The document discusses hypersensitivity reactions, categorizing them into four types based on mechanisms and timing: Type I (immediate, IGE-dependent), Type II (cytotoxic), Type III (immune complex-mediated), and Type IV (delayed). It explains the pathophysiology, clinical manifestations, and examples of each type, including allergic reactions, anaphylaxis, autoimmune responses, and delayed hypersensitivity conditions like contact dermatitis. Management strategies for these reactions are also highlighted, including avoidance of allergens and pharmacological interventions.

2. DEPARTMENT OF ORAL AND MAXILLOFACIAL SURGERY
Allergy
and
Hypersensitivity

3. Index
 Introduction
 Classification
 Type I (Anaphylactic, IgE or reagin dependent)
 Type II (cytotoxic/ cell stimulating)
 Type III(immune complex or toxic complex disease)
 Type IV(delayed or cell mediated hypersensitivity)
 Conclusion
 References

4. Introduction
Immunity is considered a protective process
helping body to overcome infectious agents
Under certain circumstances inflammatory
response can have deleterious effects,
resulting in significant tissue damage or even
death

5. Hypersensitivity
Hypersensitivity refers to undesirable (damaging,
discomfort producing and sometimes fatal) reactions
produced by the normal immune system.
Hypersensitivity reactions require a pre-sensitized
(immune) state of the host.

6. Hypersensitivity is what happens to the host as
a result of immune reaction
Allergy is most commonly a synonym for
hypersensitivity
Allergy means: altered state of reactivity to an
antigen and includes both types of immune
responses protective as well as injurious

7. For induction of hypersensitivity reaction host
should have had contact with antigen
Sensitising /priming dose:
Initial contact sensitizes the immune system
leading to priming of appropriate T or B
lymphocytes
Subsequent contact with allergen causes
manifestations of hypersensitivity – shocking
dose

8. Traditional classification
Based on time required for the sensitized host
to develop clinical reactions on re-exposure to
antigen
Immediate hypersensitivity(B cell / antibody
mediated)
Anaphylaxis
Atopy
Antibody mediated cell damage
Arthus phenomenon
Serum sickness

9. Delayed hypersensitivity
(t cell mediated)
Infection(tuberculin type)
Contact dermatitis type

10. Gell and Coombs Classification 1963
Based on different mechanisms of pathogenesis:
Type I (Anaphylactic, IgE or reagin dependent)
Type II (cytotoxic/ cell stimulating)
Type III (immune complex or toxic complex
disease)
Type IV(delayed or cell mediated hyperensitivity)

12. TYPE I : IgE DEPENDENT

13. Anaphylaxis : (by Richet 1902)
Ana=without phylaxis=protection
Classical immediate hypersensitivity reaction
Sensitization most important when antigen is
introduced parenterally
In susceptible host very minute amount can
sensitize host

14. Antigen as well as hapten can induce
hypersensitivity
There should be atleast 2-3 weeks between
sensitizing dose and shocking dose
Shocking dose most effective when injected
intravenously and less effective intraperitoneally/
subcutaneously and least effective intradermally

15. Shocking antigen should be identical/
immunologically closely related to sensitizing
antigen
Clinical effects are due to smooth muscle
contraction and increased vascular permeability
Oedema, decreased coagulability of blood, fall in
blood pressure and temperature, leucopenia,
thrombocytopenia also occur

16. Symptoms and signs of anaphylactic
shock
Itching of the scalp and tongue
Flushing of the skin over the whole body
Difficulty in breathing due to bronchial spasm.
Nausea, vomiting, abdominal pain and
diarrhoea
Sometimes with blood in the stool.
Acute hypotension,
Loss of consciousness
Death

17. IMPORTANT EXAMPLES
 Urticaria (hives)
 Angioedema
 Allergic conjunctivitis
 Allergic Rhinitis
 Allergic Asthma
 Anaphylaxis
Seen with
Injections of antibiotics
Insect sting

19. Characteristics of allergens
Small 15-40,000 MW proteins.
Specific protein components
Often enzymes.
Low dose of allergen
Mucosal exposure

20. Dermatophagoides pteronyssinus
(common dust mite)
Allergens
Example: Der P1
Der P1 is an enzyme allergen
from the fecal pellets
of the dust mite.

21. Clinical manifestations

22. Urticaria Angioedema

23. Angioedema of
oropharynx

24. Cutaneous anaphylaxis
Small shocking dose of an antigen is administered
intradermally to sensitised host there will be local
wheal and flare response
Is useful in testing for hypersensitivity and in
identifying the allergen responsible in atopic
diseases.

