Hypersensitivity seminar

1. HYPERSENSITIVITY

2. IMMUNOPATHOLOGY
■ Defects or malfunction in either innate or acquired immune
response provokes the illness or disease.
■ Overactive immune response-Hypersensitivity
■ Inappropriate reaction to self-autoimmunity
■ Ineffective immune response-immunodeficiency

3. HYPERSENSITIVITY
■ Undesired immune response
■ Hypersensitivity is a state existing in a previously sensitized
individual which leads to tissue damage on later exposure to
the allergen.
■ It depends on the individual.

4. HISTORY
■ 2000 years ago, Lucretius states that “Differences are so great that one
man’s meat is another man’s poison”.
■ Paul Poiter and Charles Richet- Pysalia the jelly fish- aqueous glycine
extract administered to 5 dogs but they didn’t die. But after the second
dose immediately reacted with illness, vomiting, diarrhea, asphyxia and
died within few minutes.
■ Hence they coined this overreaction as anaphylaxis.
■ Awarded Noble Prize in physiology or medicine in 1913 .

5. ■ 1st exposure-sensitization
■ 2nd exposure- shocking dose
■ Anaphylaxis- without protection rather than an anamnestic (non
forgetting) protective response.
■ Anaphylaxis :
■ humoral immunity – immediate hypersensitivity
■ Cell- mediated immunity – delayed-type hypersensitivity.

6. CAUSES OF HP DISEASES
■ Reaction against environmental antigens – production of IgE
antibodies cause allergic reactions.
■ Reaction against microbes
■ Autoimmunity

7. CLASSIFICATION OF HYPERSENSITIVITY
■ In 1960s Gell and Coombs classified it into 4 types .
■ Type I – Immediate anaphylaxis
■ Type II – antibody – dependent cytotoxic hypersensitivity
■ Type III – Immune complex-mediated cytotoxicity
■ Type IV – delayed type hypersensitivity

9. TYPE I HYPERSENSITIVITY
■ CHARACTERISTICS:
■ occur quickly after 2nd exposure to the antigen or allergen
■ Inflammation reaction consists of accumulation of basophils, eosinophils,
neutrophils,Th2 cells
■ IgE mediated response
■ Antigens – plants, foods, drugs, insect products, mold spores, animal hair,
foreign serum, vaccines
■ Atopy：the genetic predisposition to synthesize inappropriate levels of
IgE specific for external allergens

10. MECHANISM

11. Slow reacting substance of anaphylaxis

12. Degranulate and release the biological mediators
Preformed granule mediators New generated mediators
Histamine Bradykinin Leukotrienes Platelet activating factor Prostaglandin D2
Dilate capillaries,increase permeability, increase mucus secretion, contract smooth muscle
Systemic anaphylaxis Skin Respiratory tract Degist tract

13. Drug therapy: sodium
chromoglcate-stabilize PM &
inhibit degranulation
Antihistamine &
acetyl salicylic acid
Treat target organs

14. TYPE II HYPERSENSITIVITY
■ CHARACTERISTICS:
■ Antibody dependent cell-mediated cytotoxicity (ADCC)
■ Antibody (IgM & IgG) activate the complement system which lyse the cell
and destroy it.

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

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

17. DISEASES
■ TRANSFUSION SYNDROME
■ ERYTHROBLASTOSIS FOETALIS
■ DRUG INDUCEDAUTO HEMOLYTICANEMIA

18. Free Ag + Primed Ab Larger immune complex
Deposit in tissue or blood vessel wall
Inflammation
TYPE III HYPERSENSITIVITY

19. MECHANISM
Formation of the intermediate immune complex
Deposition of the intermediate immune complex
Tissue injury by the immune complex

