Hypersensitivity reactions are harmful immune responses that occur upon reexposure to an antigen in sensitized individuals. There are four main types of hypersensitivity: Type I is immediate and involves IgE antibodies and mast cells/basophils; Type II involves antibody-antigen interactions on cell surfaces; Type III involves immune complex deposition; Type IV is cell-mediated and delayed. The document defines key terms and outlines the mechanisms, mediators, clinical manifestations of each hypersensitivity type.

1. Hypersensitivity
Speaker : Dr Joyshree Panda
Moderator : Dr Atanu kumar Bal

2. Headings I will be covering:
 Definitions
 Class switching
 Complement System
 Classification of hypersensitivity
 Type I hypersensitivity
 Type II hypersensitivity
 Type III hypersensitivity
 Type IV hypersensitivity

3. Definitions
 Hypersensitivity - Immune & inflammatory responses that are
harmful to the host (von Pirquet, 1906)
 Hypersensitivity reactions - Harmful antigen-specific immune
responses, occur when an individual who has been primed by an
innocuous antigen subsequently encounters the same antigen,
produce tissue injury and dysfunction.
 Atopy: Genetic tendency to develop classic allergic diseases.
 Allergy: Damaging immune response by the body to a substance.
 Allergen: Substance causing allergic reaction.

4.  Immunogen: Substance that induces immune response.
 Complete Antigen: Substance that induces immune response and reacts
with products of immune response.
 Incomplete Antigen: Substance that reacts with products of immune
system but not induce an immune response
 Hapten: low molecular weight molecule that is recognized by preformed
antibody but is not itself immunogenic unless conjugated to a carrier
molecule that provides epitopes recognized by helper T cells.
 Epitope: Antigenic structure recognized by antibody.
 Paratope: Paired heavy chain and light chain form antigen binding site
(on top of Y ).

5. Class switching
 Biological mechanism that changes a B cell’s production
of immunoglobulin (antibodies) from one type to another, such as from
the isotype IgM to the isotype IgG.
 During this process, the constant-region portion of the antibody heavy
chain is changed, but the variable region of the heavy chain stays the
same
 Since the variable region does not change, class switching does not
affect antigen specificity. Instead, the antibody retains affinity for the
same antigens, but can interact with different effector molecules.

6. Structure of Immunoglobulin

7. Complement system
 The complement system is activated when
antigen combines with antibody
 It consists of more than 20 proteins, some of
which are numbered C1 through C9.
 C1 is a helical structure made of C1q, 2 C1r,
2C1s.
 C1q binds to antibody and fixes the
complement pathway.
 Complements C2-C5 are cleaved into two parts.
One big (b) one small (a).
 a ones are anaphylatoxins and b are opsonins
except in case of C2. (C3a, C4a, C5a and in C2 it
is C2b all are anaphylatoxins)
 C5a is chemotactic too.
 C5-C9 make membrane attack complex by joining
of multiple C9. and cell lysis occurs.

8. Coombs and Gell (in the early 1960s)
 Hypersensitivity reactions: four types;
based on
 the mechanisms involved
and
 time taken for the reaction,

9. CLASSIFICATION OF HYPERSENSITIVITY
 TYPE I – IMMEDIATE, ATOPIC, ANAPHYLACTIC,ALLERGY
 TYPE II – ANTIBODY DEPENDANT
 TYPE III – IMMUNE COMPLEX
 TYPE IV – CELL MEDIATED / DELAYED TYPE OF
HYPERSENSITIVITY

10. Immediate (Type I) Hypersensitivity
 Can be further divided into two types
( depending on the portal of entry of the allergen)
Systemic disorder- eg. Anaphylaxis
Local reaction
-skin allergy, - bronchial asthma
-allergic rhinitis - conjunctivitis
-hay fever,
-allergic gastroenteritis

11. Immediate/Type I hypersensitivity
 Rapid immunologic reaction
 Occuring in a previously sensitized individual
 Triggered by binding of IgE antibody on to surface of mast cell.
 Occurs in 2 phases
-Immediate reaction
- Late reaction