25. Passive cutaneous anaphylaxis (PCA):
Extremely sensitive in vivo method for detection of
antibodies
Antibody is injected intradermally into a normal animal
Antigen, along with a dye such as Evans blue, is injected
intravenously 4-24 hours afterwards
There will be an immediate blueing at the site of`
intradermal injection due to vasodilatation and increased
capillary permeability (wheal-and-flare reaction)

26. Mechanism of anaphylaxis
The immunologic basis for hypersensitivity is
cytotropic IgE antibody
IgE molecules are bound to surface receptors
on mast cells and basophils.
These cells carry large numbers of such
receptors called Fc ER receptors

29. 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.

30. Pharmacological Mediators
1)Primary mediators which are the preformed
contents of mast cell and basophil granules
Histamine, serotonin,
Eosinophil chemotactic factor of anaphylaxis
Neutrophil chemotactic factor
Heparin and various proteolytic enzymes

31. 2) Secondary mediators which are newly formed
upon stimulation by mast cells, basophils and
other
Leucocytes (slow reacting substance of
anaphylaxis)
Prostaglandins and platelet activating factor,
and
Cytokines such as IL3, IL4, IL5, IL6;

33. Anaphylactoid reaction:
Intravenous injection of peptone, trypsin and certain
other substances provokes a clinical reaction resembling
anaphylactic shock. This is termed `anaphylactoid
reaction`
The clinical resemblance is due to the same chemical
mediators participating in both reactions.
The only difference is that anaphylactoid shock has no
immunological basis

34. Atopy ( out of place or strangeness]
 The term ‘atopy` was introduced by coca[1923]
 Naturally occurring familial hypersensitivities of human beings,
typified by hay fever and asthma.
 The antigens commonly involved in atopy are
characteristically
 Inhalants (pollen, house dust)
 Ingestants (for example, eggs, milk).

36.  Some of them are contact allergens, to which the skin
and conjunctiva may be exposed.
 These atopens are generally not good antigens when
injected parenterally but induce IgE antibodies
 Atopic sensitisation is developed spontaneously
following natural contact with atopens.
 It is difficult to induce atopy artificially.

37. Predisposition to atopy is genetically
determined
probably linked to MHC genotypes.
Atopy runs in families.
What is inherited is tendency to produce IgE
antibodies in unusually large quantities.

38. What causes the deaths?
Laryngeal edema and acute
bronchospasm >70%
Circulatory collapse >25%
other <5% - ?brain ?MI

39. In USA
30,000 emergency room visits each year
400 to 800 deaths/year
IV penicillin accounts for 100 to 500 deaths per
year
Hymenoptera stings account for 40 to 100
deaths per year
Risk factors: protracted course, betablockers,
adrenal insufficiency

40. Clinical expression depends on:
Degree of hypersensitivity
Quantity, route, rate of antigen
exposure
Pattern of mediator release
Target organ sensitivity and
responsiveness

41. Management
Adrenaline is to be administered
0.5 ml of a 1 in 1000 solution,
subcutaneously or intramuscularly,
the dose being repeated upto a
total of 2 ml over 15 minutes

43. Controlling Hypersensitivity reaction (Type I)
 To avoid contact with known allergens
 Immunotherapy
repeated injections of increasing doses of allergens
(hyposensitization)
 Use of drugs that block release of allergic mediators
by interfering with various biochemical steps in mast-
cell activation and degranulation

44. TYPE II (CYTOTOXIC
REACTION)

45. Cytotoxic reactions are defined as
those reactions which cause injury to
the cell by combining humoral
antibodies with cell surface antigens;
blood cells being affected more
commonly.

46. Types of mechanisms
 1. Cytotoxic antibodies to blood cells.
This mechanism involves direct cytolysis of blood cells
(red blood cells, leucocytes and platelets) by
combining the cell surface antigen with IgG or IgM
class antibodies.
In the process, complement system is activated
resulting in injury to the cell membrane.
The cell surface is made susceptible to phagocytosis
due to coating or opsonisation from serum factors or
opsonins.

48.  i) Autoimmune haemolytic anemia:-
Red cell injury is brought about by auto-antibodies
reacting with antigens present on red cell surface.
 ii) Transfusion reactions due to incompatible or
mismatched blood transfusion
iii) Haemolytic disease of the newborn :-
Fetal red cells are destroyed by maternal
isoantibodies crossing placenta.

