1. Types of Hypersensitivity
Excessive immune response in a sensitized individual leading to tissue damage.
Types of Hypersensitivity:
Types I,II,III------>Immediate, Abs.
Type IV >Delayed, T cells.

2. Cooms and Gell (in the early 1960s) Type I, II, III:
Cooms and Gell (in the early 1960s) Type I, II, III: Ab mediated Type IV: T cell mediated TYPE I :IgE-mediated Reactions Immediate hypersensitivity TYPE II: ANTIBODY-MEDIATED CYTOTOXIC Reactions TYPE III: IMMUNE COMPLEX REACTIONS TYPE IV: T-CELL-MEDIATED, DELAYED-TYPE HYPERSENSITIVITY (DTH)

3. 1. Basic concepts
Hypersensitivity reactions are 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 dysfuntion.
Allergen：the antigens that give rise to immediate hypersensitivity
Atopy：the genetic predisposition to synthesize inappropriate levels of IgE specific for external allergens
Types of hypersensitivity：I、II、III、IV

4. 2. Type I hypersensitivity
1)、Characteristics
2)、Components and cells
3)、The process and mechanism
4)、Commen diseases of type I Hypersensitivity
5)、Therapy for type I Hypersensitivity

5. Type I Hypersensitivity
Known as:
Immediate hypersensitivity
Anaphylaxis
IgE-associated immune responses
Immunreaktionen der Haut

6. 1) Characteristics Occur and resolve quickly Mediated by serum IgE
Systemic and regional tissue dysfuntion
Genetic predisposition

7. pollen、dust mite、insects etc
2) Components and cells in Type I hypersensitivity
Allergen ：
pollen、dust mite、insects etc
selectively activate CD4+Th2 cells and B cells
Allergin（IgE）and its production
IgE： mainly produced by mucosal B cells
IL-4 is essential to switch B cells to IgE production
Only Ab that can bind mast cells.
Cross linking of IgE Fc receptors leads to Mast cell degranulation.
High affinity receptor of the IgE on mast cell and basophil
Eosinophil

9. Pathogenic mechanisms
* First exposure to allergen
Allergen stimulates formation of antibody (Ig E type) Ig E fixes, by its Fc portion to mast cells and basophiles
* Second exposure to the same allergen
It bridges between Ig E molecules fixed to mast cells leading to activation and degranulation of mast cells and release of mediators
Three classes of mediators derived from mast cells:
1) Preformed mediators stored in granules (histamine)
2) Newly sensitized mediators:
leukotrienes, prostaglandins, platelets activating factor
3) Cytokines produced by activated mast cells, basophils
e.g. TNF, IL3, IL-4, IL-5 IL-13, chemokines
* These mediators cause: smooth muscle contraction,
mucous secretion and bronchial spasm, vasodilatation,
vascular permeability and edema

10. Type-I Hypersensitivity: Animation I
Production of IgE in Response to an Allergen

11. Type-I Hypersensitivity: Animation II
Allergen Interaction with IgE on the Surface of Mast Cells triggers the Release of Inflammatory Mediators

12. Summary of Mast cell activation
IgE
Fc Receptor
Mast cells
Histamine
granule release
activated phospholipase A2
arachidonic acid
cyclo-oxygenase
pathway
lipoxygenase
pathway
histamine,proteolytic enzymes,
heparin, chemotactic factors
prostaglandins
leukotrienes
Preformed Mediators
Newly Synthesized

13. Physiological Effects of mast cell mediators
Chemo-attractants
Attract neutrophils,
eosinophils,
monocytes and
basophils
NCF
ECF
LTB4 Y Y
IgE
Fc Receptor
Activators
Mast cells
Histamine
PAF
Tryptase
Kininogenase
vasodilatation &
vascular permeability
Histamine
and other
mediators
Microthrombi
Activation of C
Kinins-->vasodilatation
spasmogens
Bronchial smooth muscle
contraction, mucosal
oedema, mucus
secretion
Histamine
Prostaglandins
Leukotrienes

15. Type I Hypersensitivity Reaction

17. Anaphylaxis
* Systemic form of Type I hypersensitivity * Exposure to allergen to which a person is previously sensitized * Allergens: Drugs: penicillin Serum injection : anti-diphtheritic or ant-tetanic serum, anesthesia or insect venom * Clinical picture: Shock due to sudden decrease of blood pressure, respiratory distress due to bronhospasm, cyanosis, edema, urticaria * Treatment: corticosteroids injection, epinephrine, antihistamines

