Hypersensitivity reactions are immune responses that are harmful or unpleasant for the host. There are four main types of hypersensitivity reactions classified based on the mechanisms involved: Type I reactions are immediate and mediated by IgE antibodies binding to mast cells. Common examples include allergic rhinitis and anaphylaxis. Type II reactions are cytotoxic and involve IgG or IgM binding to cell surfaces and activating the complement system. Examples include blood transfusion reactions and hemolytic disease of the newborn. Type III reactions are immune complex-mediated where circulating immune complexes deposit in tissues, activating the complement system and causing inflammation. Examples include serum sickness and hypersensitivity pneumonitis. Type IV reactions are delayed and

1. Introduction to HYPERSENSITIVITY
• 1906 – Von Pirquet coined term: hypersensitivity
• Hypersensitivity excessive, undesirable reactions produced by the
normal immune system
• Hypersensitivity reactions require a pre-sensitized (immune) state of
the host

2. Hypersensitivity
• Hypersensitivity (Immunological reaction) refers to undesirable immune
reactions produced by the normal immune system.
• Hypersensitivity reactions: When an immune response result in
exaggerated or in appropriate reactions harmful to the host the term
hypersensitivity or allergy used.
• Hypersensitivity reactions are four types, based on the mechanisms
involved and time taken for the reaction, a particular clinical condition
(disease) may involve more than one type of reaction.

3. Gell and Coombs classified the reactions into
four types based on the mechanisms
involved and time taken for the reaction

4. continuation
• Three involve antibody
• • Type I (immediate): mediated by IgE (Mast Cells)
• • Type II: mediated by IgG or IgM
• • Type III (immune complex disease): IgG & complement
• One involves antigen specific cells
• • Type IV: Delayed type hypersensitivity, T-cell mediated immune memory
response.

5. Type I (Immediate) Hypersensitivity
• • Immediate or anaphylactic hypersensitivity is mediated by IgE
• • The primary cellular component in this hypersensitivity is the mast cell or basophil
• • The reaction is amplified by neutrophils and eosinophils
• Commonly called allergy
• Mediated by IgE antibodies produced by plasma cells in response to stimulation of
Th2 cells by an antigens.
• The antigens that stimulate it are called allergens (i.e. House dust, Pollens,
Cosmetics, Insects, Clothing and Drug)
• Exposure may be ingested, inhalation, injection or direct contact.
• Type I hypersensitivity reactions can be systemic (e.g., systemic anaphylaxis) or
localized to a specific target tissue or organ (e.g., allergic rhinitis, asthma, Hay fever,
eczema, bee stings, food allergies).

7. Allergens
• • Allergens are non-parasite antigens
that can stimulate a type I
hypersensitivity response.
• • Allergens bind to IgE and trigger
degranulation of chemical mediators

8. Characteristics of allergens
• • Small proteins
• • Protein components – Often enzymes
• • Low dose of allergen
• • Mucosal exposure
• • Most allergens promote a Th2 immune

10. ATOPY
• Atopy is the term for the genetic trait to have a predisposition for
localized anaphylaxis
• • Atopic individuals have higher levels of IgE and eosinophils

11. Mechanisms of allergic response Sensitization
• • Repeated exposure to allergens initiates immune response that
generates IgE isotype
• • Th2 cells required to provide the IL-4 required to get isotype
switching to IgE

12. Mechanisms of allergic response Sensitization
• • The IgE can attach to Mast cells by Fc receptor, which increases the life span of
the IgE
• • Half-life of IgE in serum is days whereas attached to FcεR it is increased to
months
• FcεR1 - high affinity IgE receptor found on mast cells/basophils/activated
eosinophils
• Allergen binding to IgE attached to FcεR1 triggers release of granules from the
mast cell

13. Mechanisms of allergic responseEffector Stage of
Hypersensitivity
• • Secondary exposure to allergen
• • Mast cells are primed with IgE on surface
• • Allergen binds IgE and cross-links to activate signal with tyrosine
phosphorylation, Ca++influx, degranulation and release of
mediators

