PATHOGENESIS OF TYPE I, II, III & IV HYPERSENSITIVITY REACTIONS

1. HYPERSENSITIVITY
REACTIONS
T. SOUJANYA
16DC1T0021
PHARM. D

2. CONTENT:
 Definition & types
 Type I: Anaphylactic (Atopic) reaction
 Type II: Cytotoxic (Cytolytic) reaction
 Type III: Immune complex mediated (Arthus) reaction
 Type IV: Delayed hypersensitivity (Cell-Mediated) reaction

3. DEFINITION & TYPES:
Hypersensitivity is defined as an exaggerated or inappropriate
state of normal immune response with onset of adverse effects on the
body.
The lesions of hypersensitivity are a form of antigen-antibody
reaction. These lesions are termed as hypersensitivity reactions or
immunologic tissue injury, of which 4 types are described:
 Type I: Anaphylactic (Atopic) reaction
 Type II: Cytotoxic (Cytolytic) reaction
 Type III: Immune complex mediated (Arthus) reaction
 Type IV: Delayed hypersensitivity (Cell-Mediated) reaction

4. CONTD...
Depending upon the rapidity, duration and type of the immune
response, these 4 types of hypersensitivity reactions are grouped into:
i) Immediate type ii) Delayed type
Properties Immediate Delayed
Type I, II, III IV
Time to manifest Minutes to hours Days
Mediators Antibodies T cells
Route of sensitization Any route Intradermal
Passive transfer with serum Possible Not possible
Desensitization Easy but short lived Difficult but long lasting

5. CONTD...
i) IMMEDIATE TYPE:
Immediate type in which on administration of antigen, the
reaction occurs immediately (within seconds to minutes). Immune
response in this type is mediated largely by humoral antibodies (B
cell mediated). Immediate type of hypersensitivity reactions include
type I, II and III.
ii) DELAYED TYPE:
Delayed type in which the reaction is slower in onset and develops
within 24-48 hrs and the effect is prolonged. It is mediated by cellular
response (T cell mediated) and it includes type IV reaction.

6. TYPE I: ANAPHYLACTIC (ATOPIC)
REACTION:
Type I hypersensitivity is defined as a state of rapidly, developing
or anaphylactic type of immune response to an antigen (i.e. allergen)
to which the individual is previously sensitized (anaphylaxis is the
opposite to prophylaxis). The reaction appears within minutes of
exposure to antigen.

7. ETIOLOGY:
Type I reaction is mediated by humoral antibodies of IgE type or
reagin antibodies in response to antigen. Although definite cause for
this form of immediate reaction to allergen is not known, following
are the possible hypotheses:
1. Genetic basis: There is evidence that ability to respond to antigen
and produce IgE are both linked to genetic basis. e.g. there is a 50%
chance that a child born to both parents allergic to an antigen, may
have similar allergy.

8. CONTD...
2. Environmental pollutants: Another proposed hypothesis is that
environmental pollutants increase mucosal permeability and thus
may allow increased entry of allergen into the body, which in turn
leads to raised IgE level.
3. Concomitant factors: An alternate hypothesis is that allergic
response in type I reaction may be linked to simultaneous occurrence
of certain viral infections of upper respiratory tract in a susceptible
individual.

9. PATHOGENESIS:
Type I reaction includes participation by B lymphocytes and
plasma cells, mast cells and basophils, neutrophils and eosinophils.
During the first contact of the host with the antigen, sensitization
takes place. In response to initial contact with antigen, circulating B
lymphocytes get activated and differentiate to form IgE-secreting
plasma cells. IgE antibodies so formed bind to the Fc receptors
present on the surface of mast cells and basophils, which are the
main effector cells of type I reaction. Thus, these cells are now fully
sensitized for the next event.

10. CONTD...
During the second contact with the same antigen, IgE antibodies on
the surface of mast cells-basophils are so firmly bound to Fc
receptors that it sets in cell damage-membrane lysis, influx of
sodium & water and degranulation of mast cells-basophils.
The released granules contain important chemicals and enzymes
with proinflammatory properties-histamine, serotonin, vasoactive
intestinal peptide (VIP), chemotactic factors of anaphylaxis for
neutrophils and eosinophils, leukotrienes B4 and D4, prostaglandins
(thromboxane A2, prostaglandin D2 and E2) and platelet activating
factor.

11. CONTD...
The effects of these agents are:
 Increased vascular permeability
 Smooth muscle contraction
 Early vasoconstriction followed by vasodilation
 Shock
 Increased gastric secretion
 Increased nasal and lacrimal secretions
 Increased migration of eosinophils and neutrophils at the site of
local injury as well as their rise in blood (eosinophilia and
neutrophilia).

