of antigen (i.e. dust mite, cat allergen. pollen etc.) specific IgE in the
skin. The only mechanism that gives a reaction like this is the histamine release. False ve response
occurs if the patient has taken anti-histamine (to treat allergies), and a false +ve response can occur in
the presence of the angry/itchy skin phenomenon in which merely scratching of the skin may cause a
+ve reaction.

2- Patients on antihistamine therapy and children (in whom the skin test is very annoying) can be tested
by another test other than Skin test; the Radio Allergo-Sorbent Test (R.A.S.T. test); it involves
demonstration of antigen specific IgE in vitro. It is a radioimmunoassay test used to detect the IgEbound allergens that are responsible for tissue hypersensitivity and allergy. The allergen is bound to
insoluble material and the patients serum is reacted with this conjugate; if the serum contains antibody
to the allergen, it will be complexed to the allergen, and thus, demonstrating the presence of allergen
specific IgE in vitro rather than in the patient's skin (vivo).
We need three purposes form these tests:
1. To reach to a specific diagnosis: for example, we say, this is a bronchial asthmatic patient who is
allergic to dust mite for ex. And so on.
2. Avoidance advice and treatment: if the patient knows the allergen that causes his allergy problem,
he will try to avoid it as much as he can; this is the best treatment and control; advise your patient
to avoid certain allergen (the allergens or antigens that gave +ve results in the skin or RAST tests)
e.g. if somebody has dust mite allergy, tell your patient to remove the carpet, putting new specific
sheets (mshamma3 6ebby), etc. (this might be impossible and expensive), or if there is cat allergy,
tell your patient to get rid of the cat (bel shalloo6 labarra el manzel) rightaway.

3. Desensitization: desensitization is effective only for IgE mediated reactions; it can be offered for
selected cases only; not for every patient. The problem is not that the desensitization doesnt work,
it definitely works against the antigen you are desensitizing against, but in these three diseases, it is
not useful; it's not very successful with aeroallergen, why? Because there are hundreds of antigens in
the air, so desensitization of one does not abolish the effect of the others. In contrast, the
desensitization for the drug allergy, bee sting allergy, and insect bite allergy works better (in which
the allergen is very clear, specific, and localized (not in the air)) than the desensitization for
aeroallergens. Desensitization is done by giving 25 injections of the allergen starting with a very
small dose, and increasing it gradually with the last being a full dose.

Dermatological allergies
The single most important factor in diagnosing skin diseases is to know where is the site/ location of the
lesion. Know where the lesions are present in any patient with any skin disease, because knowing the
description of the locality of each lesion often gives an indication about the disease and sometimes it is very
characteristic for certain diseases. Always ask the patient, which appeared first, the rash or the itch (the
rash first or the itch first?), for example, in mosquito bite, the rash (wheal and flare) appears first, and then
the itch follows.
A- Atopic Eczema (Atopic Dermatitis): is an itch that rashes; the itch starts before rashes; no rashes in the
beginning (skin is normal) but after the patient starts to itch, the rash/redness starts to appear. Usually
it starts in new born babies, affecting mainly the face and scalp; but as the child gets older, he starts to
exhibit the lesions on his body (on trunk or back). In adults, the distribution is on the flexures areas
(behind knees and elbows; in the antecupital and popliteal fossae); very characteristic sign. The rash
distribution depends on the reach of the patient's hand; so actually, almost all the body is affected by
the disease, but because the babies can't reach (to itch) except to their faces and scalps, the rashes
appear there only, and as the patient grows up, he can reach to more further sites so that the rashes
will appear at the site where the patient starts to itch. Acutely, the lesion is red and swelled, and is
composed of dry hyper or hypo-pigmented small papules that get darkened and thickened as the disease
becomes more progressive and chronic; this is called lichenification of the skin, is secondary to rubbing
and scratching (itching) process. Usually eczema has ill defined margins. In eczema, IgE level is very
high, but the allergen to which the IgE is directed is still unknown; eczema is not related to any external
allergens (food & drug allergies or aeroallergens). Eczema has strongly inherited traits.
B- Urticaria ( ): a skin lesion which is identical to that induced by prick test or a mosquito bite
(the local histamine release phenomenon). It is an acute condition characterized by reddened, itchy, and
edematous (raised) skin. It affects the trunk mainly. Usually it lasts for few hours but it shouldn't
persist for more than 24 hours (characteristic feature), and there should be, after the clearing of the
disease, no skin changes. If there is skin changes (not from the itching but from the disease itself) after
the clearing of the disease; this is called urticarial vasculitis or vasculitis; it is not the regular or the
typical Urticaria. Urticaria occurs on the superficial part of the skin; on the cutaneous tissue.
C- Urticaria Angioedema is an acute non-itchy (it's more painful than itchy) edematous subcutaneous
tissue (face, lips, mouth, tongue, hand, feet). It is dangerous only in two conditions:
1- If it occurs in the upper airways (leading to internal swelling of the airways & difficulty in breathing
and even sometimes to death), and if it is associated with difficulty in swallowing or talking.
2- If it gets generalized, where it can reach to the stage of anaphylaxis (characterized by hypotension
with tachycardia).

Usually angioedema recurs in the same site it came up previously; for example, if the patient had the 1st
episode in his hands, the 2ed, 3rd, 4th episodes recur also in the hands, so usually they dont change.
There are many causes for angioedema. Around 85- 90% of patients with urticaria angioedema have an
entity called chronic Idiopathic urticaria (most common cause); a form without known cause and
usually all workups are negative (Angioedema for up to 3-6 months without any other dierential
diagnosis and cause suggests chronic idiopathic urticaria as the main cause). However, around 10-15 %
of patients with acute angioedema have a secondary cause like thyroid disease (hyper- hypo-thyroidism),
prodrome of hepatitis B, SLE, C1 esterase inhibitor deciency, insect (wasp) sting, parasitic infections, or
food & drug allergies. These secondary causes are most of the time well controlled.