12. Mechanism involved in immediate
hypersensitivity

14. CD 4 T Cell
TCR

15. Activation of TH2 cells and production of
IgE antibody
 Presentation of antigen to naïve CD4 helper T cells,Produce cytokines and
interleukins IL-4, IL-5, and IL-13
TH2 cells
Acts on B
cells IL13
Enhance IgE
production
Acts on epithelial
cells to stimulate
mucus secretion
IL-5
Eosinophil
development
and
activation.
IL-4
Class switching
to IgE

16. T cell
B cell

17. B cell

21. Antigen

25. Mast cells can also be triggered by other
stimuli- Anaphylactoid reactions.
 C3a, C5a- Act by binding to receptor on mast cell
membrane
 Chemokines – IL8
 Drugs like Codeine, Morphine, Adenosine etc
 Mellitin(present in bee venom), physical stimulus
like heat , cold, sunlight.

26. Late reaction
 Occurs in 2-12 hours.
 No additional exposure to antigen.
 Caused by mediators like Slow Reacting Substances- A which are
synthesised after cell degranulates.
 Characterised by infilteration of tissues by eosinophils,
basophils, monocyte and CD4 Tcell.

27. Atopy
•Agent Inhaled – Pollens /Dust
•Ingested – Egg , Milk
 Ig E is over produced
 Increased TH2 cells
 Increased IL4 to IgE synthesis.
•Estimation of Ig E by RAST(Radioallergosorbent test)

29. Type II hypersensitivity reactions
 Antibodies that react with antigens present on cell surface
or extracellular membrane cause disease by destroying
these cells , triggering inflammation or interfering with
normal function.
Type-II.
Cell destruction
without
inflammation
Cell destruction
with
inflammation
No cell
destruction only
cell dysfunction

30. Cell destruction without inflammation.
Phagocytosis and opsonisation
 Responsible for depletion of cells coated with
antibody
 Cells opsonized by IgG are recognized by
Phagocyte Fc receptors
 Classical complement activated
Antibody dependant cellular toxicity
 Cells coated with IgG are killed directly by cells
like Macrophages, NK cells, eosinophills,
neutrophils.
 The effector cells binds to target by their receptor
for Fc fragment of IgG.
 Cell lysis occurs without phagocytosis
C3b and C4b deposited on
surface
Recognised by phagocytes
Opsonisation and destruction
Formation of MAC
disruption of memb. by
drilling holes
osmotic lysis of cells.

31. Clinical conditions-
Cell destruction without inflammation
Autoimmune
hemolytic anemia
Red cell membrane
proteins (Rh blood
group antigens, I
antigen)
Opsonization and
phagocytosis of red
cells
Hemolysis, anemia
Autoimmune
thrombocytopenic
purpura
Platelet membrane
proteins (Gpllb: Illa
integrin)
Opsonization and
phagocytosis of
platelets
Bleeding

32. Cell destruction with inflammation
When antibodies deposit in fixed tissues, such as basement membranes and
extracellular matrix, the resultant injury is due to inflammation.
The deposited antibodies activate complement, generating by-products,
including chemotactic agents (mainly C5a), which direct the migration of
polymorphonuclear leukocytes and monocytes and anaphylatoxins (C3a and
C5a), which increase vascular permeability
release or generation of a variety of pro-inflammatory substances, including
prostaglandins, vasodilator peptides, and chemotactic substances
Damage of tissues by lysosomal enzymes, including proteases capable of
digesting basement membrane, collagen, elastin, and cartilage, and reactive
oxygen species.

