Dr. ihsan edan abdulkareem alsaimary PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY ihsanalsaimary@gmail.com mobile : 009647801410838 university of basrah - college of medicine - basrah -IRAQ

1. Dr. Ihsan Edan Alsaimary (Ph.D)
Dept. Microbiology , Coll. Medicine , Univ. Basrah

3. Impact of allergic diseases
Allergic condition Estimated number
affected (million)
Allergic rhinitis 19.6
Chronic sinusitis 32.5
Contact dermatitis & eczema 5.8
12
Skin rashes
Asthma 9-12
Anaphylaxis 1-2

4. 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.

5. Hypersensitivity Mechanisms
 Type I: IgE mediated
 Type II: Tissue specific
 Type III: Immune complex mediated
 Type IV: Cell mediated
 Type V: Stimulatory ?!

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

7. Type I or Immediate
Hypersensitivity
Egg Albumin
Repeat Inj. 2 Weeks later
Dies from asphyxia
Anaphylaxis:

8. Guinea Pig dies from anaphylaxis.
Egg albumin IgE Abs Mast cells
Histamine
•Bronchoconstriction
•Vasodilation
Lungs

9. Vasodilatation:
Loss of intravascular fluid Shock
Epinephrine Life saving drug.
Endothelial cells

10. Sensitization against allergens
and type-I hypersensitivity
B
cell
Histamine,
tryptase,
kininegenase,
ECFA
Leukotriene-B4, C4, D4,
prostaglandin D, PAF
Newly
synthesized
mediators
TH2
Mast cells
Plasma
cell
IgE

11. Alternate Pathways of Mast Cell Activation
Y IgE
Histamine
Mast cells
Fc Receptor
Complement
C3a, C5a
Anaphylotoxins
Drugs (calcium
ionophore, codeine,
morphine, mellitin,
In addition to the traditional immunological mechanism of
Mast cell activation , they can also be activated through
alternative pathways that bypass IgE. The common feature
in each case is the influx of Calcium ions which triggers mast
cell degranulation and release of mediators.

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

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

14. Clinical Examples
 Hay fever and Asthma----To pollen,
house dust, pets etc.
 Urticaria(Hives)---Drugs,food.
Reddening and itching of skin.
 Systemic anaphylaxis---Inj. of
Penicillin,Insect bites.

15. Allergic reaction in the skin
eczema

16. List of Allergens
 Grasses/Pollens
 Weeds
 Foods-->Crab, shrimp, potato,
tuna etc
 Epidermals--> dog,cat, mouse
 Insect bites
 House dust
 Molds
 Drugs

17. Mediators of allergic reaction:
 Allergens:
 Proteins or Haptens bound to
proteins.
 Trigger IgE
 IL-4, IL-5, IL-13 and Th2
response.

18. IgE Abs
 2) IgE:
 Only Ab that can bind mast
cells.
 Cross linking of IgE Fc
receptors leads to Mast cell
degranulation.

19. Skin test for allergy

20. Skin test for allergy

21. 25
IgE levels in immediate
hypersensitivity
IgE
Helminthic
(worm)
infections
Atopic diseases
allergic asthma
allergic eczema
hay fever
Miscellaneous diseases
 Bronchopulmonary
 aspergillosis
 IgE myeloma
Immunodeficiency
 hyper-IgE syndrome
 Wiscott-Aldrich
syndrome

22. Allergy symptoms and cAMP
β-agonist
(epinephrine, isoproterenol)
α-blocker
(phenoxybenzamine)
Phosphodiasterase
inhibitor
(theophylline)
α-agonists
phenyl epinephrine, nor-
epinephrine
β-blocker
(propanolol)
cAMP
Relief from symptoms Worsening of symptoms

23. Treatments for allergy
 Symptomatic
Receptor blockers
antihistamine, antileukotriene
Bronchodialators
β-agonists (inhahants)
 Prevent mast cell degranulation
Ca influx inhibitor (chromolyn sodium)
Phosphodiesterase (theophylline)
 Immunotherapy
Hyposensitization
Anti-IgE(Fc) Ab

24. Principles of immunotherapy

25. Role of IgE in parasitic worm infections
Gut Lumen parasitic worm
Soluble
Ag
APC
Th cells
B cells
Y Y
Y IgE
Histamine
& other
mediators
Mast cells
Eosinophils
Y
Y
Y
B cells
Y
gut mucosa

26. Hypersensitivity Types II-V
 Type II: Cytotoxic (ITH)
 Type III: Toxic Complex (ITH)
 Type IV: T Cell-Mediated (DTH)
 Type V: Stimulatory

27. Type II hypersensitivity
role of complement and phagocytes

28. Type II hypersensitivity induced
by exogenous agents

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

30. Blood Group Ags
Blood Group Ag Ab
A A anti-B
B B anti-A
AB A&B None
O ---- anti-A&
anti-B
Abs against blood group Ags are naturally
present and are IgM type.