Food & drug allergies

Again, taking good and detailed history is a very helpful way to reach a successful diagnosis. Some patients,
while taking the history, may tell you that they have allergy to penicillin and that he did skin test for that
drug and there was a small reaction happened and the doctor decided not to give him this drug. From that,
you can conclude that the test was ve, why? Because he told you a small reaction resulted, and if you did
the test again it will be ve, so you can proceed and give him the drug. But if he told you, I had extensive
rash and erythema multiforme (i.e. Stevens Johnson syndrome; it is a rounded erythematous multiforme
with target lesions that appear on the upper limbs(palm and fingers), mucous membranes(lips, urethra..)
and face as a result of the hypersensitivity reaction to a drug exposure or administration (sulphonamide,
penicillin, etc.). It is a very serious condition in which the skin test is contraindicated in these patients
(because some drugs antigens may exacerbate their condition), so you just let them avoid the drug because
it can be life threatening), then you need to take it seriously and to note it in your history sheet because it
is very helpful in establishing the diagnosis of his disease (Steven Johnson Syndrome) and you have to tell
the patient to avoid that drug. Doing the food challenge test is quite useful. This test is the best test used
for food & drug allergies; it is done by asking the patient to eat something without knowing what is it, and
to wait to see if there is a reaction to that food or not. Skin test or RAST test (there are allergy panels, for
R.A.S.T. in our hospital, for inhalational aeroallergens and the food allergens) can be beneficial.

There are two forms of food allergies according to age:

In Children, more important, the common allergens are cow's milk (abates as the child ages),
peanut (may persist in adulthood), eggs (abates as ages), wheat (abates as ages), sea food (fish,
may persist in adulthood).
In Adults, the allergens may present in sea food, peanuts and strawberries.

Food allergies are more common during early life, but as the child ages (at the 3rd year), s/he will lose
his/her allergy to them, but for peanut & fish; there may be persistence to the allergy present in some
patients. In general, if these children or patients are positive to these allergens in skin tests, then the main
treatment is to avoid these allergens or this food, but if the patient is a new born or a little child, we will
be worried about the growth and development, so we try to avoid whatever is causing the problem, for ex,
if it's milk allergy, start with partially digested formulas & then primitive full digested formulas and amino
acids. Be sure that the nutrition, growth and development of the child are maintained without causing
malnutrition by the same type avoiding that offending antigen.

In drug allergy (penicillin, sulphonamide, aspirin etc.), the treatment is the avoiding of allergic drug.
Desensitization works slightly (it's better than for aeroallergens) but avoiding is still the best. In case the
drug is really indicated and there are no other alternatives, desensitization is choice of the treatment in this
case, (e.g. pregnant lady with neurosyphilis, the only drug that works without any complication is crystalline
penicillin, and if she is allergic to that drug, we try to desensitize her). So just let the patient knows name
of the drug so that he will not buy/use it again. Please differentiate between the allergic reaction and the
side effect of the drugs. Drug side effects might be toxicological, pharmacological or idiosyncratic form of
reaction.

Insect bite allergy

It is the first documented type of allergic reactions (spp. of honey bees, wasp & mosquitoes, fire- ants (in
USA) etc.). The reaction due to sting allergy can be local or systematic (more dangerous where the patient
may feel SOB and dizziness (hypotension) and may end with anaphylaxis). Honey keepers are at high risk.
Again, take a good history then do skin testing or RAST test, if the result is positive & there was local or
systemic reaction, then doing the desensitization is a must.

Anaphylaxis
Anaphylaxis is a systemic degranulation of mast cells (in the tissues) & basophiles (in the blood) that leads
to a huge histamine release. This leads to hypotension, tachycardia, bronchospasm and even loss of
consciousness, it is can be caused by:

Food & drug allergies.

Insect sting allergy (Bee sting allergy).
Radio contrast material.
Blood transfusion and blood products

Anaphylaxis is an IgE mediated reaction, but a reaction with a non-IgE mediated degranulation of mast cells
is called an anaphylactoid reaction (usually associated with radio contrast material and opiates). C1, C4a,
and C5a are the common mediators of the degranulation in this reaction.

Anaphylaxis is a medical emergency situation; so you have to give IV or IM adrenalin (epinephrine) >> start
with the ABC>> maintain the cardiopulmonary resuscitation (CBR) >> make sure that the patient continue
to be alive>> so if there is no contraindications, the drug of choice is adrenaline (IV or IM); subcutaneous
(S.C.) rout administration of adrenalin is useless and is contraindicated in emergency conditions.

Remember: shock following an insect sting or drug injection is not always an anaphylaxis; it might be due
to vaso-vagal attack as well. Vaso-vagal attack and anaphylaxis are differentiated from each others by
checking the pulse or heart rate. In vaso-vagal attacks, there is bradychardia (40 or 50 bpm). In
anaphylaxis, on the other hand, there is tachycardia.

This is the
dermatophagoides
pteronyssin-us
producing the
dust mite
(feces).

This is
grass
pollens

This is
intradermally
skin test

Not the
flare &wheal
reaction at
some sites of
allergens

This is angioedema
(mild, moderate and
severe)

This is
urticaria

This is
eczema on
the
antecupital
area.

Done by: Abdullah Yaqti