12. Schematic representation of pathogenesis of type-I hypersensitivity reactions

13. EXAMPLES OF TYPE I REACTION:
1. Systemic anaphylaxis:
i) Administration of antisera e.g. Anti-tetanus serum (ATS).
ii) Administration of drugs e.g. Penicillin.
iii) Sting by wasp or bee.
The clinical features of systemic anaphylaxis include itching,
erythema, contraction of respiratory bronchioles, diarrhoea,
pulmonary oedema, pulmonary haemorrhage, shock and death.

14. CONTD...
2. Local anaphylaxis:
i) Hay fever (seasonal allergic rhinitis) due to pollen sensitization of
conjunctiva and nasal passages.
ii) Bronchial asthma due to allergy to inhaled allergens like house
dust.
iii) Food allergy to ingested allergens like fish, cow’s milk, eggs etc.
iv) Cutaneous anaphylaxis due to contact of antigen with skin
characterised by urticaria, wheal and flare.
v) Angioedema, an autosomal dominant inherited disorder
characterised by laryngeal oedema, oedema of eyelids, lips,
tongue and trunk.

15. TYPE II: CYTOTOXIC (CYTOLYTIC)
REACTION:
Type II cytotoxic reaction is defined as reactions by humoral
antibodies that attack cell surface antigens on the specific cells and
tissues and cause lysis of target cells. Type II reaction too appears
generally within 15-30 minutes after exposure to antigen but in
myasthenia gravis and thyroiditis it may appear after longer
duration.

16. ETIOLOGY AND PATHOGENESIS:
In general, type II reactions have participation by complement
system, tissue macrophages, platelets, natural killer cells,
neutrophils and eosinophils while main antibodies are IgG and IgM.
Type II hypersensitivity is tissue-specific and reaction occurs after
antibodies bind to tissue specific antigens, most often on blood cells.
The mechanism involved is as under:
The antigen on the surface of target cell (foreign cell) attracts and
binds Fab portion of the antibody (IgG or IgM) forming antigen-
antibody complex.
The unattached Fc fragment of antibodies (IgG or IgM) forms a link
between the antigen and complement.

17. CONTD...
The antigen-antibody binding with Fc forming a link causes
activation of classical pathway of serum complement which
generates activated complement component, C3b, by splitting C4 and
C2 by C1.
Activated C3b bound to the target cell acts as an opsonin and
attracts phagocytes to the site of cell injury and initiates
phagocytosis.
Antigen-antibody complex also activates complement system and
exposes membrane attack complex (MAC) that attacks and destroys
the target cell.

18. Schematic representation of pathogenesis of type-II hypersensitivity reactions

19. EXAMPLES OF TYPE II
REACTION:
1. Cytotoxic antibodies to blood cells: Most common examples of type
II reaction are on blood cells.
i) Autoimmune haemolytic anaemia
ii) Transfusion reactions
iii) Haemolytic disease of the new-born (erythroblastic fetalis)
iv) Idiopathic thrombocytopenic purpura (ITP)
v) Leukopenia with agranulocytosis
vi) Drug-induced cytotoxic antibodies

20. CONTD...
2. Cytotoxic antibodies to tissue components: Cellular injury may be
brought about by autoantibodies reacting with some components of
tissue cells in certain diseases.
i) Graves’ disease (primary hyperthyroidism)
ii) Myasthenia gravis
iii) Male sterility
iv) Type I diabetes mellitus
v) Hyperacute rejection reaction

21. TYPE III: IMMUNE COMPLEX
MEDIATED (ARTHUS) REACTION:
These reactions result from deposition of antigen-antibody
complexes on tissues, which is followed by activation of the
complement system and inflammatory reaction, resulting in cell
injury. The onset of type III reactions takes place about 6 hours after
exposure to the antigen.

22. ETIOLOGY:
Type III reaction is not tissue specific and occurs when antigen-
antibody complexes fail to get removed by the body’s immune system.
There can be 3 types of possible etiologic factors precipitating type III
reaction:
1. Persistence of low-grade microbial infection.
2. Extrinsic environmental antigen.
3. Autoimmune process.

23. CONTD…
1. Persistence of low-grade microbial infection:
A low grade infection with bacteria or viruses stimulates a weak
antibody response. Persistence of infection (antigen) and
corresponding weak antibody response leads to chronic antigen-
antibody complex formation. Since these complexes fail to get
eliminated from body fluids, they are instead deposited in tissues.
e.g. in blood vessel wall, glomeruli, joint tissues etc.

