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Hypersensitivity

2. Hyperfunctioning immune response
•Autoimmunity-immune system fails to
recognise self from non self
•Immunodeficiency- deficient or absent immune
response
•Hypersensitive reaction 2 types
•Immediate-on admin of Ag rection occurs
imediately (humoral antibodies mediated types-
I,II,III)
•Delayed type-slow onset reaction with
prolonged effect(T cell mediated -type IV)

3. Type I (Immediate
Hypersensitivity)
Anaphylaxis, Allergy, Atopy,
Asthma
Type II (Antibody
mediated)
Auto Immune Hemolytic
Anemia, Good Pasture
syndrome
Type III (Immune
complex mediated)
SLE, Serum sickness, Arthus
reaction
Type IV (Delayed
Hypersensitivity)
Contact dermatitis, Multiple
sclerosis, Type I DM,
Transplant rejection,
Tuberculosis
CLASSIFICATION BASED ON
IMMUNE MECHANISMS

4. MECHANISMS OF
HYPERSENSITIVITY RN:
Type I: Immediate hypersensitivity:
•Production of IgE antibody, release of
vasoactive amines and other mediators from
mast cells; recruitment of other inflammatory
cells (late phase reaction).
•Pathologic lesions: Vascular dilatation, edema,
smooth muscle contraction, mucus production,
inflammation.

5. Immediate (type I) hypersensitivity:
•Rapidly developing reaction
•Occurring within minutes, a state of shock is
produced; may be fatal.
•In individuals previously sensitized.
1.Immediate response: vasodilatation, vascular
leakage, smooth muscle spasm, glandular
secretions.
2.Late phase: infiltration of tissue by eosinophils,
basophils, monocytes; tissue destruction, mucosal
epithelium damage.

6. Occurring
within
minutes
Occurring
in 2-24hrs

8. Prototype disorders:
•Anaphylaxis
•Allergies (food allergy, allergic rhinitis and
conjunctivitis)
•Asthma (Bronchial)
•Atopic forms (Hay fever)

9. Mast cells:
•BM derived cells, widely distributed in tissues.
•Cytoplasm bound granules+ve (metachromatic
dye); contain
1.Histamine,
2.Enzymes (protease, acid hydrolase),
3.Proteoglycans (Heparin, chondratin sulphate).
•ACTIVATION OF ANAPHYLOTOXINS: (C5a
and C3a).

10. Never forget:
1.Dendritic cells—capture antigens
2.T cells differentiate to TH-2 cells
3.IL 4 activates B cells to produce Ig E
4.Ig E attracts mast cells
(Mast cells and basophils express Ig E
receptors).
5. IL 5 activates eosinophils
6. IL 13 activates epithelial cells to produce
mucous.

11. Primary mediators:
•Biogenic amines: Histamine: smooth muscle
contraction, increased vascular permeability.
•Enzymes: Protease (chymase, tryptase) acid
hydrolases : tissue damage.
•Proteoglycans: Heparin (anticoagulant) &
Chondratin sulphate.

12. SECONDARY MEDIATORS OF
ALLERGY
•Lipid mediators:: Leukotrienes- LTC4,
LTD4; Prostaglandins- PGD2
•Cytokines:: PAF, TNF, IL-1, 4, 5, 6.
Eotaxin
•IL-4 is mast cell regulator; released by T
cells.

13. Secondary mediators:
•Arachidonic acid derivatives: Leukotriens B4, C4,
D4—bronchial smooth muscle spasm,
vasodilatation, chemotactic for neutrophils,
eosinophils.
•Prostaglandin D2: intense bronchospasm, mucous
secretion.
•PAF (Platelet Activating Factor): platelet
aggregation, bronchospasm, vasodilatation.
•Cytokines

14. Susceptibility: Genetically
determined
•ATOPY: predisposition to develop immediate
hypersensitivity reaction to a variety of inhaled
and ingested allergens.
•Atopic individuals have increased serum levels
of Ig E levels, and more IL 4 producing TH 2
cells.

15. Systemic Anaphylaxis:
•C/F: Vascular shock, wide spread edema, difficulty
in breathing, laryngeal edema, vomiting diarrhea,
even may die.
•Occur after antisera, drugs (penicillin), hormones,
enzymes.
•Previous history of allergy is important.