31. ABO Blood Group Reactivity
blood group genotypes antigens
antibodies to
(phenotype) ABO in serum
A AA, AO A anti-B
B BB, BO B anti-A
AB AB A and B none
O OO H anti-A/B

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

33. ABO Blood
Group Antigens
Precursor
oligosaccharide H antigen
B antigen
NAcGA
Gal
NAG
Fuc
NAG Gal
NAG Gal
Fuc
H
Fuc
Gal
Gal
NAG
B
A
A antigen
NAcGA (N-acetylgalactoseamine)
Gal (galactose)

34. Transfusion Reaction:
+Complement
Fc
K
cell lysis
Result:
Anaphylactic Shock due to Complement
activation.
RBC
RBC
IgM

35. Hemolytic Disease of the New Born
RhD-ve mother
RhD +ve fetus
Anti-RhD Abs
RhD +ve fetus

36. ‘A’ blood group
mother
‘B’ blood group fetus
Anti-B Abs
If mother and fetus have different blood
groups, hemolytic disease does not occur.

37. Child with Hemolytic Disease
 Mother is Rh- and fetus is Rh+.
 Fetal RBC entering mother, will trigger anti-
Rh Abs.
 Such Abs cross placenta and can destroy
fetal RBC.

38. Prophylaxis
RhD-ve mother
RhD +ve fetus
Anti-RhD Abs
RhD +ve fetus

39. Hemolytic Disease of the
Newborn
RhD positive
red cells
RhD
negative
mother
RhD positive
fetus
Lysis
Of
RBC’s
B cell
anti-RhD
first birth post partum subsequent
anti-RhD
RhD positive
fetus

40. Prophylaxis
Inject Anti-RhD Abs mothers
immediately after delivery
Prevents sensitization

41. Characteristics of Cytotoxic
Hypersensitivity
 Directed against cell surface or
tissue antigen
 Characterized by complement
cascade activation and various
effector cells

42. Complement
 Formation of membrane attack complex
(lytic enzymes)
 Activated C3 forms opsonin recognized by
phagocytes
 Formation of chemotactic factors
- Effector cells possess Fc and
complement receptors
• macrophages/monocytes
• neutrophils
• NK cells

43. Examples of Type II
Hypersensitivity
 Blood transfusion reactions
 Hemolytic disease of the newborn (Rh
disease)
 Autoimmune hemolytic anemias
 Drug reactions
 Drug-induced loss of self-tolerance
 Hyperacute graft rejection
 Myasthenia gravis (acetylcholine receptor)
 Sensitivity to tissue antigens

44. Diseases associated with immune complexes
 Persistent infection
- microbial antigens
- deposition of immune complexes in kidneys
 Autoimmunity
- self antigens
- deposition of immune complexes in kidneys,
joints, arteries and skin
 Extrinsic factors
- environmental antigens
- deposition of immune complexes in lungs

45. Type III Hypersensitivity
Immune complexes not cleared
Activation of Complement
C3a & C5a
Mast cells
Inflammation

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

47. Serum sickness

48. Systemic lupus erythematosus

49. Type III hypersensitivity
mechanism

50. Type III hypersensitivity
mechanism

51. Inflammatory Mechanisms in Type
III
 Complement activation
- anaphylatoxins
- Chemotactic factors
 Neutrophils attracted
- difficult to phagocytize tissue-trapped
complexes
- frustrated phagocytosis leads to tissue
damage

52. Disease Models
 Serum sickness
 Arthus reaction

53. Serum Sickness

54. Arthus Reaction

55. Type IV Hypersensitivity
 Mediated by T cells
 Delayed, takes 24-48 hours
 Examples:
 1) Contact Hypersens:
Nickel
 Chromate
 Poison Ivy

56. Contact Dermatitis

57. Reaction to Poison Ivy

58. Mechanism of Type IV Hypersens.
skin
poison Ivy
APC Th1
Inflammation
urushiol
serum protein
Mo

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

60. Tuberculin test

61. Role of DTH in Infection:
Plays a major role in acute infections
caused by intracellular pathogens.
Ex: Listeria, Salmonella, Brucella
Macrophage
Th1

62. DTH can cause severe damage to the
host during chronic intracellular
infections.
Ex: Tuberculosis
Leprosy
Leishmaniasis
T M
cavities

63. Leprosy
Hypo
response
Normal
response
Hyper
response
Fluid
filled
blebs
with
bacteria
small
skin lesion
Severe
tissue
damage

64. Granuloma in a leprosy patient

65. Leprosy:
 1)Tuberculoid:
 Strong immune response
 +ve skin test
 Few leprae bacilli
 Severe nerve damage
 2) Lepromatous:
 Weak or no immune response
 -ve skin test
 Large numbers of leprae bacilli
 Less severe nerve damage

66. Immediate hypersens. Delayed hypersens
 Immediate Delayed
 Abs(IgE, IgG, IgM) T helper cells(Th1)
 Histamine, Leuko- Cytokines(IFN-, MAF)
trienes
 Inflammation consists Macrophages and T cell
mainly of neutrophils
 Protection: IgE against Protection: Acute intra-
parasites cellular pathogens and
tumors

67.  Immediate hypersens. Delayed hypersens
 Most reactions cause Damage during chronic
damage to host intracellular infections.
Ex: Allergies,immune Ex: granuloma,
complex disease contact hypersens.