49. 2. Cytotoxic antibodies to tissue
components
 Cell injury may be brought about by auto-
antibodies reacting, with some components of
tissue cells in certain diseases,
 Example
In myasthenia gravis, antibody to acetylcholine
receptors of skeletal muscle is formed
which blocks neuromuscular transmission at the
motor end-plate resulting in muscle weakness

51. 3)Antibody-dependent cell-mediated
cytotoxicity (ADCC).
 Cytotoxicity by this mechanism is
mediated by leucocytes like monocytes,
neutrophils, eosinophils & NK cells.
 The antibodies involved are mostly IgG
 The cellular injury occurs by lysis of
antibody-coated target cells through Fc
receptors on leucocytes.
 The examples of target cells
killed by this mechanism
are tumour cells, parasites etc.

52. IMMUNE COMPLEX
DISEASES
Type III

53. Arthus reaction
 Arthus [1903] observed that when rabbits were repeatedly
injected subcutaneously with normal horse serum,
 the initial injections had no local effect
 later injections  intense local reaction consisting of edema,
induration and hemorrhagic necrosis.
 This is known as the Arthus reaction and is a local
manifestation of generalised hypersensitivity

54. The tissue damage is due to formation of antigen—
antibody precipitates causing
complement activation and release of inflammatory
molecules.
This leads to increased vascular permeability and
infiltration of the site with neutrophils.
 Leucocyte—platelet thrombi are formed that
reduce the blood supply and lead to tissue necrosis

55. Immune Complex mediated local
inflammation in Arthus Reaction

56. Arthus reaction forms a pathogenic
component of many clinical syndromes.
Eg: intrapulmonary Arthus-like reaction to
inhaled antigens, such as thermophilic
actinomycetes from mouldy hay or grain
causes Farmer`s lung and other
types of hypersensitivity pneumonitis

57. Serum sickness
As originally described by von Pirquet
and Schick (1905)
Appeared 7-12 days following a single
injection of a high concentration of
foreign serum such as the diphtheria
antitoxin.
Systemic form of Type lll hypersensitivity

58. The clinical syndrome consists of
 Fever
 Lymphadenopathy
 Splenomegaly
 Arthritis,
 Glomerulonephriris
 Endocarditis
 Vasculitis,
 Urticarial rashes,
 abdominal pain, nausea and vomiting.

59. Pathogenesis
Formation of immune complexes (consisting
of the foreign serum
and antibody to it that reaches high
enough titres by 7-12 days)
Which get deposited on the endothelial
lining of blood vessels in various parts of the
body, causing inflammatory infiltration.

60. The plasma concentration of
complement falls due to
massive complement
activation and fixation by the
antigen antibody complexes.
The disease is self limited

61. With continued rise in antibody
production, the immune complexes
become larger and more susceptible to
phagocytosis and immune elimination.
 When all foreign antigen is thus
eliminated and free antibody appears,
the symptoms clear without any sequelae

62. The latent period of 7-12 days is required
only for serum sickness following a single
injection.
With subsequent injections, the disease
manifests earlier.
Serum sickness differs from other types of
hypersensitivity reaction in that a single
injection can serve both as the sensitising
dose and the shocking dose.

63. Syndrome is currently more commonly seen
following injections of penicillin or other
antibiotics.
Immune complexes occur in many diseases
including
bacterial, viral and parasitic infections
Disseminated malignancies
Autoimmune conditions.

64. The nephritis and arthritis seen
in these conditions may be
caused by deposition of
immune complexes.

65. Type IV reactions : Delayed
Hypersensitivity

66. They constitute one aspect of cell
mediated immunity
Provoked by specific antigens
Evolve slowly and consist of a mixed
cellular reactions involving lymphocytes
and macrophages in particular

67. Reaction is not induced by
circulating antibodies but by
sensitized T cells which on
contact with specific
antigen ,release lymphokines
that cause biological effects
on leucocytes, macrophages
and tissue cells.