33. Clinical conditions:Cell destruction with inflammation
Pemphigus
vulgaris
Proteins in intercellular
junctions of epidermal cells
(epidermal cadherin)
Antibody-mediated
activation of proteases,
disruption of intercellular
adhesions
Skin vesicles
(bullae)
Vasculitis caused
by ANCA
Neutrophil granule proteins,
presumably released from
activated neutrophils
Neutrophil degranulation
and inflammation
Vasculitis
Goodpasture
syndrome
Noncollagenous protein in
basement membranes of kidney
glomeruli and lung alveoli
Complement- and Fc
receptor–mediated
inflammation
Nephritis, lung
hemorrhage
Acute rheumatic
fever
Streptococcal cell wall antigen;
antibody cross-reacts with
myocardial antigen
Inflammation, macrophage
activation
Myocarditis,
arthritis

34. No cell destruction only cell dysfunction
 Antibody directed against cell surface receptors impair or dysregulate
function without causing cell injury or inflammation
 Myasthenia gravis, antibodies reactive with acetylcholine receptors in
the motor end plates of skeletal muscles block neuromuscular
transmission and therefore cause muscle weakness.
 In Graves disease antibodies against the thyroid-stimulating hormone
receptor on thyroid epithelial cells stimulate the cells, resulting in
hyperthyroidism

35. No cell destruction only cell dysfunction
Myasthenia gravis Acetylcholine
receptor
Antibody inhibits
acetylcholine binding,
down-modulates receptors
Muscle weakness,
paralysis
Graves disease
(hyperthyroidism)
TSH receptor Antibody-mediated
stimulation of TSH
receptors
Hyperthyroidism
Insulin-resistant diabetes Insulin receptor Antibody inhibits binding of
insulin
Hyperglycemia,
ketoacidosis
Pernicious anemia Intrinsic factor of
gastric parietal cells
Neutralization of intrinsic
factor, decreased
absorption of vitamin B12
Abnormal erythropoiesis,
anemia

36. Immune Complex–Mediated (Type III)
Hypersensitivity
Antigen-antibody complexes produce tissue damage mainly by eliciting
inflammation at the sites of deposition.
 The pathologic reaction is initiated when antigen combines with antibody
within the circulation (circulating immune complexes), and these are
deposited typically in vessel walls

37. Antigens that form immune complexes
 Exogenous- foreign protein that is injected or
produced by an infectious microbe
 Endogenous - individual produces antibody against
self-components (autoimmunity).

38. Formation of Immune Complexes.
Introduction of a protein antigen
triggers an immune response
formation of antibodies, a week after the injection of the
protein.
These antibodies are secreted into the blood,
react with the antigen still present in the circulation and
form antigen-antibody complexes.

39. Deposition of immune complex depends on
Size
 Large immune complexes are deposited in tissues or phagocytosed.
 Tiny immune complexes are easily cleared by phagocytosis
 Medium sized immune complexes most pathogenic
Ratio of Antigen: antibody
 Slight antigen excess more pathogenic
Blood Flow
 Places where blood is filtered at high pressure are more prone.
Eg glomeruli, joints

40. Systemic Immune Complex Disease
 Acute serum sickness is the prototype of a systemic
immune complex disease; occurs due to administration
of large amounts of foreign serum (e.g., serum from
immunized horses used for protection against
diphtheria).
 The pathogenesis can be divided into three phases:
 (1) formation of antigen-antibody complexes in the
circulation;
 (2) deposition of the immune complexes in various
tissues
 (3) an inflammatory reaction at the sites of immune
complex deposition

41. Pathogenesis of immune complexed mediated

42. Local Immune Complex Disease (Arthus Reaction)
 The Arthus reaction is a localized area of tissue
necrosis resulting from acute immune complex
vasculitis, usually elicited in the skin.
 experimental intracutaneous injection of antigen
in a previously immunized person.
 antigen diffuses into the vascular wall, it binds the
preformed antibody, and large immune complexes
are formed locally.
 These complexes precipitate in the vessel walls
and cause fibrinoid necrosis, and superimposed
thrombosis worsens the ischemic injury.