18. Atopy * Local form of type I hypersensitivity
* Exposure to certain allergens that induce production of specific Ig E
* Allergens :
Inhalants:dust mite faeces, tree or pollens, mould spor.
Ingestants: milk, egg, fish, choclate
Contactants: wool, nylon, animal fur
Drugs: penicillin, salicylates, anesthesia insect venom
* There is a strong familial predisposition to atopic allergy
* The predisposition is genetically determined

19. Type I Hypersensitivity: Systemic or Localized
Systemic (Anaphylaxis shock)
Symptoms include: labored breathing, drop in blood pressure, smooth muscle contraction, bronchiole constriction (suffocation)
Localized
Examples: Hay fever (allergic rhinitis), asthma (allergic or intrinsic), food allergies, atopic dermatitis (eczema)

20. Bee venom has Mellitin which can directly trigger mast cells
Anaphylaxis to bee venom
Bee venom has Mellitin which can directly trigger mast cells

21. IgE binds to the FceRI on mast cell and basophil
Mechanism of type I hypersensitivity
Primary
Generation
Allergen
Individual
IgE
Adhesion
Secondary
IgE binds to the FceRI on mast cell and basophil
Allergen binds to the IgE on primed target cell
Crosslikage of FceRI
Degranulate and release the biological mediators
Preformed granule mediators
New generated mediators
Histamine
Bradykinin
Leukotrienes
PAF
Prostaglandin D2
Dilate capillaries,increase permeability, increase mucus secretion, contract smooth muscle
Systemic anaphylaxis
Skin
Respiratory tract
Degist tract

22. Non-steroidal anti-inflammatories
Treatment for Type I
Pharmacotherapy
Drugs.
Non-steroidal anti-inflammatories
Antihistamines block histamine receptors.
Steroids
Theophylline OR epinephrine - prolongs or increases cAMP levels in mast cells which inhibits degranulation.

24. Desensitization (hyposensitization) also known as allergy shots.
Treatment for Type I
Immunotherapy
Desensitization (hyposensitization) also known as allergy shots.
Repeated injections of allergen to reduce the IgE on Mast cells and produce IgG.

25. Type II Hypersensitivity
Cytotoxic or Cytolytic Reactions
1. Characteristic features
2. Mechanism of Type II Hypersensitivity
3. Common diseases of Type II Hypersensitivity

26. + 1. Characteristic features Primed IgG or IgM
Antigen or hapten on membrane
Injury and dysfunction of target cells

27. Type II: Cytotoxic or Cytolytic Reactions
An antibody (Ig G or Ig M) reacts with antigen on the cell surface
* This antigen may be part of cell membrane or circulating antigen (or hapten) that attaches to cell membrane

28. Mechanism of Cytolysis
* Cell lysis results due to :
1) Complement fixation to antigen antibody complex on cell surface. The activated complement will lead to cell lysis
2) Phagocytosis is enhanced by the antibody (opsinin) bound to cell antigen leading to opsonization of the target cell

29. Mechanism of cytolysis
3) Antibody depended cellular cytotoxicity (ADCC): - Antibody coated cells e.g. tumour cells, graft cells or infected cells can be killed by cells possess Fc receptors - The process different from phagocytosis and independent of complement - Cells most active in ADCC are: NK, macrophages, neutrophils and eosinophils

30. Type II Hypersensitivity Antibody-Complement Dependent Mediated Lysis
Animation: IgG or IgM reacts with epitopes on the host cell membrane and activates the classical complement pathway. Membrane attack complex (MAC) then causes lysis of the cell.
Immunreaktionen der Haut

31. A. Opsonic phagocytosis
Allergen
Stimulate
Antibody
Cell
A. Opsonic phagocytosis
Combined opsonic activities
D. ADCC of NK
C. Effect of complement
Cell injury ways of type II hypersensitivity

32. Type II Hypersensitivity Antibody-Complement Dependent Mediated Lysis
Example: Autoimmune Hemolytic Anemia

33. Type II Hypersensitivity Antibody Dependent Cell Mediated Cytotoxicity
Animation: Antibodies react with epitopes on the host cell membrane and NK cells bind to the Fc of the antibodies. The NK cells then lyse the cell with pore-forming perforins and cytotoxic granzymes

34. Drug-Induced Reactions: Adherence to Blood Components
blood cell adsorbed drug
or antigen drug metabolite
antibody to drug
complement
lysis

35. Change the function ofTarget cell
Antigen or hapten on cell
Antibody (IgG, IgM)
Activate complement
Opsonic phagocytosis
NK , phagocyte
Stimulate / block
Lyse target cell
Destroy target cell
ADCC
Target cell injury
Change the function ofTarget cell
Mechanism of Type II hypersensitivity