20. 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
Combine and activate complement system
C3a,C5a,C3b
Infiltration of neutrophils
Phagocytose complex
Release the enzymes in lysosome
Tissue injury
Eliminate by phogacytosis
Platelets
Thrombus
Aggregation of platlets
BloodClotting Mechanisms
Release of vasoactive amine
Increase vascular permeability
Bleeding Edema
Basophils and mast cells
Release of vasoactive amine
Increase vascular permeability
Edema
Local or systemic immune complex diseases

21. 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

22. TYPE IV HYPERSENSITIVITY
1、characteristics of type IV hepersensitivity
2、 mechanism of type IV hepersensitivity
3、common diseases of type IV hepersensitivity

23. 1. Characteristics
Interaction of primedT cells and associated antigen
Infiltration of Mononuclear Cells, Inflammatory response

24. 2. Mechanism of type IV hypersensitivity
Formation of effector and memoryT cells
Inflammation and cytotoxicity caused by effectorT 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

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

26. Common disease of type IV hypersensitivity
1) Infectious delayed type hypersensitivity
OT( OldTuberculin ) 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

27. IMMUNITY
27

28. Immunology
■ Immunology is the study of our
protection from foreign
macromolecules or invading
organisms and our responses to
them.
■ Host – e.g. me!!!!
■ Foreign macromolecule, antigen – e.g. virus protein, worm, parasite
(Everything that should not be in my body)
28

29. 29

30. Dr.T.V.Rao MD 30

31. Immunology
■ Clinical Application
Host defense reactions to foreign
Antigen
Substance is not self
Antigen recognizing Cell Mediated
Host defense functions
31

32. Definitions■ Immune system = cells, tissues, and molecules that mediate resistance to
infections
■ Immunology = study of structure and function of the immune system
■ Immunity = resistance of a host to pathogens and their toxic
effects
■ Immune response = collective and coordinated
response to the introduction of foreign substances in
an individual mediated by the cells and molecules of
the immune system
32

33. Role of the immune system
■ Defense against microbes
■ Defense against the growth of tumor cells
– kills the growth of tumor cells
■ Homeostasis
– destruction of abnormal or dead cells
(e.g. dead red or white blood cells, antigen-
antibody complex)

34. Jenner - Smallpox
vaccine■ Noticed that milkmaids that had contracted cowpox did
NOT get smallpox
■ Test on an 8 year old boy, injected cowpox into him (NOT
very nice……)
■ Follwed by exposure to smallpox
■ Vaccine was invented (latin vacca means ”cow”)
34

35. First insights into mechanics of immunity…
1880’s- Metchnikoff
discovered phagocytic
cells that ingest microbes
and particles
cells conferred immunity
1890- von Behring and
Kitasato discovered
blood sera could transfer
immunity
liquid of blood conferred
immunity
Q: Which confers immunity…
cells or serum?
35
Emil von Behring
S. Kitasato
Elie Metchnikoff

36. Louis
Pasteur
watching as
Joseph
Meister
receives
attenuated
rabies
vaccine
(1885)
36

37. Subjects In Immunology
■ Cell mediated host defense functions
■ Antibody related defense mechanisms
■ Hypersensitivity reactions ( IncludingAllergy )
■ Auto Immunity
■ Immunodeficiency
■ Transplantation
37

38. What is immune system?
■ Protect against pathogens
■ Eliminate damaged or malignant cells
38

39. What is Response to
Infection
■ Immunity
can be
Innate
(
Nonadapative
)
■ Adaptive - 39

40. Immunology is a Complex
Subject
40

41. Two types of immunity
1. Innate (non-adaptive)
– first line of immune response
– relies on mechanisms that exist before infection
2. Acquired (adaptive)
– Second line of response (if innate fails)
– relies on mechanisms that adapt after infection
– handled byT- and B- lymphocytes
– one cell determines one antigenic determinant
41

42. Distinction Between Innate
and Adaptive Immune
Responses
■ Innate immunity is non-adaptive and helps to initiate adaptive
immune responses (= first line of defense – but LIMITED)
– Immediate (0-4 hours)
■ Adaptive immunity provides a more universal line of defense
and has long-lived memory to provide protection upon re-
infection
– Second line of defense
– Generation of Ag-specific effector cells
– Early (4-96 hours)
– Late (>96 hours)
42