15. Primary Mediators
Pre-formed mediators in granules
• • Histamine
• • Cytokines TNF-α, IL-1, IL-6.
• • Chemo-attractants for Neutrophils and Eosinophils
• • Enzymes
• – Tryptase, Cathepsin
• – Changes in connective tissue matrix, tissue breakdown

16. Secondary mediators Mediators formed after
activation
• • Leukotrienes
• • Prostaglandins
• • Th2 cytokines- IL-4, IL-5, IL-13, GM-CSF

17. Mediators of Type I Hypersensitivity
Immediate effects
• Histamine:
• Constriction of smooth muscles.
• Bronchiole constriction = wheezing.
• Constriction of intestine = cramps-diarrhea.
• Vasodilation with increased fluid into tissues.
• Causing increased swelling or fluid in mucosa.
• Activates enzymes for tissue breakdown.
• • Leukotrienes
• • Prostaglandins

20. Continuation of sensitization cycle
• • Mast cells control the immediate response
• • Eosinophils and neutrophils drive late or chronic response.
• • More IgE production further driven by activated Mast cells,
basophils, eosinophils

21. Localized anaphylaxis
• • Target organ responds to direct contact with allergen
• • Digestive tract contact results in vomiting, cramping,
diarrhea
• • Skin sensitivity usually reddened inflamed area resulting
in itching
• • Airway sensitivity results in sneezing and rhinitis or
wheezing and asthma

22. Systemic anaphylaxis
• • Systemic vasodilation and
smooth muscle contraction
leading to severe
bronchiole constriction,
edema, and shock

23. Diagnostic tests for immediate hypersensitivity
Skin (prick and intradermal) tests
• • Measurement of total IgE and specific IgE antibodies
against the suspected allergens
• • Total IgE and specific IgE antibodies are measured by
a enzyme immunoassay (ELISA)
• • Increased IgE levels are indicative of an atopic
condition
• • A genetic predisposition for atopic diseases

25. Type II hypersensitivity reaction: Mechanism
and examples
• Type II hypersensitivity reaction involves antibody mediated destruction of
cells.
• It is also known as cytotoxic reaction.
• In this hypersensitivity reaction, specific antibody (IgG or IgM) bound to cell
surface antigen and destroy the cell.
• If the cell is microorganism, killing of cell is beneficial to host.
• However in Type II hypersensitivity, the cells are own RBC.
• The killing of cell can occurs by one of the three mechanisms. They are-
• Complement mediated cell lysis
• Antibody dependent cell mediated cytotoxicity (ADCC)
• Opsonization

27. Type II (Cytotoxic) Hypersensitivity
• 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 of the newborn are
examples of type II hypersensitivity.

28. Some examples of Type II hypersensitivity reaction:
• 1. Blood transfusion reaction:
• ABO blood transfusion reaction is an example of type II hypersensitivity reaction.
• Human RBCs contains A and/or B antigen as major antigen on the surface of RBC. Other minor
antigens such as Rh, Kell, Duffy etc are also present.
• Antibodies to ABO antigen are called isohemagglutinin and are usually of IgM class whereas
antibodies to other minor antigen are of IgG class.
• If individual with blood group A is transfused with blood containing B antigen then transfusion
reaction occurs in which anti-B isohemagglutinin ( antibodies) binds with B- blood cells and mediate
destruction of transfused RBC by complement activation.
• Since lysis of RBC occurs in intravascular space, free hemoglobin appears in urine. Hemoglobin may
be converted into billirubin which is highly toxic to tissues.
• For treatment of this hypersensitivity reaction, transfusion should be stopped immediately.
Furthermore patients should be given diuretic to eliminate hemoglobin in urine.
• Blood transfusion reaction occurs immediately in case of mismatched ABO antigen. In this case
transfused RBCs are lysed by complement.
• In case of minor antigen (Rh) mismatched, delayed reaction occurs and in this case transfused RBCs
are lysed by opsonization (IgG antibody) and no free hemoglobin appears in urine.