36. Clinical Conditions 1) Transfusion reaction due to ABO incompatibility
2) Rh-incompatability (Haemolytic disease of the newborn)
3) Autoimmune diseases
The mechanism of tissue damage is cytotoxic reactions
e.g. SLE, autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, myasthenia gravis, nephrotoxic nephritis, Hashimoto’s thyroiditis
4) A non-cytotoxic Type II hypersensitivity is Graves’s disease
It is a form of thyroditits in which antibodies are produced against TSH surface receptor. This lead to mimic the effect of TSH and stimulate cells to over- produce thyroid hormones

37. Clinical Conditions 5- Graft rejection cytotoxic reactions:
In hyperacute rejection the recipient already has performed antibody against the graft
6- Drug reaction:
Penicillin may attach as haptens to RBCs and induce antibodies which are cytotoxic for the cell-drug complex leading to haemolysis
Quinine may attach to platelets and the antibodies cause platelets destruction and thrombocytopenic purpura

38. Examples of drug-induced type II hypersensitivity
Red cells:
Penicillin, chloropromazine, phenacetin
Granulocytes:
Quinidine, amidopyridine
Platelets:
sulphonamides, thiazides

39. TYPE III HYPERSENSITIVITY
Antigen antibody immune complexes. IgG mediated
1. Characteristics
2. Mechanism of type III hepersensitivity
3. Common disease of type III hepersensitivity

40. Free Ag + Primed Ab Larger immune complex
1、characteristics
Free Ag + Primed Ab Larger immune complex
Deposit in tissue or blood vessel wall  
Inflammation

41. Types of immune complex disease
cause
antigen
site of deposition
persistent infection
bacterial, viral, parasitic, etc.
infected organ, kidney
inhaled antigens
mold, plant or animal antigen
lung
injected material
serum
kidney, skin, arteries, joint
autoimmunity
self antigen
kidney, joint, arteries, skin

42. 2、Mechanism of type III hypersensitivity
Formation of the intermediate immune complex
Deposition of the intermediate immune complex
Tissue injury by the immune complex

43. Large amount of antigen and antibodies form complexes in blood.
If not eliminated can deposit in capillaries or joints and trigger inflammation.
PMNs and macrophages bind to immune complexes via FcR and phagocytize the complexes.
BUT
If unable to phagocytize the immune complexes can cause inflammation via C’ activation ---> C3a C4a, C5a and "frustrated phagocytes".

44. "Frustrated Phagocytes"
If neutrophils and macrophages are unable to phagocytize the immune complexes these cells will degranulate in the area of immune complex deposition and trigger inflammation.
Unable to eat try to digest outside cell.
Complexing of antigen plus antibody facilitates phagocytosis and clearing of antigen
Large amounts of these complexes can lead to tissue damage

45. Immune processes involved:
“Immune complex disease”
Soluble Ag/IgG or IgM
high titers of each required
Immune processes involved:
classical complement pathway
phagocytic cells

46. Immune complexes not cleared
Activation of Complement
C3a & C5a
Inflammation
Mast cells

47. Type III hypersensitivity mechanism

48. Type III hypersensitivity mechanism

49. Type II Hypersensitivity Antibody-Mediated Cell Disfunction
Example: Myasthenia Gravis
Immunreaktionen der Haut

50. TYPE III Immune Complex Disease Localized disease
Deposited in joints causing local inflammation = arthritis.
Deposited in kidneys = glomerulonephritis.

51. Arthus Reaction

52. Serum sickness
Serum sickness from large amounts of antigen such as injection of foreign serum.
Serum sickness is usually transient immune complex disease with removal of antigen source.
Occurs when antigen enters bloodstream, circulating immune complexes form
Symptoms include:
Fever
Weakness
Rashes
And many others

53. Complement initiates mast cell degranulation
Neutrophils are chemotactically attracted to the site
Neutrophils release lytic enzyme after failed attempts to endocytose the immune complex

54. Local or systemic immune complex diseases
Soluble antigen
Body
Antibody
Immune complex
Small molecular soluble
Immune complex
intermediate molecular soluble
Immune complex
Large molecular insoluble
Immune complex
Deposit on the basement of capillaries
Eliminate by phogacytosis
Combine and activate complement system
Basophils and mast cells
Platelets
C3a,C5a,C3b
Infiltration of neutrophils
Blood Clotting Mechanisms
Release of vasoactive amine
Phagocytose complex
Release of vasoactive amine
Aggregation of platlets
Release the enzymes in lysosome
Increase vascular permeability
Increase vascular permeability
Thrombus
Edema
Tissue injury
Bleeding
Edema
Local or systemic immune complex diseases