43. THE EVOLUTION OF
IMMUNITY
43
Immunity
Innate immunity Acquired immunity
Non-specific SpecificImmediate onset Delay onset
Humoral
Immune Response
Cellular
Immune Response
Antibodies production T-cell activation

44. Basic classification of
Immunity
Designed by Dr.T.V.Rao MD 44

45. Different types of
Immunity
A - Non specific
1 Species
2 Racial
3 Individual
B Specific
1.Species
2 Racial
3 Individual 45

46. The immune system
46
Immune system
•Anatomic barriers (Skin, mucous
membranes)
•Physiological barriers
(temperature, pH)
•Phagocytic Barriers (cells that eat
invaders)
•Inflammatory barriers (redness,
swelling, heat and pain)
•Antigen specificity
•Diversity
•Immunological memory
•Self/nonself recognition
Innate (non-specific) immunity Adaptive (specific) immunity

47. Innate, Surface Defenses
■ Skin
– physical barrier to microbes
– Keratin resistant to most bacterial enzymes & toxins
– secretions are acidic pH 3-5
■ Mucosa
– physical barrier & produces a variety of protective
chemicals
■ Gastric mucosa
– very acidic & produces proteolytic enzymes
■ Saliva & lacrimal fluid contain lysozyme
■ Mucous
– traps bacteria & moves them away from epithelial

48. 48

49. Different types of
ImmunityA - Non specific
1 Species
2 Racial
3 Individual
B Specific
1.Species
2 Racial
3 Individual
49

50. Types of Immunity
Acquired Immunity
A Active
Natural
Artificial
B Passive
Natural
Artificial
50

51. Resistance to Infectious Disease
■ Innate immunity (nonspecific resistance)
protects us against all pathogens: “over-the-counter defenses”
■ Adaptive immunity (specific resistance) is
defenses against specific pathogens: “prescription defenses”

52. Innate Immunity
Innate Immunity is resistance that is
preexisting and is not acquired through
contact with a foreign substance known
as antigen
Individual has innate Immunity by
genetic or constitutional Make Up
Non related to prior contact with Microorganisms or Immunization
52

53. Physical and Chemical Barriers
■ Skin, mucus membranes
■ Cilia, mucus, reflexes
■ pH, lysozyme, fatty acids,
defensins
■ Normal flora
■ Genetic resistance
– species differences
– individual differences

54. It is Dependent on
■ Species
■ Race
( Racial )
■ Individual
54

55. Species and Immunity
■ Immunity refers to total resistance
to a Pathogen by all members of
the species
■ Eg Human do not get plant
diseases
Humans do not get some animal
diseases
55

56. Race - Immunity
■ Genetic resistance Plasmodium
falciparum malaria resistance in
Africa
■ In sickle cell anemia immune to
malaria
56

57. Individual - Immunity
■ Twins homozygous
twins exhibit similar
resistance
■ Susceptibility similar in
Leprosy
■ Tuberculosis similar
resistance
57

58. Factors Influencing Innate Immunity
■ Placenta prevent infection
■ But still can infected with
Toxoplasmosis, Rubella, CMV
and Herpes infection.
■ Can produce congenital
malformations
58

59. Immunity In Adults
■ Polio infection
, and
Chickenpox
highly severe
in adults.
■ Enlargement
of prostate
59

60. Hormonal Influence on
Immunity
■ Diabetes
mellitus
■ Hypothyroidism
in adults
■ Adrenal
dysfunction
■ Stress increases
steroids
predisposes to 60

61. Nutrition
■Some
protectio
n in some
diseases
61

62. Mechanism's of Immunity
■ Epithelial surfaces
Skin and Epithelial surfaces cover the body and protects the
individuals
Healthy skin poses bactericidal influence, salt, drying sweat , Long
fatty acids
Wet hand predisposes to Mycotic and pyogenic infections
62