16. ANTIBODY MEDIATED
(TYPE II) HYPERSENSITIVITY:

17. •Complement system- activation by
•1) classical path through Ag-Ab complex
•2)Alternate pathway-non immunologic agentslike bacterial
toxins,venom
•on activation will form-
•Anaphylotoxins C3a C4a C5a-which activate-mast cells ,basophils
•Membrane attack complex(C5b-C9)-holes in phospholipid
membrane
•C3b as opsonin(enhanced phagocytosis when microbes coated with
proteins from serum)
•C5a as chemotactic for leucocytes

18. Mechanism:
•Antibodies are directed against antigens present on
cell surface or extracellular substances.
•Role of complements and IgG and IgM
•TISSUE SPECIFIC and Ab bind to sp Ag
•Three different mechanisms:
1.Opsonization & compliment & Fc-receptor –
mediated phagocytosis.
2.Compliment and Fc receptor mediated
inflammation.
3.Antibody mediated cellular dysfunction.

20. Type II hypersensitivity:
•O: Autoimmune hemolytic anemia, ATP,
Transfusion rn, erythroblastosis fetalis.
•C: Vasculitis, Goodpasture syndrome, ARF,
glomerulonephritis.
•A: Myasthenia Gravis, Grave’s disease, insulin
resistant DM, Pernicious anemia, Pemphigus
vulgaris.

21. EXAMPPLES OF TYPE II
REACTION: (MDP TEA)
•Transfusion reaction
•Erythroblastosis fetalis
•Autoimmune hemolytic anemia, leukopenia,
thrombocytopenia
•Drug reactions: Hemolysis following
Penicillin
•Phemphigus vulgaris
•Myasthenia gravis, Graves disease (Ab
mediated cellular dysfunction)

22. Type III hypersensitivity:
•IMMUNE COMPLEX MEDIATED: Ag-Ab
complexes produces tissue damage mainly by
eliciting inflammation at the site of deposition.
•Circulating immune complexes are deposited
typically in vessel wall.
•It represents normal mechanism of Ag removal.
•Two types: Systemic/ Localized.

23. Immune complex mediated:
•SP-PARAS:
•S: Systemic lupus erythematosis (SLE)
•P: Polyathritis nodosa (PAN)
•P: Post-streptococcal GN
•A: Acute GN (AGN)
•R: Reactive Arthritis
•A: Arthus reaction
•S; Serum sickness

24. Mechanisms:
•Phase I: Immune complex formation
•Phase II: Immune complex deposition
•Phase III: Immune complex mediated
inflammation

25. Factors influencing:
•Size of immune complexes: larger complexes –
rapidly removed. So relatively harmless; smaller –
circulate longer—dangerous.
•Functional status of mononuclear phagocytic
system: intrinsic dysfunction of phagocytic system
—persistence of immune complexes in circulation.
•Charge, affinity, structure, hemodynamic
factors…,etc.

27. CELL MEDIATED (type IV)
Hypersensitivity:
•Types:
1.Delayed- type hypersensitivity: CD4 +
T- cell mediated toxicity.
2.Direct T- cell mediated cytolysis: CD 8
+ T- cells.

28. CELL MEDIATED (type IV)
Hypersensitivity:

29. Delayed Type Hypersensitivity:
•Classic E.g..is Tuberculosis reaction:
tuberculin injection-intracutaneous-
reddening and induration appear in 8-12
hours; reaches peak by 24 –72 hours;
thereafter gradually subsides.
•Morphology: perivascular mononuclear cells
cuffing.

30. DELAYED HYPERSENSITIVITY
Tuberculin reaction
•To identify susceptible persons in the population
prone for tuberculosis
•Screening procedure; not diagnostic of disease.
•Performed in family members of patient with
open tuberculosis
•To know the family members who can get
afflicted, who are already exposed and Immune.

31. TUBERCULIN TEST
•Procedure: Intracutaneous Inj. of Protein
Lipopolysaccharide (LPS) extract of
Tubercle bacillus (0.1ml)
•Mark the skin site (Volar aspect of forearm)
•Read the result after 8 to 12 hrs
•Erythema, induration appear and peak by 24
to 72 hrs
•Response measured on size of induration.

32. •Persons are categorized as Mild, Severe and
No reaction
•Persons who are immune and sensitized
show mild reaction:::: Normal.
•Persons who are not Immune, Immune
suppressed, Immune deficient show--No
response
•Persons who are Very sensitive are more
susceptible show Severe reaction.
•Conversion of Negative to Positive Tuberculin
is more significant.

33. •This test is not used to detect tuberculosis
•Done to see susceptible persons who are
around a case of Tuberculosis
•Persons who show No reaction and Severe
reaction----- need Anti Tb prophylaxis
•Mild reaction persons need not be given
prophylaxis.
•Persons with No reaction: Immune
suppression to be ruled out.