55. common disease of type III hypersensitivity
1. Local immune complex disease
Arthus reaction ：Experimental local reaction,
Necrotic vasculitis vasculitis, Ulcer
Human local reaction: insulin-dependent diabetes mellitus (IDDM)
2. Acute systemic immune complex disease
   serum sickness 
Anti-serum Ab+Ag systemic tissue injury ,fever, arthritis, skin rash
Pinicillin、Sulfanilamide
Acute immune complex glomerulonephritis : Streptococcus infection
3. Chronic immune complex disease
SLE
Rheumatoid arthritis ：RF+IgG Deposit on synovial membrane

56. 5. Type IV hypersensitivity
1、characteristics of type IV hepersensitivity
2、 mechanism of type IV hepersensitivity
3、common diseases of type IV hepersensitivity

57. 1. Characteristics
Interaction of primed T cells and associated antigen
Infiltration of Mononuclear Cells, Inflammatory response

58. 2. Mechanism of type IV hypersensitivity
Formation of effector and memory T cells
Inflammation and cytotoxicity caused by effector T cells
1) Inflammation and tissue injury mediated by CD4+Th1
Release chemokines and cytokines
Immune injury mainly caused by infiltration of mononuclear cells and lymphocytes
2) Cytotoxicity of CD8+CTL

59. Delayed type hypersensitivity Th1 cells and macrophages
DTH response is from:
Th1 cells release cytokines to activate macrophages causing inflammation and tissue damage.
Continued macrophage activation can cause chronic inflammation resulting in tissue lesions, scarring, and granuloma formation.
Delayed is relative because DTH response arise hours after exposure rather than within minutes.

60. Stages of Type IV DTH
Sensitization stage
Memory Th1 cells against DTH antigens are generated by dendritic cells during the sensitization stage.
These Th1 cells can activate macrophages and trigger inflammatory response.

61. Stages of Type IV DTH Effector stage
Secondary contact yields what we call DTH.
Th1 memory cells are activated and produce cytokines.
IFN-g, TNF-a, and TNF-b which cause tissue destruction, inflammation.
IL-2 that activates T cells and CTLs.
Chemokines- for macrophage recruitment.
IL-3, GM-CSF for increased monocyte/macrophage

62. Stages of Type IV DTH Effector stage
Secondary exposure to antigen
Inflamed area becomes red and fluid filled can form lesion.
From tissue damage there is activation of clotting cascades and tissue repair.
Continued exposure to antigen can cause chronic inflammation and result in granuloma formation.

63. Inflammation characterized by infiltration of Mf , monocyte,
monocyte and Mf
Proliferation of T cell
Exudation and edema
Cytotoxicity
Cytokines
IL-2
TNF-b
INF-g TF
MCF
MIF
MAF
SRF
Induce
Antigen
T cell
(CD4+,CD8+)
Release
CD4+
T cell
Secondary
contact
Primed T cell
CD8+
T cell
Directly kill target cells
Inflammation characterized by infiltration of Mf , monocyte,
And tissue injury
Mechanism of type IV hypersensitivity

64. Figure 16.1 The DTH reaction

65. 3. Common disease of type IV hypersensitivity
1) Infectious delayed type hypersensitivity
OT( Old Tuberculin ) test
2) Contact dermatitis :
Paint, drug red rash, papula, water blister, dermatitis
3) Acute rejection of allogenic transplantation and
immune response in local tumor mass
Same disease (SLE), multiple immune injury ,hypersensitivity involved
Same drug (penicillin), several types of hypersensitivity

66. Tuberculin-type Hypersensitivity
Tuberculosis Patient
PPD(Ag derived from M.tuberculosis)
Erythema & Induration
Used as a diagnostic Test
Not accurate.

67. Type IV DTH Contact dermatitis
The response to poison oak is a classic Type IV.
Small molecules act as haptens and complex with skin proteins to be taken up by APCs and presented to Th1 cells to get sensitization.
During secondary exposure Th1 memory cells become activated to cause DTH.

68. Four types of Hypersensitivity Reactions
Type II
Type I Ag
Target cell Y Y Y Y
IgG
IgE
Target
cell
Fc receptor
Fc recep-
tor
Killer cell
Mast cells Y Ab
Histamine
Complement
Type III
Type IV Ag Ag
Complement Y Y Th Th
cell
Endothelial cells Ab
Macrophage Y Y
Cytokines
Neutrophils
Activated Macrophage

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