44. Immune complex mediated diseases
Systemic lupus erythematosus Nuclear antigens Nephritis, skin lesions,
arthritis, others
Poststreptococcal
glomerulonephritis
Streptococcal cell wall
antigen(s); may be “planted”
in glomerular basement
membrane
Nephritis
Polyarteritis nodosa Hepatitis B virus antigens in
some cases
Systemic vasculitis
Reactive arthritis Bacterial antigens (e.g.,
Yersinia)
Acute arthritis
Serum sickness Various proteins, e.g., foreign
serum protein (horse anti-
thymocyte globulin)
Arthritis, vasculitis, nephritis
Arthus reaction (experimental) Various foreign proteins Cutaneous vasculitis

45. When immunofluorescence
staining with an antibody to
complement or immunoglobulin
is performed, a brightly
fluorescent signal staining the
dermal epidermal junction is
visible indicating immune
complex deposition.
Immunofluorescence staining pattern
with antibody to IgG staining immune
complexes at the dermal-epidermal
junction. If such a pattern is seen only in
skin involved by a rash, then the
diagnosis is probably DLE, but if this
pattern appears even in skin uninvolved
by a rash, then the diagnosis is SLE.
DEPOSITION OF IMMUNE COMPLEXES IN THE SKIN OF
SLE PATIENTS

46. Type IV hypersensitivity reactions
Cell-mediated hypersensitivity
Initiated by sensitized T lymphocytes
2 types
 Reactions of CD4+ T Cells: Delayed-Type
Hypersensitivity and Immune Inflammation
 Reactions of CD8+ T Cells: Cell-Mediated
Cytotoxicity

47. 1. Delayed-type hypersensitivity
 Mediated by CD4 T cells
 As seen in
• Contact dermatitis
• Tuberculin skin test
• Granulomatous inflammation

48. Delayed Hypersensitivity
Naive CD4+ T cells recognize peptides displayed by dendritic cells
secrete IL-2
autocrine growth factor to stimulate proliferation of the antigen-
responsive T cells.
TH1 TH17
cytokines produced by
APCs at the time of T-cell
activation
IL12
On repeated exposures cytokines and
IFNgamma released which
• activates macrophages
• Augments phagocytosis
• Secretes TNF,IL1,Chemokine
• Promotes inflammation
• IL12 amplifies TH1response
IL17 , IL22, chemokines secreted
• -recruits neutrophils and
monocyte to reaction and
promote inflammation
• - IL12 amplifiesTH17 response
CLONAL SELECTION
Normal person has
lymphocytes specific for a
large number of antigens,
but when an antigen enters it
selectively activates the
antigen specific cells and
their proliferation occurs

50. Mechanism of T-cell mediated contact dermatitis

53. MHC 2
Antigen
T-Cell

55. IL2
released

56. Th1 cells
Clonal selection :
multiplication of sensitized
Th1 cells

59. Macrophages
IL1, TNF

61. Pathogenesis of tuberculosis and tuberculin test
Mtb activate TLR2 which
makes apc produce IL12

63. T Cell-Mediated Cytotoxicity
 Mediated by CD8+ T cells
 Sensitized CD8+ T cells kill antigen-bearing target cells
 Two mechanisms:
a)Perforin-granzyme-dependent killing  cause
perforation of plasma membrane
b)Fas-FasL-dependent killing  activation of apoptosis
Seen in
Graft rejection, virus infections, tumor immunity

64. APOPTOSIS
o Intrinsic Pathway
o Mitochondria , regulated by
Bcl2
o Cytochrome C released
which attaches to APAF
complex
o Forms Apoptosome
o Activation of initiator
caspase (8/9)
Extrinsic Pathway
 Extracellular signals
 Surface death
receptors(fas)
 Adaptor protein(FADD)
binds to Fasl
 Activation of initiator
caspase(8/9)
Executional
cascpase 3/6
Apoptotic
fragmentation
GRANZYME
Fas-FasL-
dependent
killing
Fas-FasL-
dependent
killing

65. Perforin-granzyme-dependent killing

66. Fas-FasL-dependent killing

68. Hypersensitivities 68
SUMMARY
4 types of hypersensitivities (Gel and Combs classification)
Immune
Name system involved Effectors Effects Onset
Type 1 “Atopic” Humoral (IgE) mast cells inflammation seconds
eosinophils (anaphylaxsis)
Type II “Cytotoxic” Humoral/ macrophages cell destruction hours
Complement complement (hemolysis)
Type III “Im. Complex” Humoral/ granulocytes inflammation hours
Complement
Type IV “Delayed type” Cell-mediated macrophages inflammation days
-- TH1