30. 2. Hemolytic disease of new born
(Erythroblastosis fetalis):

31. • Hemolytic disease of newborn develops when maternal IgG antibodies specific for fetal
blood group crosses placenta and destroy fetal RBCs.
• The consequences of such transfer of antibody can be minor, serious or lethal to fetus.
• Serious hemolytic diseases of new born develops when Rh –ve mother conceive Rh +ve
fetus, which causes erythroblastosis fetalis.
• During pregnancy fetal RBCs are separated from mother’s circulation by a layer of cell in
placenta called trophoblast. During her 1st pregnancy with Rh+ve fetus, mother circulation is
not exposed to enough fetal RBC to activate Rh specific B cells for antibody production.
• At the time of delivery, large amount of fetal umbilical cord blood enter to mother’s
circulation. These fetal blood activates mother Rh specific B cells resulting in production of
plasma cell and memory cell. The plasma cell produce IgM antibodies which binds and
destroy fetal RBCs from mother’s circulation but the memory cell remains which threat any
subsequent pregnancy with Rh+ve fetus.
• Activation of memory cells in subsequent pregnancy with Rh+ve fetus causes production of
IgG antibodies which can cross placenta and destroy fetal RBCs.
• Mild to severe anemia develops in fetus and sometime fetal. The conversion of hemoglobin
to billirubin produces additional threat to new born because billirubin may accumulate in
brain and damage it.
• This hemolytic disease of new born can be prevented by injecting preformed antibodies
against Rh antigen to mother at around 28 weeks of pregnancy and within 24-48 hours of
1st The antibodies marketed as Rhogam. These antibodies bind to RBCs of fetus in mother
circulation and clear before B cell activation.

32. Drug induced hemolytic anemia:
• Certain drugs such as penicillin, cephalosporin and streptomycin can
absorb non-specifically to protein on surface of RBC forming complex
similar to hepten-carrier complex.
• In some patients these complex induce formation of antibodies,
which binds to drugs on RBC and induce complement mediated lysis
of RBC and thus produce progressive anemia.
• This drug induced hemolytic anemia is an example of Type II
hypersensitivity reaction.

33. Type III (ICM) Hypersensitivity
• Type III (Immune Complex–Mediated) Hypersensitivity
• Type III hypersensitivity is also known as immune complex
hypersensitivity.
• The reaction may take 3 - 10 hours after exposure to the antigen (as
in Arhus reaction).
• The reaction may be general (e.g., serum sickness) or may involve
individual organs including or other organs.
• Antigens causing immune complex mediated injury are:
• Exogenous & Endogenous

34. Hypersensitivity type -3 reactions
• Immune Complex-Mediated (Type III) Hypersensitivity:
• Antigen combines with antibody within the circulation (circulating immune complexes) ,
and these are deposited.
• Antigen-antibody complexes produce tissue damage by eliciting inflammation at sites
of deposition.
• Two types of antigens cause immune complex- mediated injury:
• (1) exogenous antigens: such as foreign protein, bacterium, or virus.(microbial
proteins)
• (2) endogenous antigens: individual can produce antibody against self-components
such as nucleoproteins.

35. Type III (ICM) Hypersensitivity Mechanism of
Type III Hypersensitivity
• Antigens combines with antibody within circulation and form immune
complex
• Wherever in the body they deposite
• They activate compliment system
• Polymorphonuclear cells are attracted to the site
• Result in inflammation and tissue injury

37. • ype III (ICM) Hypersensitivity Hypersensitivity Type III Reactions Local
Reactions Arthus Reaction: Arthus Reaction: It is named for Dr. Arthus.
It is named for Dr. Arthus. Inflammation caused by the Inflammation
caused by the deposition of immune deposition of immune complexes at a
localized site. complexes at a localized site. Clinical Manifestation is ::
Clinical Manifestation is Hypersensitivity Pneumonitis Hypersensitivity
Pneumonitis Systemic Reactions Serum Sickness: Serum Sickness:
Systemic inflammatory response Systemic inflammatory response to
deposited immune complexes at to deposited immune complexes at many
areas of body. many areas of body. Few days to 2 weeks after Few days
to 2 weeks after injection of foreign serum or drug itit injection of foreign
serum or drug results in :: results in Fever, Urticaria, Artheralgia, Fever,
Urticaria, Artheralgia, Eosinophila, Spleenomegally, and Eosinophila,
Spleenomegally, and Lymph adenopathy Lymph adenopathy