24. CONTD…
2. Extrinsic environmental antigens:
Exogenous antigens may be inhaled into the lungs.
e.g. antigens derived from moulds, plants or animals. The inhaled
antigen combines with antibody in the alveolar fluid and forms
antigen-antibody complex which is deposited in the alveolar walls.

25. CONTD…
3. Autoimmune process:
Another sequence in type III reaction can be formation of
autoantibodies against own tissue (self antigen) forming
autoantibody-self antigen complex. Such self antigens can be
circulating (e.g. IgA) or tissue derived (e.g. DNA). Immune complexes
containing both components from body’s own system can thus be
deposited in tissues.

26. PATHOGENESIS:
Type II and type III reactions have antigen-antibody complex
formation but the two can be distinguished – antigen in type II is
tissue specific while in type III is not so; moreover the mechanism of
cell injury in type II is direct but in type III it is by deposition of
antigen-antibody complex on tissues and subsequent sequence of cell
injury takes place.
Type III reaction has participation by IgG and IgM antibodies,
neutrophils, mast cells and complement. The sequence of underlying
mechanism is as under:

27. CONTD…
Immune complexes are formed by interaction of soluble antibody
and soluble or insoluble antigen.
Immune complexes which fail to get removed from body fluid get
deposited into tissues.
FC component of antibody links with complement and activates
classical pathway of complement resulting in formation of C3a, C5a
and membrane attack complex.
C3a stimulates release of histamine

28. CONTD…
C3a stimulates release of histamine from mast cells and its resultant
effects of increased vascular permeability and oedema.
C5a releases proinflammatory mediators and chemotactic agents for
neutrophils.
Accumulated neutrophils and macrophages in the tissue release in
tissue destruction.

29. Schematic representation of pathogenesis of type-III hypersensitivity reactions

30. EXAMPLES OF TYPE III
REACTION:
1. Immune complex glomerulonephritis
2. Goodpasture syndrome
3. Systemic lupus erythematosus (SLE)
4. Rheumatoid arthritis
5. Farmer’s lung
6. Polyarteritis nodosa and Wegener’s granulomatosis
7. Henoch- Schoenlein purpura
8. Drug induced vasculitis

31. TYPE IV: DELAYED
HYPERSENSITIVITY (CELL-
MEDIATED) REACTION:
Type IV or delayed hypersensitivity reaction is tissue injury by cell
mediated immune response without formation of antibodies (contrary
to type I, II and III) but is instead a slow and prolonged response of
specifically-sensitized T lymphocytes. The reaction occurs about 24
hours after exposure to antigen and the effect is prolonged which may
last up to 14 days.

32. ETIOLOGY & PATHOGENESIS:
Type IV reaction involves role of mast cells and basophils,
macrophages and CD8+ T cells. Briefly, the mechanism of type IV
reaction is as under:
The antigen is recognized by CD8+ T cells (cytotoxic T cells) and is
processed by antigen presenting cells (APCs).
Antigen-presenting cells migrate to the lymph node where antigen is
presented to helper T cells (CD4+ T cells).

33. CONTD…
Hepler T cells release cytokines that stimulate T cell proliferation
and active macrophages.
Activated T cells and macrophages release proinflammatory
mediators and cause cell destruction.

34. Schematic representation of pathogenesis of type-IV hypersensitivity reactions

35. EXAMPLES OF TYPE IV
REACTION:
Type IV reaction can explain tissue injury in following common
examples:
1. Mycobacterial infection (e.g. tuberculosis, leprosy)
2. Virally infected cells
3. Malignant cells in the body
4. Organ transplantation (e.g. graft versus host reaction, transplant
rejection)

36. COMPARISON OF
HYPERSENSITIVITY REACTIONS:
TYPE I TYPE II TYPE III TYPE IV
Antigen Exogenous Cell surface Soluble Tissue & organ
Antibody IgE IgG, IgM IgG, IgM None
Reaction time 15-30 minutes Minutes to hours 3-8 hours 48-72 hours
Transfer Antibody Antibody Antibody T cells
Conditions Hay fever,
allergy &
asthma
Erythroblastic fetalis
and Goodpasture’s
syndrome
SLE, serum
sickness
Tuberculin test,
poison ivy etc.

37. REFERENCES/BIBLIOGRAPHY:
1. Text book of pathology by Harsh Mohan
2. Hypersensitivity reactions- brainkart.com