63. Mucous Membranes
■Respiratory
tract Shape
of Nose,
Nasal
orifice
63

64. Mechanism's of Immunity
■Epithelial surfaces
Skin and Epithelial surfaces cover the
body and protects the individuals
Healthy skin poses bactericidal influence, salt, drying sweat , Long
fatty acids
Wet hand predisposes to Mycotic and pyogenic infections
64

65. ■ Cilia in
Respiratory
tract
■ Propel the
foreign particles
■ Respiratory
secretion contain
65

66. Oral Cavity
■Saliva
■Stomach HCl
■Large intestine
large number
of bacteria
66

67. Conjunctiva
■ Contain lachrymal secretions
■ Tears contains antibacterial
substances
■ Lysozyme present except in CSF,
Sweat, Urine
67

68. Other Mechanisms
■ Flushing
action of
urination
drives out
Microbes in
the Urethra
■ Spermine in
68

69. Innate, Internal Defenses
■ Phagocytes
– Macrophages: derived from monocytes
■ Free Macrophages: roam through tissues
■ Fixed Macrophages: Kupffer cells (liver) & microglia (brain)
■ Ingest cellular debris, foreign material, bacteria, fungi
– Neutrophils: ingest pathogens
– Eosinophils: weakly phagocytic of pathogens. Attack parasites
(degranulation)
– Mast Cells: phagocytic of various bacteria

70. Antibacterial Substances
■ May be present Blood as
Complement
■ Antibacterial substances in
Blood
Betalysin,
Leukin
Lactoperoxidase in Milk 70

71. Interferon's in
Immunity
■ Interferon's (IFNs) are natural proteins produced by the cells of
the immune system of most vertebrates in response to
challenges by foreign agents such as viruses, parasites and
tumour cells. Interferon's belong to the large class of
glycoproteins known as cytokines
■ Interferon's are more useful than Antibodies
71

72. Microbial Antagonists
Normal flora Help us
■ Normal Microbial flora
Dr.T.V.Rao MD 72

73. Normal flora Helps Us
■ We harbour near 1014 bacteria.This group of organisms, traditionally
referred to as "normal flora" (although they are not plants) is composed
of a fairly stable set of genera, mostly anaerobes.While each person has
a relatively unique set of normal flora, members of the Streptococcus and
Bacteroides make up a large percentage of the inhabitants.These
organisms contribute to our existence in several ways’
73

74. Other Normal Flora
■ Streptococcus and Bacteroides make up a large percentage of
the inhabitants.These organisms contribute to our existence in
several ways’
■ Help us by competing with pathogens such as Salmonella
■ Help us by providing vitamins or eliminating toxins
(e.g. Bacteroides)
■ Harm us by promoting disease (e.g. dental caries)
■ Cause neither help nor harm (e.g. "commensals").
74

75. Normal Bacterial Flora of
Conjunctiva
75

76. Cellular Factors in Innate Immunity
■ Metchnikoff 1883
■ Cells called as Phagocytic cells
Microphages,
Macrophages
Microphages Polymorph nuclear neutrophils
Macrophages Histiocytes wandering Amoeboid
cells
Monocytes in Blood
Cells in Reticuloendothelial System
76

77. Phagocytes
■ Phagocytes = eating cells
– Neutrophils (PMNs) are present in
the highest numbers in blood
– Macrophages (“big eaters”) in the
tissues encounter the pathogen first
■ Secrete cytokines --->
inflammation, systemic responses

78. How Phagocytes act
■ Phagocytic cells reach the site o
Inflammation
■ Attracted by Chemo tactic
substances
■ Ingest particle material
78

79. Cellular and Inflammatory
Components of Innate Immunity
■ Cellular
– Phagocytic
cells
■ Inflammator
y
– Vasodilation
– Capillary
79

