Allergy and Hypersensitivity

1. Allergy and Anaphylaxis/Hypersensitivity
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2. What is an Allergy?
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 IgE‐mediated hypersensitivity (e.g., asthma, eczema, hay
fever, and food allergy)
or
 A damaging immune response by the body to a substance,
especially a particular food, pollen, fur, or dust, to which it
has become hypersensitive.
or
 Allergy is a disorder of the immune system that is often
called atopy. Allergic reactions occur to the environmental
substances known as allergens; these reactions are
acquired, predictable and rapid.

3. What is Anaphylaxis?
 An often fatal hypersensitivity reaction, triggered by IgE or
anaphylatoxin‐mediated mast cell degranulation, leading to
anaphylactic shock due to vasodilatation and smooth muscle
contraction.
 An acute allergic reaction to an antigen (e.g. a bee sting) to which the
body has become hypersensitive.
 Anaphylaxis is an acute systemic (multi-system) and severe Type 1
Hypersensitivity allergic reactions in humans and the other mammals.
The term comes from Greek words “ava” ana (against) and phylaxis
(protection).
 Atopy (Greek Atottia-placelessness) or atopic syndrome is an allergic
hypersensitivity affecting parts of the body not in direct contact with
allergen. It may involve Eczema (atopic dermatitis), Allergic
conjunctivitis, allergic rhinitis and asthma. There appears to be a strong
hereditary component. 3

4. Anaphylaxis
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Anaphylaxis is a type I hypersensitivity reaction. In type I
hypersensitivity reactions antigens bind to preformed IgE
present on mast cells and stimulate mast cell degranulation.
Anaphylactic reactions are differentiated from simple allergic
reactions by the severe systemic manifestation of mast cell
degranulation including hypotension, respiratory distress and
cardiovascular collapse that occur after exposure to the
antigen. Anaphylactoid reactions do not require preformed IgE
and therefore are not technically type I hypersensitivities but
are clinically indistinguishable. Therefore both anaphylactic and
anaphylactoid reactions should be approached in the same
manner clinically.

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6. Fc receptor
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is a antibody
receptor involved in antigen
recognition which is located at
the membrane of certain immune
cells including B lymphocytes,
NK cells, macrophages,
neutrophils, and mast cells etc.
Such receptors recognize Fc
fragment of antibodies and that
is the name of Fc receptor
derived from.
Fc Receptor

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8. Illustration depicting mast cell activation and anaphylaxis
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9. Anaphylaxis
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Symptoms usually start within 5 to 30 minutes of coming into
contact with an allergen to which an individual is allergic. In
some cases, however, it may take more than an hour to notice
anaphylactic symptoms. Warning signs include:
 Red rash (usually itchy and may have welts/hives)
 Swollen throat or swollen areas of the body
 Passing out
 Chest tightness
 Trouble breathing
 Hoarse voice

10. Anaphylaxis (cont.…
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 Trouble swallowing
 Vomiting
 Diarrhea
 Stomach cramping
 Pale or red color to the face and body
 Anaphylaxis may occur in people with allergies to foods,
insect stings, medications or latex. If you are at risk for
anaphylaxis, be prepared with an anaphylaxis action plan.

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12. Allergy vs Anaphylaxis
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 A major difference between anaphylaxis and other allergic
reactions is that anaphylaxis typically involves more than one
system of the body.
 Allergy is the result of an immune system's response to a
substance. Immune responses can be mild, from coughing
and a runny nose, as compared to a life-threatening reaction
know as anaphylaxis.
 Anaphylaxis is a severe allergic reaction of rapid onset
affecting many body systems. It is due to the release of
inflammatory mediators (histamine) and cytokines from
mast cells and basophils, typically due to an immunologic
reaction but sometimes non-immunologic mechanism.

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14. Allergy/Sensitivity/Intolerance
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The primary difference between an allergy, a sensitivity, and
an intolerance is that an allergy is characterized by an
immune system reaction to a substance, a sensitivity involves
non immune response and an intolerance is characterized by
the body lacking an chemical or enzyme needed to digest
certain food.