34. •Microscopy: Perivascular (Cuffing)
accumulation of CD4+ helper T cells,
Macrophages
•Dermal edema, Fibrin deposition
•Pathogenesis of Tuberculin Reaction:
- First exposure.. The CD 4+ T cells are
formed and stay in circulation as memory T
cells
- Subsequent exposure there is response of
memory T cells to antigens

35. TUBERCULOSIS

36. TUBERCULOSIS
Infects one third of the Worlds population
Kills about 3 million patients each year
Single most infectious cause of death on
Earth

37. Etiology
•Mycobacterium tuberculosis
•Mycobacterium bovis
•Mycobacterium avium
•Mycobacterium intracellulare
Mycobacteria - aerobic , non-spore bearing, non-
motile , waxy coat, AFB – positive;

38. Z-N stain

39. Caseation
•Lysis of Macrophages
•Direct toxicity of mycobacteria to macrophages
•Cytokines released by macrophages such as
TNF
•Inadequate blood supply
Mycobacteria cannot grow in this acidic
environment lacking oxygen & so infection is
controlled

40. Types
•PRIMARY
•SECONDARY
•PROGRESSIVE PULMONARY
- Cavitary Fibrocaseous Tuberculosis
- Miliary Tuberculosis
- Tuberculous Bronchopneumonia

41. GHONS
COMPLEX

42. GHONS
COMPLEX

43. MILIARY
TUBERCULOSIS

49. Type IV Hypersensitivity Rn

50. TRANSPLANT REJECTION
•Complex phenomenon
•Both Cell and Ab mediated immune response
•Renal, Hepatic, Cardiac, Bone marrow
•Recognition of graft as Foreign is by Direct &
Indirect pathway
•Damage is mediated by parenchymal &
endothelial cell disruption
•Cytokine, Microvascular injury, Ischemia

51. Transplant Rejection
•Graft rejection is an immunological response
mediated primarily by T-cells
•Major antigens involved : MHC complex
•Minor antigens: Minor H antigens
–Variable non-MHC proteins
–Presented via MHC I molecules
–Rejection is slower

54. MORPHOLOGY OF GRAFT
REJECTION
•Hyperacute, Acute Cellular, Acute Humoral,
Chronic
•HYPERACUTE: Preformed Anti donor Ab are
present in circulation.
•Rejection occurs within minutes (On table)
•Graft is Cyanotic, Mottled, Flaccid.
•Widespread Acute arteritis, thrombosis, necrosis
•Can be avoided by screening Antibodies and
Cross reaction methods

55. Hyperacute Graft Rejection
•Donor has preexisting ABO antibodies
–Previous blood transfusions
–ABO antigens also present on leukocytes, endothelial
cells
•During surgery antibodies bind to endothelial
vessels of graft
•Immediate activation of complement, blood clotting
•Can be prevented by cross matching donor and
recipient

56. •ACUTE REJECTION: Days to weeks to
months
•Both Humoral & Cellular rejection.
•Can be delayed by Immunosuppression
•Humoral rejection Vasculitis
•Cellular rejection  Edema, parenchymal
damage

57. •CHRONIC REJECTION: Months to years
•There is vascular damage, loss of
parenchyma, interstitial fibrosis
•Compromised blood supply, chronic
healing, effects of immunosuppressant on
parenchyma, hyalinization, fibrosis, atrophy

58. METHODS TO INCREASE
GRAFT SURVIVAL
•HLA matching of donor & recipient
•Cross matching
•Autograft, Isograft, Allograft, Xenograft
•Immunosuppression of recipient.
•Azathioprine, Corticosteroids, Cyclosporine,
Anti lymphocyte globulins
•More Immunosuppression is not advisable

59. GRAFT Vs HOST DISESE
•Seen commonly in Allogenic bone marrow
transplants
•Recipient is Immunosuppressed. Donor gives
immunocompetent cells (Transplanted)
•Donor cells recognize host tissue as foreign
and cause T cell dependant injury (delayed
hypersensitivity & CTL response)

60. MORPHOLOGY OF GVHD
•Acute GVHD: Days to weeks
•Epithelial necrosis in Skin, Liver, GIT
•Jaundice, Mucosal ulceration, Diarrhea, Rash
•Chronic GVHD: Skin lesions resemble
systemic sclerosis
•Can avoid GVHD by depleting Donor T cells,
Irradiation of graft