80. 80

81. Phagocytosis

82. Capsule In Innate immunity
■ Some bacteria have
capsules
■ Streptococcus pneumonia
■ Klebsiella pneumonia
■ Bacteria with capsules are
not ingested by
Phagocytes unless in the
presence of opsonins
■ Bacteria are fixed against
fixed surface such as alveoli
82

83. Mechanism of Phagocytosis
■ Bacteria are
phagocycosed into
vacuole (Phagosome)
■ Forms phagolysosome
■ Lytic enzymes destroy
the Bacteria
■ Brucella and Leprosy
83

84. Natural Killer cells
NK cells
84

85. Mediators of inflammation
Vasodilation, smooth muscle contraction
Increased vascular permeability
Edema, extravasation
(histamines, prostaglandins, kinins)
Extravasation
Chemo taxis
(cytokines, chemokine's, complement)
Systemic response- fever, acute-phase
proteins
C-reactive protein

86. Interferon  and b Function

87. Anti-Viral Interferons
■ IFN and IFNb made by virus-
infected cells
■ Not virus-specific
■ Bind neighboring host cells and
induce synthesis of anti-viral
proteins to block virus
replication

88. Natural Killer Cells
■ All nucleated cells in body have
membrane MHC = tissue typing
antigens
■ In virus-infected cells, MHC is reduced
in amount or contains virus peptides
■ NK cells recognize this ‘altered’ MHC
and kill virus-infected cells (also tumor
cells)

89. Role of Natural killer Cells
■ Natural killer cells (or NK cells) are a type of cytotoxic
lymphocyte that constitute a major component of the Innate
immune system. NK cells play a major role in the rejection of
tumours and cells infected by viruses.The cells kill by releasing
small cytoplasmic granules of proteins called perforin and
granzyme that cause the target cell to die by apoptosis
89

90. Inflammation
■ Tissue Injury
■ Irritation
■ Arterioles constrict initially and
then dilate
■ Slow the Blood flow and Margi
nation of Leucocytes
■ Escape into tissues by diapedesis
and accumulate in large numbers 90

91. 91

92. Inflammation
■ Outpour plasma, and dilute the
toxic material
■ Produce fibrin barrier and
localized the infection
92

93. Fever
■ Natural defense
Mechanisms
■ Destroy infectious
agents
■ Therapeutic –
Trepanoma palladium
■ Production of
Interferon's
93

94. Antibacterial substances in
Blood andTissues
■ The complement system possess bacterial activity and plays
role in the bactericidal activity and destroys the pathogenic
bacteria
■ Betalysin – anthrax
■ Leukins and Plakins
■ Lactic acid found in muscles
■ Lacto peroxidase in milk
94

95. Acute Phase proteins too
play a great role in Immunity
■ Infection and Injury produces Acute phase proteins
■ C- Reactive proteins CRP
■ Mann in binding proteins
■ CRP activates alternative pathway
■ Increases host defenses
■ Prevents issue injury
■ Repair inflamed lesions.
95

96. Acute Phase proteins
■ Infection and Injury produces Acute phase proteins
■ C- Reactive proteins CRP
■ Mann in binding proteins
■ CRP activates alternative pathway
■ Increases host defenses
■ Prevents issue injury
■ Repair inflamed lesions.
96

97. Adaptive immunity:
second line of response■ Based upon resistance acquired during life
■ Relies on genetic events and cellular growth
■ Responds more slowly, over few days
■ Is specific
– each cell responds to a single epitope on an antigen
■ Has anamnestic memory
– repeated exposure leads to faster, stronger response
■ Leads to clonal expansion
97

98. Adaptive immunity:
mechanisms■ Cell-mediated immune response (CMIR)
– T-lymphocytes
– eliminate intracellular microbes that survive within phagocytes or other
infected cells
■ Humoral immune response (HIR)
– B-lymphocytes
– mediated by antibodies
– eliminate extra-cellular
microbes and their toxins
98
Plasma cell
(Derived from B-lymphocyte,
produces antibodies)