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16. The Complement System
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• The complement system is a part of the immune system that
enhances (complements) the ability of antibodies and
phagocytic cells to clear microbes and damaged cells from
an organism, promote inflammation, and attack the
pathogen's cell membrane.
• It is part of the innate immune system which is not acquired
and does not change during an individual's lifetime.
• The complement system brought into action by the
antibodies produced by the adaptive immune system.
• The complement system consists of a number of small
proteins that are synthesized by the liver, and circulate in the
blood as inactive precursors.

17. The Complement System
• When it triggers, proteases in the system cleave specific
proteins to release cytokines and initiate an amplifying
cascade of further cleavages.
• The end result of this complement activation or
complement fixation cascade is stimulation of phagocytes
to clear foreign and damaged material, inflammation to
attract additional phagocytes, and activation of the cell-
killing membrane attack complex (MAC).
• Over 30 proteins or protein fragments make up the
complement system.
• Three biochemical pathways activate the complement
system: the classical complement pathway, the
alternative complement pathway, and the lectin pathway 17

18. The Complement System
The classical complement pathway requires antigen-
antibody complexes for activation (specific immune
response), whereas the alternative pathway can be activated
by spontaneous complement component 3 (C3) hydrolysis.
The mannose-binding lectin pathway can be activated by
C3 hydrolysis or antigens without the presence of antibodies
(non-specific immune response). In all three pathways, C3-
convertase cleaves and activates component C3, creating
C3a and C3b, and causes a cascade of further cleavage and
activation events. C3b binds to the surface of pathogens,
leading to greater internalization by phagocytic cells by
opsonization (identify the invaders).
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19. The Complement System
In the alternative pathway, C3b binds to different factors and
cleaves C5 (complement component 5 is a protein in humans
which is encoded by the C5 gene) into C5b and C5a. C5a is
an important chemotactic protein, helping recruit
inflammatory cells. C3a is the precursor of an important
cytokine. Both C3a and C5a have anaphylatoxin activity,
directly triggering degranulation of mast cells as well as
increasing vascular permeability and smooth muscle
contraction. C5b initiates the membrane attack pathway,
which results in the membrane attack complex (MAC),
consisting of C5b, C6, C7, C8, and polymeric C9. MAC is
the cytolytic end product of the complement cascade; it
forms a transmembrane channel, which causes osmotic
lysis of the target cell. 19

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21. Types of Hypersensitivity
There are four types of hypersensitivity reactions:
 Bsed on the mechanisms involved and time taken for the
particular reaction. A specific clinical condition (disease)
may involve more than one type of hypersensitivity
reactions
 Type I hypersensitivity
 Type II hypersensitivity
 Type III hypersensitivity
 Type IV hypersensitivity
Type I, II and III
Type IV
Antibody Mediated
Cell Mediated
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23. Types I (Immediate) Hypersensitivity
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 Commonly known as “allergy” or Anaphylaxis
 Mediated by IgE antibodies generated by plasma cells in
response to stimulation of TH2 cells by an antigens.
 The antigen that stimulates it is called allergen (that may
include: dust, pollens, cosmetics, insects bite, clothing and
medicine etc.)
 Routes of exposure may be ingestion, inhalation, injection
or direct contact with body.
 Type I hypersensitivity reactions can be systemic
(systemic anaphylaxis) or localized to a specific target
tissue or organ (for example, allergic rhinitis, asthma etc.).

24. Types I (Immediate) Hypersensitivity
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25. Types II (Cytotoxic) Hypersensitivity
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 Cytotoxic
 Type II hypersensitivity involves IgG or IgM antibody-
mediated
 IgM or IgG immunoglobulin react with cell-surface
antigens to activate the complements system and produce
direct damage of the sell surface.
 Transfusion reactions and hemolytic disease
(erythroblastosis fetalis) of the newborn are examples of
type II hypersensitivity.