68. Delayed hypersensitivity can
be transferred by lymphocytes
or other transfer factors not by
serum
Two types
Tuberculin type
Contact dermatitis type

69. Tuberculin type
 Archetype of delayed hypersensitivity is the
tuberculin reaction
 When small dose of tuberculin is injected
intradermally in an individual sensitised to
tuberculoprotein by prior infection or
immunisation
 An indurated inflammatory reaction occurs at the
site within 48-72 hours

71.  If unsensitised no response
 Its different from the skin test for Type 1
hypersensitivity :
 longer interval of appearance
 its morphology and histology
 Seen in many infections especially its subacute
and pathogen intracellular
 Also seen in allograft reaction and many
autoimmune disease

73. Cutaneous basophil hypersensitivity
 Produced by intradermal injection of some protein antigen
 Resembles tuberculin response
 It can be passively transferred by serum so its not delayed
hypersensitivity
 Formerly known as Jones Mote reaction.
 Characterised by prominent basophil infiltration
 Significance unknown

74. Contact dermatitis type
 Results from skin contact with variety of chemicals ,
drugs , metals
 Sensitization is liable when contact is with an inflamed
area of skin and when chemical is applied in an oily
base
 Substances involved themselves not antigenic but may
acquire antigenicity in combination with skin proteins

75.  Most of substances are fat soluble, so passage along
sebaceous gland may be method of entry of allergens
 Langherhan cells of skin capture locally applied haptens, along
with modified tissue protein and migrate to draining
lymphnode where they present the processed antigens along
with MHC molecules to Tcells
 The sensitised Tcells travel to the skin site, where on contacting
the antigen release various lymphokines Th1 cells secrete IFN-r
and IL-2 which activate macrophages and lymphocytes.

76.  Th2 cells release IL4,IL5, GM-CSF and other
factors that lead to an influx of eosinophills and
tissue damage.
 Activated Tc cells mediate killing of target cells
 Lesions of contact dermatitis varies from papule
to macule to vesicle, that breakdown, leaving
behind raw weeping areas typical of acute
eczematous disease

78. Patch test
 Allergen is applied to the skin under an adherent
dressing.
 Sensitivity is indicated by itching appearing in 4-5
hours
 Local reaction may vary from erythema to vesicle or
blister formation after 24-48 hours.

80. Shwartzman reaction
 Its not an immune reaction,it has
superficial resemblance with
hypersensitivity
 Alteration in factors affecting
intravascular coagulation

81. Shwartzman 1928 observed
that if a culture trait of S.Typhi is
injected intradermally in a
rabbit followed by same filtrate
intravenously, a hemorrhagic
necrotic lesion develops at the
site of intradermal inj

82. Injections need not be of same
or even related endotoxins.
Culture suspension or filtrates of
variety of bacteria will sensitize
the skin intravenous injection
by an equally wide variety of
cultures and infiltrates

83.  Initial or preparatory dose is an endotoxin
 Intravenous or provoctive injection can be a
variety of substances (bacterial endotoxins,antigen
antibody complex etc)
 Initial inj can cause accumulation of leucocytes
which condition the site by release of lysosomal
enzymes damaging capillary walls.

84. If both inj are given IV the
animal die 12-24 hours after 2nd
inj
Autopsy shows bilateral cortical
necrosis of the kidney and
patchy hemorrhagic necrosis in
liver , spleen, other organs

85. An essentially similar
phenomenon was described
by sanarelli in experimental
cholera
The reaction is called Sanarelli -
Shwartzman reaction or
generalised shwartzman
reaction

86. Similar kind of mechanisms are
seen in:-
Purpuric rashes of
meningococcal septicaemia
Acute hemorragic adrenal
necrosis (Waterhouse-
Frederichsen)

87.  Massive activation of compliment by the
alternative pathway, associated with release of
thromboxane A2 and prostaglandin may lead to
DIC
 The mechanism may be execessive release of
cytokines such as TNF and
IL 1&6 by macrophages and endothelial cells in
response to contact with large number of
lipopolysacchride endotoxin

88.  Staphylococcus aureus can induce TNF secretion by
macrophages and peptidoglycan mediated
platelet aggregation, leading to DIC
 Staphylococcal enterotoxins can act as super
antigen activating whole families of Tcells
irrespective of their antigen specificity and causing
massive release of cytokines ,leading to toxic shock
syndrome
 These conditions has similar pathogenic mechanism
and resemble those in immune inflammation

89. Conclusion
 Hypersensitive reactions can be as mild as rashes to severe life
threatening condition
 A thorough history of the patient is mandatory before undergoing any
medical treatment to avoid an emergency.
 Drugs for anaphylactic reactions should always be kept ready in the
vicinity.
 Good presence of mind and prompt reaction of the practitioner can
bring a patient back to life…..

90. References
 Text book of micobiology-
Ananthanarayan 2nd
edition
 Text book of introductory immunology-
Nandini Shetty
 Microbiology5th Edition Lansing M.
Prescott
 Abbas, Lichtman Basic Immunology 2nd
Edition
 Kuby immunology- Richard Goldsby
 Robinsons book of pathology – 7th
edition