68. T-Cell Mediated Hypersensitivity
(Type IV / Delayed-Type)

69. Manifestations of T-Cell Mediated
Hypersensitivity
 Allergic reactions to bacteria, viruses
and fungi
 Contact dermatitis due to chemicals
 Rejection of tissue transplants

70. General Characteristics of
DTH
 An exaggerated interaction between antigen and
normal CMI-mechanisms
 Requires prior priming to antigen
 Memory T-cells recognize antigen together with
class II MHC molecules on antigen-presenting
cells
 Blast transformation and proliferation
 Stimulated T-cells release soluble factors
(cytokines)
 Cytokines
- attract and activate macrophages and/or eosinophils

71. Inducers of
Type IV
Hypersensitivity

72. Types of Delayed
Hypersensitivity
Delayed Reaction maximal
reaction time
Jones-Mote 24 hours
Contact 48-72 hours
tuberculin 48-72 hours
granulomatous at least 14
days

73. Jones-Mote Hypersensitivity
 Now referred to as “cutaneous basophil
hypersensitivity”
 Basophils are prominent as secondary infiltrating
cells.
 Basophilic infiltration of area under epidermis
 Induced by soluble (weak) antigens
 Transient dermal response
 Prominent in reactions to viral antigens, in contact
reactions, skin allograft rejections, reactions to
tumor cells and in some cases of hypersensitivity
pneumonitis (allergic alveolitis)

74. Contact Hypersensitivity
 Usually maximal at 48 hours
 Predominantly an epidermal reaction
 Langerhans cells are the antigen
presenting cells
- a dendritic antigen presenting cell
- carry antigen to lymph nodes draining skin
 Associated with hapten-induced eczema
- nickel salts in jewellry
- picryl chloride
- acrylates
- p-Phenylene diamine in hair dyes
- chromates
- chemicals in rubber

75. Poison Ivy
contact
dermatitis

76. Tuberculin Hypersensitivity
 Maximum at 48-72 hours
 Inflitration of lesion with mononuclear
cells
 First described as a reaction to the
lipoprotein antigen of tubercle bacillus
 Responsible for lesions associated with
bacterial allergy
- cavitation, caseation, general toxemia seen in
TB
 May progress to granulomatous reaction
in unresolved infection

77. Granulomatous
Hypersensitivity
 Clinically, the most important form of DTH,
since it causes many of the pathological
effects in diseases which involve T cell-
mediated immunity
 Maximal at 14 days
 Continual release of cytokines
 Leads to accumulation of large numbers of
macrophages
 Granulomas can also arise from persistence of
“indigestible” antigen such as talc (absence of
lymphocytes in lesion)

78. Epitheloid Cell Granuloma
Formation
 Large flattened cells with increased
endoplasmic reticulum
 Multinucleate giant cells with little ER
 May see necrosis
 Damage due to killer T-cells recognizing
antigen-coated macrophages, cytokine-
activated macrophages
 Attempt by the body to wall-off site of
persistent infection

79. Granuloma Formation

80. Examples of Microbial-Induced
DTH
 Viruses (destructive skin rashes)
- smallpox
- measles
- herpes simplex
 Fungi
- candidiasis
- dematomycosis
- coccidioidomycosis
- histoplasmosis
 Parasites (against enzymes from the eggs lodged
in liver)
- leishmaniasis
- schistosomiasis

81. Type V Stimulatory
Hypersensitivity
 Interaction of autoantibodies with cellular
receptors
 Antibody binding mimics receptor-ligand
interaction
 Examples
- thyroid stimulating antibody (mimics thyroid
stimulating hormone [TSH] of pituitary binds
to thyroid cell receptor
- activation of B-cell by anti-immunoglobulin

82. Innate Hypersensitivity Reactions
 Toxic shock syndrome (S. aureus TSS toxin)
- hypotension, hypoxia, oliguria and microvascular abnormalities
- excessive release of TNF, IL-1, IL-6
- intravascular activation of complement
 Septicemia - Septic Shock
- primarily due to lipopolysaccharide
 Adult respiratory distress syndrome
- overwhelming accumulation of neutrophils in lung
 Platelet aggregation/adherence to macrophages by gram-
positive bacteria
 Superantigens
- Gram positive enterotoxins
- react directly with T-cell receptors and induce massive cytokine
release

83. The End