26. Types II Hypersensitivity Mechanism
 In type II hypersensitivity reactions, the antibodies
produced by the immune response bind to antigens on the
patient’s own cell surfaces. The antigens recognized in this
way may either be intrinsic (“self” antigen, innately part of
the patient’s cells) or extrinsic (absorbed onto the cells
during exposure to some foreign antigen, possibly as part of
infection with a pathogen).
 IgG and IgM antibodies bind to these antigens to form
complexes that activate the classical pathway of
complement activation. That is, mediators of acute
inflammation are generated at the site and membrane
attack complexes cause cell lysis and death. The reaction
takes hours to a day. 26

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28. Types III (ICM) Hypersensitivity
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 Type III hypersensitivity is also called as Immune
Complex Mimics (ICM).
 The reaction may take 3 - 10 hours after the exposure to the
antigen.
 The reaction may be generalized (for example: serum) or
may involve individual organs including or other organs.
 Antigens causing immune complex mediated injury are:
• Exogenous
• Endogenous.

29. Types III Hypersensitivity Mechanism
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 Antigens combines with antibody within circulation and
form immune complex
 Wherever in the body they deposited
 They activate compliment system
 Polymorphonuclear cells are attracted to the site
 Result in inflammation and tissue injury

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32. Types III (ICM) Hypersensitivity
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 Immune Complex Diseases:
 Hypersensitivity Pneumonitis
 Glomerulonephritis
 Rheumatoid Arthritis
 Systemic Lupus Erythematosus

33. Types III (ICM) Hypersensitivity
• Hypersensitivity pneumonitis: Inhalation of antigens into lungs
stimulates antibody production, subsequent inhalation of the same
antigen results in formation of immune complexes and activation of the
complement.
• Glomerulonephritis: Immune complexes in the blood are deposited in
glomeruli. Damage to the glomerular cells impedes blood filtration.
Results kidney failure and ultimately, death.
• Rheumatoid arthritis: Immune complexes deposited in the joint,
which results in release of inflammatory chemicals and the joints begin
to break down and become distorted. How it triggers not well
understood. Treated with anti-inflammatory drugs.
• Systemic lupus erythematosus: Autoantibodies against DNA result in
immune complex formation and may trigger other autoantibodies;
against red blood cells, platelets, lymphocytes, muscle cells. Trigger not
known. Immunosuppressive drugs reduce autoantibody formation. 33

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Types III (ICM) Hypersensitivity
Rheumatoid arthritis Systemic lupus erythematosus

35. Types IV (Cell Mediated ) Hypersensitivity
Cell mediated or delayed hypersensitivity is triggered by T
Lymphocytes, not antibodies.
 It starts in hours (or days) after contact with the antigen and
often lasts for days.
 It can be transferred by immunologically committed
(sensitized) T cells, not by serum.
 Principal pattern of immunologic response to variety of
intracellular microbiologic agents;
• Mycobacterium tuberculosis
• Viruses
• Fungi
• Parasites 35

36. Mechanism of Type IV Hypersensitivity
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Activated T Lymphocytes:
 Release of cytokines and macrophage activation
 T-cell mediated cytotoxicity

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39. The tuberculin response:
 An injection of tuberculin beneath the skin causes reaction in
individual exposed to tuberculosis or tuberculosis vaccine
 Used to diagnose contact with antigens of Mycobacterium
tuberculosis
 No response when individual not infected or vaccinated
 Red, hard swelling develops in individuals previously
infected or immunized
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Clinically Important Delayed
Hypersensitivity Reaction

40. A Positive Tuberculin Test
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41. Type IV (Cell Mediated) Hypersensitivity
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Graft rejection:
 Rejection of tissues or organs that have been transplanted
 Grafts perceived as foreign by a recipient undergo rejection
 Immune response against foreign MHC on graft cells
 Rejection depends on degree to which the graft is foreign to
the recipient
• Based on the type of graft

42. Type of Grafts
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 Autograft–tissue grafted back on to the original donor.
 Isograft–graft between syngeneic individuals (identical
genetic constitution) such as identical twins or mice of the
same pure inbred strain.
 Allograft–graft between allogeneic individuals (members
of the same species but different genetic constitution), for
example, human to human and one mouse strain to another.
 Xenograft–graft between xenogeneic individuals (different
species), for example, pig to human

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44. Graft Rejection
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