99. Cell-mediated immune
response
1.T-cell
– recognizes peptide
antigen on
macrophage in
association with
major histo-
compatibility
complex (MHC)
class
– identifies molecules
on cell surfaces
– helps body
distinguish self from
non-self 99

100. Cell mediated immune
responsePrimary response
– production of specific clones of effectorT cells and memory clones
– develops in several days
– does not limit the infection
Secondary response
– more pronounced, faster
– more effective at limiting the infection
Example - cytotoxic reactions against intracellular parasites, delayed
hypersensitivity (e.g.,Tuberculin test) and allograft rejection
100

101. Humoral immune response
1. B lymphocytes recognize
specific antigens
– proliferate and
differentiate into
antibody-secreting plasma
cells
2. Antibodies bind to specific
antigens on microbes;
destroy microbes via specific
mechanisms
3. Some B lymphocytes evolve
into the resting state -
memory cells
101

102. Antibodies (immunoglobulin's)
■Belong to the gamma-globulin
fraction of serum proteins
■Y-shaped orT-shaped polypeptides
– 2 identical heavy chains
– 2 identical light chains
■ All immunoglobulin's are not
antibodies
■Five kinds of antibodies
– IgG, IgM, IgA, IgD, IgE

103. Measurement of Immunity
■ It is not possible to measure the immunity accurately
■ Detection of antibodies
■ Detected by agglutination tests, Precipitation tests,
complement fixation HI ELISA
■ SkinTests, Schick test , DickTests
■ TuberculinTest – Delayed Hypersentivity tests inTuberculosis
103

104. Local Immunity
■ Can be produced by OralVaccines
■ Sabin's vaccine for polio given orally X Salk will not protect
Local Immunity but produces systemic Immunity
■ Locally produced Antibodies IgA protect the gut from entry of
pathogens
■ Local immunity antigen protects the individuals
104

105. Herd Immunity
■ This indicates the overall level in the community and important
in control of infections in the community (HERD )
■ When Herd immunity is low epidemics occur.
■ Eradication of communicable diseases depends on the
development of high level of herd immunity rather than high
level of Individual Immunity
105

110. ■ Immunopathology, diagnosis, and management of hypersensitivity pneumonitis.
■ Abstract
■ Hypersensitivity pneumonitis (HP) is an inflammatory interstitial lung disease caused by a wide
variety of organic particles and certain small-molecular weight chemical compounds that provoke
an exaggerated immune response in susceptible individuals.The clinical manifestations are
heterogeneous and have been classically described as acute, subacute and chronic. The chronic
form has an insidious onset over a period of months or years, with progressive dyspnea and often
evolves to fibrosis.The pathology is characterized by a bronchiolocentric interstitial mononuclear
cell infiltration, nonnecrotizing poorly formed granulomas, cellular pneumonitis and variable
degrees of fibrosis. However, morphological diagnosis of HP is complicated because the
subacute/chronic forms may be difficult to distinguish from idiopathic pulmonary fibrosis/usual
interstitial pneumonia and nonspecific interstitial pneumonia. In general, diagnosis of HP
represents a challenge for clinicians that need to weigh a constellation of clinical, laboratory,
radiographic and (when available) pathological evidence for each patient to assess the certainty
of the diagnosis.The cornerstone of therapy is antigen avoidance. Although clinical trials are
scanty, corticosteroids are usually indicated based upon expert opinion. In this review we
summarize the current evidence regarding the diagnostic criteria and therapeutic strategies as
well as the immunopathological mechanisms putatively implicated in the development of the
disease.
■ Arch Pathol Lab Med. 2008 Feb;132(2):204-5. doi: 10.1043/1543-
2165(2008)132[204:HPAIR]2.0.CO;2.
■ Hypersensitivity pneumonitis: an immunopathology review.
■ Woda BA.
■ Source