39. Examples of Immune Complex-Mediated Diseases:
[ diseases and antigens ]
• Systemic lupus erythematosus : DNA, and nucleoproteins antigens.
• Polyarteritis nodosa : Hepatitis B virus surface antigen
• Poststreptococcal glomerulonephritis : Streptococcal cell wall antigen.
• Acute glomerulonephritis : Bacterial antigens (Treponema); parasite antigens
(malaria, schistosomes); and tumor antigens.
• Reactive arthritis : Bacterial antigens (Yersinia).
• Hypersensitivity Pneumonitis

40. Immune complex-mediated diseases can be:
generalized (systemic) ; or localized .
• Systemic Immune Complex Disease:
• Acute serum sickness:
• Once complexes are deposited in tissues, they initiate an acute
inflammatory reaction (approximately 10 days after antigen
administration), clinical features such as fever, urticaria, arthralgias,
lymph node enlargement, and proteinuria appear.
• Local Immune Complex Disease :
• Arthus reaction:
• a localized area of tissue necrosis resulting from acute immune
complex vasculitis, usually elicited in skin.

42. • 16. Type 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 Activates complement

45. 6. ARTHUS REACTION
• Local inflammatory reaction with Necrosis
• Few hours after Ag inoculation Inoculated Animal is previously
immunized by same Ag
• immunized animal has titers of precipitating IgG Abs
• Arthus lesions evolve over a few hours and reach a peak 4 to 10 hrs
after injection
• When injection site develops visible edema with severe hemorrhage
occasionally followed by ulceration

46. Type III (ICM) Hypersensitivity
Glomerulonephritis
• Immune complexes in the blood are deposited in glomeruli
• Damage to the glomerular cells impedes blood filtration
• Kidney failure and, ultimately, death result

47. Type III (ICM) Hypersensitivity
Rheumatoid arthritis
• Immune complexes deposited in the joint
• Results in release of inflammatory chemicals
• The joints begin to break down and become distorted
• Trigger not well understood
• Treated with anti-inflammatory drugs

48. The crippling distortion of joints
characteristic of rheumatoid arthritis

49. Type III (ICM) Hypersensitivity
Systemic lupus erythematosus
• Autoantibodies against DNA result in immune complex formation
Many other autoantibodies can also occur
• Against red blood cells, platelets, lymphocytes, muscle cells
• Trigger unknown
• Immunosuppressive drugs reduce autoantibody formation
• Glucocorticoids reduce inflammation

50. The characteristic facial rash of systemic lupus
erythematosus

51. Type IV (Delayed or Cell-Mediated) Hypersensitivity
• Delayed hypersensitivity is a function of T Lymphocytes, not antibody.
• It starts 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 intra cellular
microbiologic agents
• i.e.: Mycobacterium Tuberculosis Viruses Fungi Parasites

52. Type IV (Cell Mediated) Hypersensitivity

53. Clinically Important Delayed Hypersensitivity
Reactions
• 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 M. tuberculosis
• No response when individual not infected or vaccinated
• Red, hard swelling develops in individuals previously infected or
immunized

54. A positive tuberculin test

55. Type IV (Cell Mediated) Hypersensitivity
• Allergic contact dermatitis
• Cell-mediated immune response
• Results in an intensely irritating skin rash
• Triggered by chemically modified skin proteins that the body
regards as foreign
• Acellular, fluid-filled blisters develop in severe cases
• Can be treated with glucocorticoids

56. Allergic contact dermatitis

57. Type IV (Cell Mediated) Hypersensitivity
• 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

58. Types of grafts Autograft Isograft Genetically
identical sibling or clone Allograft Genetically
different member of same species Xenograft

59. Hypersensitivity Reactions Conclusion: